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Rare Case of Orbital Involvement from Multiple Myeloma
An orbital mass is often the “tip of the iceberg”—it may be secondary to systemic malignancy, warn clinicians from University Sains Malaysia-Health Campus and Hospital Sultanah Bahiyah, both in Malaysia. Orbital metastases usually originate from lung and breast cancers, but these authors report on an unusual case of a patient whose orbital involvement stemmed from multiple myeloma (MM).
Related: A Mysterious Massive Hemorrhage
The 85-year-old woman presented with right-eye proptosis, reduced visual acuity and diplopia. She had been bedridden with chronic back pain but had no symptoms of thyroid disorder or malignancy. Cardiovascular, breast, abdominal, and neurologic examinations were normal. She had no palpable lymph nodes. Blood investigations for infective and inflammatory causes were unremarkable.
However, a chest radiograph showed osteopenic bones, a pathologic fracture of the right clavicle, and an opacity obscuring the left retrocardiac region, suggesting a mass in the lower lobe of the left lung. The patient declined further imaging but underwent biopsy for the right orbital mass. Histopathologic examination revealed cells suggestive of MM. She was diagnosed with osseous plasmacytoma.
Orbital involvement in MM may be the first manifestation of systemic disease, the clinicians say. The diagnosis is usually based on clinical suspicion. Patients tend to present with nonspecific symptoms like back pain and fatigue. Computed tomography scanning is the imaging modality of choice, the authors say, but in older patients the findings may be hard to interpret. Thinning of the bone, for instance, may mimic metastases. Biopsy provides a definitive diagnosis and guides further management.
Related: Less Lenalidomide May Be More in Frail Elderly Multiple Myeloma Patients
Orbital involvement in MM is rare but treatable. Discovery of a plasmacytoma should always prompt investigation for systemic involvement, the authors advise, because the treatment and prognosis differ between the two. In their patient, proptosis secondary to the orbital plasmacytoma led them to discover end-organ damage in the form of multiple bone lesions. Solitary plasmacytoma would be treated with radiotherapy and resection; active MM with end-organ damage requires systemic chemotherapy.
Getting to the root of the problem can be difficult when the presentation is “insidious” and clinical features are nonspecific, the authors say. Patient and thorough investigation can make the difference in resolving the diagnostic imaging challenges.
Source:
Tai E, Sim SK, Haron J, Wan Hitam WH. BMJ Case Rep. 2017;2017: pii: bcr-2017-220895.
doi: 10.1136/bcr-2017-220895.
An orbital mass is often the “tip of the iceberg”—it may be secondary to systemic malignancy, warn clinicians from University Sains Malaysia-Health Campus and Hospital Sultanah Bahiyah, both in Malaysia. Orbital metastases usually originate from lung and breast cancers, but these authors report on an unusual case of a patient whose orbital involvement stemmed from multiple myeloma (MM).
Related: A Mysterious Massive Hemorrhage
The 85-year-old woman presented with right-eye proptosis, reduced visual acuity and diplopia. She had been bedridden with chronic back pain but had no symptoms of thyroid disorder or malignancy. Cardiovascular, breast, abdominal, and neurologic examinations were normal. She had no palpable lymph nodes. Blood investigations for infective and inflammatory causes were unremarkable.
However, a chest radiograph showed osteopenic bones, a pathologic fracture of the right clavicle, and an opacity obscuring the left retrocardiac region, suggesting a mass in the lower lobe of the left lung. The patient declined further imaging but underwent biopsy for the right orbital mass. Histopathologic examination revealed cells suggestive of MM. She was diagnosed with osseous plasmacytoma.
Orbital involvement in MM may be the first manifestation of systemic disease, the clinicians say. The diagnosis is usually based on clinical suspicion. Patients tend to present with nonspecific symptoms like back pain and fatigue. Computed tomography scanning is the imaging modality of choice, the authors say, but in older patients the findings may be hard to interpret. Thinning of the bone, for instance, may mimic metastases. Biopsy provides a definitive diagnosis and guides further management.
Related: Less Lenalidomide May Be More in Frail Elderly Multiple Myeloma Patients
Orbital involvement in MM is rare but treatable. Discovery of a plasmacytoma should always prompt investigation for systemic involvement, the authors advise, because the treatment and prognosis differ between the two. In their patient, proptosis secondary to the orbital plasmacytoma led them to discover end-organ damage in the form of multiple bone lesions. Solitary plasmacytoma would be treated with radiotherapy and resection; active MM with end-organ damage requires systemic chemotherapy.
Getting to the root of the problem can be difficult when the presentation is “insidious” and clinical features are nonspecific, the authors say. Patient and thorough investigation can make the difference in resolving the diagnostic imaging challenges.
Source:
Tai E, Sim SK, Haron J, Wan Hitam WH. BMJ Case Rep. 2017;2017: pii: bcr-2017-220895.
doi: 10.1136/bcr-2017-220895.
An orbital mass is often the “tip of the iceberg”—it may be secondary to systemic malignancy, warn clinicians from University Sains Malaysia-Health Campus and Hospital Sultanah Bahiyah, both in Malaysia. Orbital metastases usually originate from lung and breast cancers, but these authors report on an unusual case of a patient whose orbital involvement stemmed from multiple myeloma (MM).
Related: A Mysterious Massive Hemorrhage
The 85-year-old woman presented with right-eye proptosis, reduced visual acuity and diplopia. She had been bedridden with chronic back pain but had no symptoms of thyroid disorder or malignancy. Cardiovascular, breast, abdominal, and neurologic examinations were normal. She had no palpable lymph nodes. Blood investigations for infective and inflammatory causes were unremarkable.
However, a chest radiograph showed osteopenic bones, a pathologic fracture of the right clavicle, and an opacity obscuring the left retrocardiac region, suggesting a mass in the lower lobe of the left lung. The patient declined further imaging but underwent biopsy for the right orbital mass. Histopathologic examination revealed cells suggestive of MM. She was diagnosed with osseous plasmacytoma.
Orbital involvement in MM may be the first manifestation of systemic disease, the clinicians say. The diagnosis is usually based on clinical suspicion. Patients tend to present with nonspecific symptoms like back pain and fatigue. Computed tomography scanning is the imaging modality of choice, the authors say, but in older patients the findings may be hard to interpret. Thinning of the bone, for instance, may mimic metastases. Biopsy provides a definitive diagnosis and guides further management.
Related: Less Lenalidomide May Be More in Frail Elderly Multiple Myeloma Patients
Orbital involvement in MM is rare but treatable. Discovery of a plasmacytoma should always prompt investigation for systemic involvement, the authors advise, because the treatment and prognosis differ between the two. In their patient, proptosis secondary to the orbital plasmacytoma led them to discover end-organ damage in the form of multiple bone lesions. Solitary plasmacytoma would be treated with radiotherapy and resection; active MM with end-organ damage requires systemic chemotherapy.
Getting to the root of the problem can be difficult when the presentation is “insidious” and clinical features are nonspecific, the authors say. Patient and thorough investigation can make the difference in resolving the diagnostic imaging challenges.
Source:
Tai E, Sim SK, Haron J, Wan Hitam WH. BMJ Case Rep. 2017;2017: pii: bcr-2017-220895.
doi: 10.1136/bcr-2017-220895.
Multiple Myeloma: Updates on Diagnosis and Management
Multiple myeloma (MM) is a disease that is primarily treated by hematologists; however, it is important for primary care providers (PCPs) to be aware of the presentation and diagnosis of this disease. Multiple myeloma often is seen in the veteran population, and VA providers should be familiar with its diagnosis and treatment so that an appropriate referral can be made. Often, the initial signs and symptoms of the disease are subtle and require an astute eye by the PCP to diagnose and initiate a workup.
Once a veteran has an established diagnosis of MM or one of its precursor syndromes, the PCP will invariably be alerted to an adverse event (AE) of treatment or complication of the disease and should be aware of such complications to assist in management or referral. Patients with MM may achieve long-term remission; therefore, it is likely that the PCP will see an evolution in their treatment and care. Last, PCPs and patients often have a close relationship, and patients expect the PCP to understand their diagnosis and treatment plan.
Presentation
Multiple myeloma is a disease in which a neoplastic proliferation of plasma cells produces a monoclonal immunoglobulin. It is almost invariably preceded by premalignant stages of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), although not all cases of MGUS will eventually progress to MM.1 Common signs and symptoms include anemia, bone pain or lytic lesions on X-ray, kidney injury, fatigue, hypercalcemia, and weight loss.2 Anemia is usually a normocytic, normochromic anemia and can be due to involvement of the bone marrow, secondary to renal disease, or it may be dilutional, related to a high monoclonal protein (M protein) level. There are several identifiable causes for renal disease in patients with MM, including light chain cast nephropathy,
hypercalcemia, light chain amyloidosis, and light chain deposition disease. Without intervention, progressive renal damage may occur.3
Diagnosis
All patients with a suspected diagnosis of MM should undergo a basic workup, including complete blood count; peripheral blood smear; complete chemistry panel, including calcium and albumin; serum free light chain analysis (FLC); serum protein electrophoresis (SPEP) and immunofixation; urinalysis; 24-hour urine collection for electrophoresis (UPEP) and immunofixation; serum B2-microglobulin; and lactate dehydrogenase.4 A FLC analysis is particularly useful for the diagnosis and monitoring of MM, when only small amounts of M protein are secreted into the serum/urine or for nonsecretory myeloma, as well as for light-chainonly
myeloma.5
A bone marrow biopsy and aspirate should be performed in the diagnosis of MM to evaluate the bone marrow involvement and genetic abnormality of myeloma cells with fluorescence in situ hybridization (FISH) and cytogenetics, both of which are very important in risk stratification and for treatment planning. A skeletal survey is also typically performed to look for bone lesions.4 Magnetic resonance imaging (MRI) can also be useful to evaluate for possible soft tissue lesions when a bone survey is negative, or to evaluate for spinal cord compression.5 Additionally, an MRI should be performed in patients with SMM at the initial assessment, because focal lesions in the setting of SMM are associated with an increased risk to progression.6 Since plain radiographs are usually abnormal only after ≥ 30% of the
bone is destroyed, an MRI offers a more sensitive image.
Two MM precursor syndromes are worth noting: MGUS and SMM. In evaluating a patient for possible MM, it is important to differentiate between MGUS, asymptomatic
SMM, and MM that requires treatment.4 Monoclonal gammopathy of undetermined significance is diagnosed when a patient has a serum M protein that is < 3 g/dL, clonal bone marrow plasma cells < 10%, and no identifiable end organ damage.5 Smoldering MM is diagnosed when either the serum M protein is > 3 g/dL or bone marrow clonal plasma cells are > 10% in the absence of end organ damage.
Symptomatic MM is characterized by > 10% clonal bone marrow involvement with end organ damage that includes hypercalcemia, renal failure, anemia, or bone lesions. The diagnostic criteria are summarized in Table 1. The International Myeloma Working Group produced updated guidelines in 2014, which now include patients with > 60% bone marrow involvement of plasma cells, serum FLC ratio of > 100, and > 1 focal lesions on an MRI study as symptomatic MM.5,6
Most patients with MM will have a M protein produced by the malignant plasma cells detected on an SPEP or UPEP. The majority of immunoglobulins were IgG and IgA, whereas IgD and IgM were much less common.2 A minority of patients will not have a detectable M protein on SPEP or UPEP. Some patients will produce only light chains and are designated as light-chain-only myeloma.For these patients, the FLC assay is useful for diagnosis and disease monitoring. Patients who have an absence of M protein on SPEP/UPEP and normal FLC assay ratios are considered to have nonsecretory myeloma.7
Staging and Risk Stratification
Two staging systems are used to evaluate a patient’s prognosis: the Durie-Salmon staging system, which is based on tumor burden (Table 2); and the International Staging System (ISS), which uses a combination of serum beta 2 microglobulin (B2M) and serum albumin levels to produce a powerful and reproducible 3-stage classification and is more commonly used by hematologists due to its simplicity to use and reliable reproducibility (Table 3).
In the Durie-Salmon staging system, patients with stage I disease have a lower tumor burden, defined as hemoglobin > 10 g/dL, normal calcium level, no evidence of
lytic bone lesions, and low amounts of protein produced (IgG < 5 g/dL; IgA < 3 g/dL; urine protein < 4 g/d). Patients are classified as stage III if they have any of the following: hemoglobin < 8.5 g/dL, hypercalcemia with level > 12 mg/dL, bony lytic lesions, or high amounts of protein produced (IgG > 7 g/dL; IgA > 5 g/dL; or urine protein > 12 g/d). Patients with stage II disease do not fall into either of these categories. Stage III disease can be further differentiated into stage IIIA or stage IIIB disease if renal involvement is present.8
In the ISS system, patients with stage I disease have B2M levels that are < 3.5 mg/dL and albumin levels > 3.5 g/dL and have a median overall survival (OS) of 62 months. In this classification, stage III patients have B2M levels that are > 5.5 mg/dL and median OS was 29 months. Stage II patients do not meet either of these
criteria and OS was 44 months.9 In a study by Mayo Clinic, OS has improved over the past decade, with OS for ISS stage III patients increasing to 4.2 years. Overall
survival for both ISS stage I and stage III disease seems to have increased as well, although the end point has not been reached.10
All myeloma patients are risk stratified at initial diagnosis based on their cytogenetic abnormalities identified mainly by FISH studies and conventional cytogenetics,
which can serve as an alternative if FISH is unavailable. Genetic abnormalities of MM are the major predictor for the outcome and will affect treatment choice. Three risk groups have been identified: high-risk, intermediate-risk, and standard-risk MM (Table 4).11
Management of MGUS and SMM
Patients with MGUS progress to malignant conditions at a rate of 1% per year.12 Those individuals who are diagnosed with MGUS or SMM typically do not require
therapy. According to the International Myeloma Working Group guidelines, patients should be monitored based on risk stratification. Those with low-risk MGUS (IgG M protein < 1.5 g/dL and no abnormal FLC ratio) can be monitored every 6 months for 2 to 3 years. Those who are intermediate to high risk need a baseline bone marrow biopsy in addition to skeletal survey and should check urine and serum levels for protein every 6 months for the first year and then annually thereafter.
Patients with SMM are at an increased risk of progression to symptomatic MM compared with patients with MGUS (10% per year for the first 5 years, 3% per year for the next 5 years).13 Therefore, experts recommend physician visits and laboratory testing for M proteins every 2 to 3 months for the first year and then an evaluation every 6 to 12 months if the patient remains clinically stable.14 Additionally, there are new data to suggest that early therapy with lenalidomide plus dexamethasone for SMM can prolong time to disease progression as well as increase OS in individuals with SMM at high risk for progression.15
Patients With MM
All patients with a diagnosis of MM require immediate treatment. Initial choice of therapy is driven by whether a patient is eligible for an autologous stem cell transplant (ASCT), because certain agents, such as alkylating agents, should typically be avoided in those who are transplant eligible. Initial therapy for patients
with MM is also based on genetic risk stratification of the disease. Patients with high-risk disease require a complete response (CR) treatment for long-term OS
and thus benefit from an aggressive treatment strategy. Standard-risk patients have similar OS regardless of whether or not CR is achieved and thus can either
be treated with an aggressive approach or a sequential therapy approach.16
Transplant-Eligible Patients
All patients should be evaluated for transplant eligibility, because it results in superior progression-free survival (PFS) and OS in patients with MM compared
with standard chemotherapy. Transplant eligibility requirements differ, depending on the transplant center. There is no strict age limit in the U.S. for determining transplant eligibility. Physiological age and factors such as functional status and liver function are often considered before making a transplant decision.
For VA patients, transplants are generally considered in those aged < 65 years, and patients are referred to 1 of 3 transplant centers: VA Puget Sound Healthcare System in Seattle, Washington; Tennessee Valley Healthcare System in Nashville; or South Texas Veterans Healthcare System in San Antonio.17 All patients who are transplant eligible should receive induction therapy for 2 to 4 months before stem cell collection. This is to reduce tumor burden, for symptomatic management, as well as to lessen end organ damage. After stem cell collection, patients undergo either upfront ASCT or resume induction therapy and undergo a transplant after first relapse.
Bortezomib Regimens
Bortezomib is a proteasome inhibitor (PI) and has been used as upfront chemotherapy for transplant-eligible patients, traditionally to avoid alkylating agents that
could affect stem cell harvest. It is highly efficacious in the treatment of patients with MM. Two- or 3-drug regimens have been used. Common regimens include bortezomib, cyclophosphamide, dexamethasone; bortezomib, thalidomide, dexamethasone (VTD); bortezomib, lenalidomide, dexamethasone (VRD); bortezomib,
doxorubicin, dexamethasone; as well as bortezomib, dexamethasone.18 Dexamethasone is less expensive than VTD or VRD, well tolerated, and efficacious. It is
often used upfront for newly diagnosed MM.19 Threedrug regimens have shown to be more efficacious than 2-drug regimens in clinical trials (Table 5).20
Of note, bortezomib is not cleared through the kidney, which makes it an ideal choice for patients with renal function impairment. A significant potential AE with bortezomib is the onset of peripheral neuropathy. Bortezomib can be administered once or twice weekly. Twice-weekly administration of bortezomib is preferred when rapid results are needed, such as light chain cast nephropathy causing acute renal failure.21
Lenalidomide Plus Dexamethasone
Lenalidomide is a second-generation immunomodulating agent that is being increasingly used as initial therapy for MM. There is currently no data showing superiority of bortezomib-based regimens to lenalidomide plus dexamethasone in reference to OS. Bortezomib-based regimens seem to overcome the poor prognosis associated with t(4;14) translocation and thus should be considered in choosing initial chemotherapy treatment.22
Lenalidomide can affect stem cell collection; therefore, it is important to collect stem cells in transplanteligible patients who are aged < 65 years or for those who have received more than 4 cycles of treatment with this regimen.23,24 A major AE to lenalidomidecontaining regimens is the increased risk of thrombosis. All patients on lenalidomide require treatment with aspirin at a minimum; however, those at higher risk for thrombosis may require low-molecular weight heparin or warfarin.25
Carfilzomib Plus Lenalidomide Plus Dexamethasone
Carfilzomib is a recently approved PI that has shown promise in combination with lenalidomide and dexamethasone as initial therapy for MM. Several phase 2 trials
have reported favorable results with carfilzomib in combination with lenalidomide and dexamethasone in MM.26,27 More studies are needed to establish efficacy and
safety before this regimen is routinely used as upfront therapy.11
Thalidomide Plus Dexamethasone
Although there are no randomized controlled trials comparing lenalidomide plus dexamethasone with thalidomide plus dexamethasone, these regimens have been compared in retrospective studies. In these studies, lenalidomide plus dexamethasone showed both a higher response rate as well as an increased PFS and
OS compared with thalidomide plus dexamethasone. Additionally, lenalidomide’s AE profile was more favorable than that of thalidomide. In light of this, lenalidomide
plus dexamethasone is preferred to thalidomide plus dexamethasone in the management of MM, although the latter can be considered when lenalidomide is not available or when a patient does not tolerate lenalidomide.28
VDT-PACE
A multidrug combination that should be considered in select populations is the VDT-PACE regimen, which includes bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide. This regimen can be considered in those patients who have aggressive disease, such as those with plasma cell leukemia or with multiple extramedullary plasmacytomas.11
Autologous Stem Cell Transplant
Previous data suggest that ASCT improves OS in MM by 12 months.29 A more recent open-label, randomized trial comparing melphalan and ASCT to melphalanprednisone-lenalidomide showed significant prolonged PFS and OS among patients with MM.30 Although the role of ASCT may change as new drugs are
integrated into initial therapy of MM, ASCT is still the preferred approach in transplant-eligible patients. As such, all patients who are eligible should be considered
to receive a transplant.
There remains debate about whether ASCT should be performed early, after 2 to 4 cycles of induction therapy, or late after first relapse. Several randomized trials failed to show a difference in survival for early vs delayed ASCT approach.31 Generally, transplant can be delayed for patients with standard-risk MM who have responded well to therapy.11 Those patients who do not achieve a CR with their first ASCT may benefit from a second (tandem) ASCT.32 An allogeneic transplant is occasionally used in select populations and is the only potentially curative therapy for these patients. However, its high mortality rate precludes its everyday use.
Transplant-Ineligible Patients
For patients with newly diagnosed MM who are ineligible for ASCT due to age or other comorbidities, chemotherapy is the only option. Many patients will benefit
not only in survival, but also in quality of life. Immunomodulatory agents, such as lenalidomide and thalidomide, and PIs, such as bortezomib, are highly effective
and well tolerated. There has been a general shift to using these agents upfront in transplant-ineligible patients.
All previously mentioned regimens can also be used in transplant-ineligible patients. Although no longer the preferred treatment, melphalan can be considered
in resource-poor settings.11 Patients who are not transplant eligible are treated for a fixed period of 9 to 18 months, although lenalidomide plus dexamethasone is often continued until relapse.11,33
Melphalan Plus Prednisone Plus Bortezomib
The addition of bortezomib to melphalan and prednisone results in improved OS compared with that of melphalan and dexamethasone alone.34 Peripheral neuropathy is a significant AE and can be minimized by giving bortezomib once weekly.
Melphalan Plus Prednisone Plus Thalidomide
Melphalan plus prednisone plus thalidomide has shown an OS benefit compared with that of melphalan and prednisone alone. The regimen has a high toxicity rate (> 50%) and a deep vein thrombosis rate of 20%, so patients undergoing treatment with this regimen require thromboprophylaxis.35,36
Melphalan Plus Prednisone
Although melphalan plus prednisone has fallen out of favor due to the existence of more efficacious regimens, it may be useful in an elderly patient population who lack access to newer agents, such as lenalidomide, thalidomide, and bortezomib.
Assessing Treatment Response
The International Myeloma Working Group has established criteria for assessing disease response. Patient’s response to therapy should be assessed with a FLC assay
before each cycle with SPEP and UPEP and in those without measurable M protein levels. A bone marrow biopsy can be helpful in patients with immeasurable M protein levels and low FLC levels, as well as to establish that a CR is present.
A CR is defined as negative SPEP/UPEP, disappearance of soft tissue plamacytomas, and < 5% plasma cells in bone marrow. A very good partial response is defined as serum/urine M protein being present on immunofixation but not electrophoresis or reduction in serum M protein by 90% and urine M protein < 100 mg/d. For those without measurable M protein, a reduction in FLC ratio by 90% is required. A partial response is defined as > 50% reduction of the serum monoclonal protein and/or < 200 mg urinary M protein per 24 hours or > 90% reduction in urinary M protein. For those without M protein present, they should have > 50% decrease in FLC ratio.5
Maintenance Therapy
There is currently considerable debate about whether patients should be treated with maintenance therapy following induction chemotherapy or transplant. In patients treated with transplant, there have been several studies to investigate the use of maintenance therapy. Lenalidomide has been evaluated for maintenance therapy following stem cell transplant and has shown superior PFS with dexamethasone as post-ASCT maintenance; however, this is at the cost of increased secondary cancers.37
Thalidomide has also been studied as maintenance therapy and seems to have a modest improvement in PFS and OS but at the cost of increased toxicities, such as
neuropathy and thromboembolism.38,39 Still other studies compared bortezomib maintenance with thalidomide maintenance in posttransplant patients and was able to show improved OS. As a result, certain patients with intermediate- or high-risk disease may be eligible for bortezomib for maintenance following transplant.11 For transplant-ineligible patients, there is no clear role for maintenance therapy.
Refreactory/Relapsed Disease Treatments
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significance (MGUS) consistently precedes multiple myeloma: a prospective
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2. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed
multiple myeloma. Mayo Clin Proc. 2003;78(1):21-33.
3. Hutchison CA, Batuman V, Behrens J, et al; International Kidney and Monoclonal
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20. Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus
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21. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous
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23. Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem
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in patients with newly diagnosed myeloma. Leukemia. 2007;21(9):2035-2042.
24. Kumar S, Giralt S, Stadtmauer EA, et al; International Myeloma Working Group.
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regimens. Blood. 2009;114(9):1729-1735.
25. Larocca A, Cavallo F, Bringhen S, et al. Aspirin or enoxaparin thromboprophylaxis
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lenalidomide. Blood. 2012;119(4):933-939.
26. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in
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for multiple myeloma. Blood. 2012;120(9):1801-1809.
27. Korde N, Zingone A, Kwok M, et al. Phase II clinical and correlative study of
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28. Gay F, Hayman SR, Lacy MQ, et al. Lenalidomide plus dexamethasone versus thalidomide
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29. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous
bone marrow transplantation and chemotherapy in multiple myeloma.
Intergroupe Français du Myélome. N Engl J Med. 1996;335(2):91-97.
30. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance
therapy in multiple myeloma. N Engl J Med. 2014;371(10):895-905.
31. Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous
stem cell transplantation in multiple myeloma: up-front or rescue treatment?
Results of a multicenter sequential randomized clinical trial. Blood.
1998;92(9):3131-3136.
32. Elice F, Raimondi R, Tosetto A, et al. Prolonged overall survival with second
on-demand autologous stem cell transplant in multiple myeloma. Am J Hematol.
2006;81(6):426-431.
33. Facon T, Dimopoulos MA, Dispenzieri A, et al. Initial phase 3 results of the
FIRST (frontline investigation of lenalidomide + dexamethasone versus standard
thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma
(NDMM) patients (pts) ineligible for stem cell transplantation (SCT). Blood.
2013;122(21):2.
34. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan
and prednisone for initial treatment of multiple myeloma. N Engl J Med.
2008;359(9):906-917.
35. Facon T, Mary JY, Hulin C, et al; Intergroupe Français du Myélome. Melphalan
and prednisone plus thalidomide versus melphalan and prednisone
alone or reduced-intensity autologous stem cell transplantation in
elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet.
2007;370(9594):1209-1218.
36. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide
in patients older than 75 years with newly diagnosed multiple myeloma.
IFM 01/01 trial. J Clin Oncol. 2009;27(22):3664-3670.
37. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stemcell
transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782-1791.
38. Attal M., Harousseau JL, Leyvraz S, et al; Inter-Groupe Francophone du Myélome
(IFM). Maintenance therapy with thalidomide improves survival in patients with
multiple myeloma. Blood. 2006;108(10):3289-3294.
39. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose
thalidomide and prednisolone prolongs the survival of multiple myeloma patients
undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol.
2009;27(11):1788-1793.
40. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and
maintenance treatment in patients with newly diagnosed multiple myeloma:
results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol.
2012;30(24):2946-2955.
41. Richardson PG, Sonneveld P, Schuster MW, et al; Assessment of Proteasome
Inhibition for Extending Remissions (APEX) Investigators. Bortezomib
or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med.
2005;352(24):2487-2498.
42. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated
liposomal doxorubicin plus bortezomib compared with bortezomib alone
in relapsed or refractory multiple myeloma: combination therapy improves time
to progression. J Clin Oncol. 2007;25(25):3892-3901.
43. Kumar SK, Lee JH, Lahuerta JJ, et al; International Myeloma Working Group.
Risk of progression and survival in multiple myeloma relapsing after therapy
with IMiDs and bortezomib: a multicenter international myeloma working group
study. Leukemia. 2012;26(1):149-157.
44. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus lowdose
dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol.
2009;27(30):5008-5014.
45. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single agent carfilzomib
(PX-171-003-A1) in patients with relapsed and refractory multiple myeloma.
Blood. 2012;120(14):2817-2825.
46. San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib
and dexamethasone versus placebo plus bortezomib and dexamethasone
in patients with relapsed or relapsed and refractory multiple
myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol.
2014;15(11):1195-1206.
Multiple myeloma (MM) is a disease that is primarily treated by hematologists; however, it is important for primary care providers (PCPs) to be aware of the presentation and diagnosis of this disease. Multiple myeloma often is seen in the veteran population, and VA providers should be familiar with its diagnosis and treatment so that an appropriate referral can be made. Often, the initial signs and symptoms of the disease are subtle and require an astute eye by the PCP to diagnose and initiate a workup.
Once a veteran has an established diagnosis of MM or one of its precursor syndromes, the PCP will invariably be alerted to an adverse event (AE) of treatment or complication of the disease and should be aware of such complications to assist in management or referral. Patients with MM may achieve long-term remission; therefore, it is likely that the PCP will see an evolution in their treatment and care. Last, PCPs and patients often have a close relationship, and patients expect the PCP to understand their diagnosis and treatment plan.
Presentation
Multiple myeloma is a disease in which a neoplastic proliferation of plasma cells produces a monoclonal immunoglobulin. It is almost invariably preceded by premalignant stages of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), although not all cases of MGUS will eventually progress to MM.1 Common signs and symptoms include anemia, bone pain or lytic lesions on X-ray, kidney injury, fatigue, hypercalcemia, and weight loss.2 Anemia is usually a normocytic, normochromic anemia and can be due to involvement of the bone marrow, secondary to renal disease, or it may be dilutional, related to a high monoclonal protein (M protein) level. There are several identifiable causes for renal disease in patients with MM, including light chain cast nephropathy,
hypercalcemia, light chain amyloidosis, and light chain deposition disease. Without intervention, progressive renal damage may occur.3
Diagnosis
All patients with a suspected diagnosis of MM should undergo a basic workup, including complete blood count; peripheral blood smear; complete chemistry panel, including calcium and albumin; serum free light chain analysis (FLC); serum protein electrophoresis (SPEP) and immunofixation; urinalysis; 24-hour urine collection for electrophoresis (UPEP) and immunofixation; serum B2-microglobulin; and lactate dehydrogenase.4 A FLC analysis is particularly useful for the diagnosis and monitoring of MM, when only small amounts of M protein are secreted into the serum/urine or for nonsecretory myeloma, as well as for light-chainonly
myeloma.5
A bone marrow biopsy and aspirate should be performed in the diagnosis of MM to evaluate the bone marrow involvement and genetic abnormality of myeloma cells with fluorescence in situ hybridization (FISH) and cytogenetics, both of which are very important in risk stratification and for treatment planning. A skeletal survey is also typically performed to look for bone lesions.4 Magnetic resonance imaging (MRI) can also be useful to evaluate for possible soft tissue lesions when a bone survey is negative, or to evaluate for spinal cord compression.5 Additionally, an MRI should be performed in patients with SMM at the initial assessment, because focal lesions in the setting of SMM are associated with an increased risk to progression.6 Since plain radiographs are usually abnormal only after ≥ 30% of the
bone is destroyed, an MRI offers a more sensitive image.
Two MM precursor syndromes are worth noting: MGUS and SMM. In evaluating a patient for possible MM, it is important to differentiate between MGUS, asymptomatic
SMM, and MM that requires treatment.4 Monoclonal gammopathy of undetermined significance is diagnosed when a patient has a serum M protein that is < 3 g/dL, clonal bone marrow plasma cells < 10%, and no identifiable end organ damage.5 Smoldering MM is diagnosed when either the serum M protein is > 3 g/dL or bone marrow clonal plasma cells are > 10% in the absence of end organ damage.
Symptomatic MM is characterized by > 10% clonal bone marrow involvement with end organ damage that includes hypercalcemia, renal failure, anemia, or bone lesions. The diagnostic criteria are summarized in Table 1. The International Myeloma Working Group produced updated guidelines in 2014, which now include patients with > 60% bone marrow involvement of plasma cells, serum FLC ratio of > 100, and > 1 focal lesions on an MRI study as symptomatic MM.5,6
Most patients with MM will have a M protein produced by the malignant plasma cells detected on an SPEP or UPEP. The majority of immunoglobulins were IgG and IgA, whereas IgD and IgM were much less common.2 A minority of patients will not have a detectable M protein on SPEP or UPEP. Some patients will produce only light chains and are designated as light-chain-only myeloma.For these patients, the FLC assay is useful for diagnosis and disease monitoring. Patients who have an absence of M protein on SPEP/UPEP and normal FLC assay ratios are considered to have nonsecretory myeloma.7
Staging and Risk Stratification
Two staging systems are used to evaluate a patient’s prognosis: the Durie-Salmon staging system, which is based on tumor burden (Table 2); and the International Staging System (ISS), which uses a combination of serum beta 2 microglobulin (B2M) and serum albumin levels to produce a powerful and reproducible 3-stage classification and is more commonly used by hematologists due to its simplicity to use and reliable reproducibility (Table 3).
In the Durie-Salmon staging system, patients with stage I disease have a lower tumor burden, defined as hemoglobin > 10 g/dL, normal calcium level, no evidence of
lytic bone lesions, and low amounts of protein produced (IgG < 5 g/dL; IgA < 3 g/dL; urine protein < 4 g/d). Patients are classified as stage III if they have any of the following: hemoglobin < 8.5 g/dL, hypercalcemia with level > 12 mg/dL, bony lytic lesions, or high amounts of protein produced (IgG > 7 g/dL; IgA > 5 g/dL; or urine protein > 12 g/d). Patients with stage II disease do not fall into either of these categories. Stage III disease can be further differentiated into stage IIIA or stage IIIB disease if renal involvement is present.8
In the ISS system, patients with stage I disease have B2M levels that are < 3.5 mg/dL and albumin levels > 3.5 g/dL and have a median overall survival (OS) of 62 months. In this classification, stage III patients have B2M levels that are > 5.5 mg/dL and median OS was 29 months. Stage II patients do not meet either of these
criteria and OS was 44 months.9 In a study by Mayo Clinic, OS has improved over the past decade, with OS for ISS stage III patients increasing to 4.2 years. Overall
survival for both ISS stage I and stage III disease seems to have increased as well, although the end point has not been reached.10
All myeloma patients are risk stratified at initial diagnosis based on their cytogenetic abnormalities identified mainly by FISH studies and conventional cytogenetics,
which can serve as an alternative if FISH is unavailable. Genetic abnormalities of MM are the major predictor for the outcome and will affect treatment choice. Three risk groups have been identified: high-risk, intermediate-risk, and standard-risk MM (Table 4).11
Management of MGUS and SMM
Patients with MGUS progress to malignant conditions at a rate of 1% per year.12 Those individuals who are diagnosed with MGUS or SMM typically do not require
therapy. According to the International Myeloma Working Group guidelines, patients should be monitored based on risk stratification. Those with low-risk MGUS (IgG M protein < 1.5 g/dL and no abnormal FLC ratio) can be monitored every 6 months for 2 to 3 years. Those who are intermediate to high risk need a baseline bone marrow biopsy in addition to skeletal survey and should check urine and serum levels for protein every 6 months for the first year and then annually thereafter.
Patients with SMM are at an increased risk of progression to symptomatic MM compared with patients with MGUS (10% per year for the first 5 years, 3% per year for the next 5 years).13 Therefore, experts recommend physician visits and laboratory testing for M proteins every 2 to 3 months for the first year and then an evaluation every 6 to 12 months if the patient remains clinically stable.14 Additionally, there are new data to suggest that early therapy with lenalidomide plus dexamethasone for SMM can prolong time to disease progression as well as increase OS in individuals with SMM at high risk for progression.15
Patients With MM
All patients with a diagnosis of MM require immediate treatment. Initial choice of therapy is driven by whether a patient is eligible for an autologous stem cell transplant (ASCT), because certain agents, such as alkylating agents, should typically be avoided in those who are transplant eligible. Initial therapy for patients
with MM is also based on genetic risk stratification of the disease. Patients with high-risk disease require a complete response (CR) treatment for long-term OS
and thus benefit from an aggressive treatment strategy. Standard-risk patients have similar OS regardless of whether or not CR is achieved and thus can either
be treated with an aggressive approach or a sequential therapy approach.16
Transplant-Eligible Patients
All patients should be evaluated for transplant eligibility, because it results in superior progression-free survival (PFS) and OS in patients with MM compared
with standard chemotherapy. Transplant eligibility requirements differ, depending on the transplant center. There is no strict age limit in the U.S. for determining transplant eligibility. Physiological age and factors such as functional status and liver function are often considered before making a transplant decision.
For VA patients, transplants are generally considered in those aged < 65 years, and patients are referred to 1 of 3 transplant centers: VA Puget Sound Healthcare System in Seattle, Washington; Tennessee Valley Healthcare System in Nashville; or South Texas Veterans Healthcare System in San Antonio.17 All patients who are transplant eligible should receive induction therapy for 2 to 4 months before stem cell collection. This is to reduce tumor burden, for symptomatic management, as well as to lessen end organ damage. After stem cell collection, patients undergo either upfront ASCT or resume induction therapy and undergo a transplant after first relapse.
Bortezomib Regimens
Bortezomib is a proteasome inhibitor (PI) and has been used as upfront chemotherapy for transplant-eligible patients, traditionally to avoid alkylating agents that
could affect stem cell harvest. It is highly efficacious in the treatment of patients with MM. Two- or 3-drug regimens have been used. Common regimens include bortezomib, cyclophosphamide, dexamethasone; bortezomib, thalidomide, dexamethasone (VTD); bortezomib, lenalidomide, dexamethasone (VRD); bortezomib,
doxorubicin, dexamethasone; as well as bortezomib, dexamethasone.18 Dexamethasone is less expensive than VTD or VRD, well tolerated, and efficacious. It is
often used upfront for newly diagnosed MM.19 Threedrug regimens have shown to be more efficacious than 2-drug regimens in clinical trials (Table 5).20
Of note, bortezomib is not cleared through the kidney, which makes it an ideal choice for patients with renal function impairment. A significant potential AE with bortezomib is the onset of peripheral neuropathy. Bortezomib can be administered once or twice weekly. Twice-weekly administration of bortezomib is preferred when rapid results are needed, such as light chain cast nephropathy causing acute renal failure.21
Lenalidomide Plus Dexamethasone
Lenalidomide is a second-generation immunomodulating agent that is being increasingly used as initial therapy for MM. There is currently no data showing superiority of bortezomib-based regimens to lenalidomide plus dexamethasone in reference to OS. Bortezomib-based regimens seem to overcome the poor prognosis associated with t(4;14) translocation and thus should be considered in choosing initial chemotherapy treatment.22
Lenalidomide can affect stem cell collection; therefore, it is important to collect stem cells in transplanteligible patients who are aged < 65 years or for those who have received more than 4 cycles of treatment with this regimen.23,24 A major AE to lenalidomidecontaining regimens is the increased risk of thrombosis. All patients on lenalidomide require treatment with aspirin at a minimum; however, those at higher risk for thrombosis may require low-molecular weight heparin or warfarin.25
Carfilzomib Plus Lenalidomide Plus Dexamethasone
Carfilzomib is a recently approved PI that has shown promise in combination with lenalidomide and dexamethasone as initial therapy for MM. Several phase 2 trials
have reported favorable results with carfilzomib in combination with lenalidomide and dexamethasone in MM.26,27 More studies are needed to establish efficacy and
safety before this regimen is routinely used as upfront therapy.11
Thalidomide Plus Dexamethasone
Although there are no randomized controlled trials comparing lenalidomide plus dexamethasone with thalidomide plus dexamethasone, these regimens have been compared in retrospective studies. In these studies, lenalidomide plus dexamethasone showed both a higher response rate as well as an increased PFS and
OS compared with thalidomide plus dexamethasone. Additionally, lenalidomide’s AE profile was more favorable than that of thalidomide. In light of this, lenalidomide
plus dexamethasone is preferred to thalidomide plus dexamethasone in the management of MM, although the latter can be considered when lenalidomide is not available or when a patient does not tolerate lenalidomide.28
VDT-PACE
A multidrug combination that should be considered in select populations is the VDT-PACE regimen, which includes bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide. This regimen can be considered in those patients who have aggressive disease, such as those with plasma cell leukemia or with multiple extramedullary plasmacytomas.11
Autologous Stem Cell Transplant
Previous data suggest that ASCT improves OS in MM by 12 months.29 A more recent open-label, randomized trial comparing melphalan and ASCT to melphalanprednisone-lenalidomide showed significant prolonged PFS and OS among patients with MM.30 Although the role of ASCT may change as new drugs are
integrated into initial therapy of MM, ASCT is still the preferred approach in transplant-eligible patients. As such, all patients who are eligible should be considered
to receive a transplant.
There remains debate about whether ASCT should be performed early, after 2 to 4 cycles of induction therapy, or late after first relapse. Several randomized trials failed to show a difference in survival for early vs delayed ASCT approach.31 Generally, transplant can be delayed for patients with standard-risk MM who have responded well to therapy.11 Those patients who do not achieve a CR with their first ASCT may benefit from a second (tandem) ASCT.32 An allogeneic transplant is occasionally used in select populations and is the only potentially curative therapy for these patients. However, its high mortality rate precludes its everyday use.
Transplant-Ineligible Patients
For patients with newly diagnosed MM who are ineligible for ASCT due to age or other comorbidities, chemotherapy is the only option. Many patients will benefit
not only in survival, but also in quality of life. Immunomodulatory agents, such as lenalidomide and thalidomide, and PIs, such as bortezomib, are highly effective
and well tolerated. There has been a general shift to using these agents upfront in transplant-ineligible patients.
All previously mentioned regimens can also be used in transplant-ineligible patients. Although no longer the preferred treatment, melphalan can be considered
in resource-poor settings.11 Patients who are not transplant eligible are treated for a fixed period of 9 to 18 months, although lenalidomide plus dexamethasone is often continued until relapse.11,33
Melphalan Plus Prednisone Plus Bortezomib
The addition of bortezomib to melphalan and prednisone results in improved OS compared with that of melphalan and dexamethasone alone.34 Peripheral neuropathy is a significant AE and can be minimized by giving bortezomib once weekly.
Melphalan Plus Prednisone Plus Thalidomide
Melphalan plus prednisone plus thalidomide has shown an OS benefit compared with that of melphalan and prednisone alone. The regimen has a high toxicity rate (> 50%) and a deep vein thrombosis rate of 20%, so patients undergoing treatment with this regimen require thromboprophylaxis.35,36
Melphalan Plus Prednisone
Although melphalan plus prednisone has fallen out of favor due to the existence of more efficacious regimens, it may be useful in an elderly patient population who lack access to newer agents, such as lenalidomide, thalidomide, and bortezomib.
Assessing Treatment Response
The International Myeloma Working Group has established criteria for assessing disease response. Patient’s response to therapy should be assessed with a FLC assay
before each cycle with SPEP and UPEP and in those without measurable M protein levels. A bone marrow biopsy can be helpful in patients with immeasurable M protein levels and low FLC levels, as well as to establish that a CR is present.
A CR is defined as negative SPEP/UPEP, disappearance of soft tissue plamacytomas, and < 5% plasma cells in bone marrow. A very good partial response is defined as serum/urine M protein being present on immunofixation but not electrophoresis or reduction in serum M protein by 90% and urine M protein < 100 mg/d. For those without measurable M protein, a reduction in FLC ratio by 90% is required. A partial response is defined as > 50% reduction of the serum monoclonal protein and/or < 200 mg urinary M protein per 24 hours or > 90% reduction in urinary M protein. For those without M protein present, they should have > 50% decrease in FLC ratio.5
Maintenance Therapy
There is currently considerable debate about whether patients should be treated with maintenance therapy following induction chemotherapy or transplant. In patients treated with transplant, there have been several studies to investigate the use of maintenance therapy. Lenalidomide has been evaluated for maintenance therapy following stem cell transplant and has shown superior PFS with dexamethasone as post-ASCT maintenance; however, this is at the cost of increased secondary cancers.37
Thalidomide has also been studied as maintenance therapy and seems to have a modest improvement in PFS and OS but at the cost of increased toxicities, such as
neuropathy and thromboembolism.38,39 Still other studies compared bortezomib maintenance with thalidomide maintenance in posttransplant patients and was able to show improved OS. As a result, certain patients with intermediate- or high-risk disease may be eligible for bortezomib for maintenance following transplant.11 For transplant-ineligible patients, there is no clear role for maintenance therapy.
Refreactory/Relapsed Disease Treatments
Multiple myeloma (MM) is a disease that is primarily treated by hematologists; however, it is important for primary care providers (PCPs) to be aware of the presentation and diagnosis of this disease. Multiple myeloma often is seen in the veteran population, and VA providers should be familiar with its diagnosis and treatment so that an appropriate referral can be made. Often, the initial signs and symptoms of the disease are subtle and require an astute eye by the PCP to diagnose and initiate a workup.
Once a veteran has an established diagnosis of MM or one of its precursor syndromes, the PCP will invariably be alerted to an adverse event (AE) of treatment or complication of the disease and should be aware of such complications to assist in management or referral. Patients with MM may achieve long-term remission; therefore, it is likely that the PCP will see an evolution in their treatment and care. Last, PCPs and patients often have a close relationship, and patients expect the PCP to understand their diagnosis and treatment plan.
Presentation
Multiple myeloma is a disease in which a neoplastic proliferation of plasma cells produces a monoclonal immunoglobulin. It is almost invariably preceded by premalignant stages of monoclonal gammopathy of undetermined significance (MGUS) and smoldering MM (SMM), although not all cases of MGUS will eventually progress to MM.1 Common signs and symptoms include anemia, bone pain or lytic lesions on X-ray, kidney injury, fatigue, hypercalcemia, and weight loss.2 Anemia is usually a normocytic, normochromic anemia and can be due to involvement of the bone marrow, secondary to renal disease, or it may be dilutional, related to a high monoclonal protein (M protein) level. There are several identifiable causes for renal disease in patients with MM, including light chain cast nephropathy,
hypercalcemia, light chain amyloidosis, and light chain deposition disease. Without intervention, progressive renal damage may occur.3
Diagnosis
All patients with a suspected diagnosis of MM should undergo a basic workup, including complete blood count; peripheral blood smear; complete chemistry panel, including calcium and albumin; serum free light chain analysis (FLC); serum protein electrophoresis (SPEP) and immunofixation; urinalysis; 24-hour urine collection for electrophoresis (UPEP) and immunofixation; serum B2-microglobulin; and lactate dehydrogenase.4 A FLC analysis is particularly useful for the diagnosis and monitoring of MM, when only small amounts of M protein are secreted into the serum/urine or for nonsecretory myeloma, as well as for light-chainonly
myeloma.5
A bone marrow biopsy and aspirate should be performed in the diagnosis of MM to evaluate the bone marrow involvement and genetic abnormality of myeloma cells with fluorescence in situ hybridization (FISH) and cytogenetics, both of which are very important in risk stratification and for treatment planning. A skeletal survey is also typically performed to look for bone lesions.4 Magnetic resonance imaging (MRI) can also be useful to evaluate for possible soft tissue lesions when a bone survey is negative, or to evaluate for spinal cord compression.5 Additionally, an MRI should be performed in patients with SMM at the initial assessment, because focal lesions in the setting of SMM are associated with an increased risk to progression.6 Since plain radiographs are usually abnormal only after ≥ 30% of the
bone is destroyed, an MRI offers a more sensitive image.
Two MM precursor syndromes are worth noting: MGUS and SMM. In evaluating a patient for possible MM, it is important to differentiate between MGUS, asymptomatic
SMM, and MM that requires treatment.4 Monoclonal gammopathy of undetermined significance is diagnosed when a patient has a serum M protein that is < 3 g/dL, clonal bone marrow plasma cells < 10%, and no identifiable end organ damage.5 Smoldering MM is diagnosed when either the serum M protein is > 3 g/dL or bone marrow clonal plasma cells are > 10% in the absence of end organ damage.
Symptomatic MM is characterized by > 10% clonal bone marrow involvement with end organ damage that includes hypercalcemia, renal failure, anemia, or bone lesions. The diagnostic criteria are summarized in Table 1. The International Myeloma Working Group produced updated guidelines in 2014, which now include patients with > 60% bone marrow involvement of plasma cells, serum FLC ratio of > 100, and > 1 focal lesions on an MRI study as symptomatic MM.5,6
Most patients with MM will have a M protein produced by the malignant plasma cells detected on an SPEP or UPEP. The majority of immunoglobulins were IgG and IgA, whereas IgD and IgM were much less common.2 A minority of patients will not have a detectable M protein on SPEP or UPEP. Some patients will produce only light chains and are designated as light-chain-only myeloma.For these patients, the FLC assay is useful for diagnosis and disease monitoring. Patients who have an absence of M protein on SPEP/UPEP and normal FLC assay ratios are considered to have nonsecretory myeloma.7
Staging and Risk Stratification
Two staging systems are used to evaluate a patient’s prognosis: the Durie-Salmon staging system, which is based on tumor burden (Table 2); and the International Staging System (ISS), which uses a combination of serum beta 2 microglobulin (B2M) and serum albumin levels to produce a powerful and reproducible 3-stage classification and is more commonly used by hematologists due to its simplicity to use and reliable reproducibility (Table 3).
In the Durie-Salmon staging system, patients with stage I disease have a lower tumor burden, defined as hemoglobin > 10 g/dL, normal calcium level, no evidence of
lytic bone lesions, and low amounts of protein produced (IgG < 5 g/dL; IgA < 3 g/dL; urine protein < 4 g/d). Patients are classified as stage III if they have any of the following: hemoglobin < 8.5 g/dL, hypercalcemia with level > 12 mg/dL, bony lytic lesions, or high amounts of protein produced (IgG > 7 g/dL; IgA > 5 g/dL; or urine protein > 12 g/d). Patients with stage II disease do not fall into either of these categories. Stage III disease can be further differentiated into stage IIIA or stage IIIB disease if renal involvement is present.8
In the ISS system, patients with stage I disease have B2M levels that are < 3.5 mg/dL and albumin levels > 3.5 g/dL and have a median overall survival (OS) of 62 months. In this classification, stage III patients have B2M levels that are > 5.5 mg/dL and median OS was 29 months. Stage II patients do not meet either of these
criteria and OS was 44 months.9 In a study by Mayo Clinic, OS has improved over the past decade, with OS for ISS stage III patients increasing to 4.2 years. Overall
survival for both ISS stage I and stage III disease seems to have increased as well, although the end point has not been reached.10
All myeloma patients are risk stratified at initial diagnosis based on their cytogenetic abnormalities identified mainly by FISH studies and conventional cytogenetics,
which can serve as an alternative if FISH is unavailable. Genetic abnormalities of MM are the major predictor for the outcome and will affect treatment choice. Three risk groups have been identified: high-risk, intermediate-risk, and standard-risk MM (Table 4).11
Management of MGUS and SMM
Patients with MGUS progress to malignant conditions at a rate of 1% per year.12 Those individuals who are diagnosed with MGUS or SMM typically do not require
therapy. According to the International Myeloma Working Group guidelines, patients should be monitored based on risk stratification. Those with low-risk MGUS (IgG M protein < 1.5 g/dL and no abnormal FLC ratio) can be monitored every 6 months for 2 to 3 years. Those who are intermediate to high risk need a baseline bone marrow biopsy in addition to skeletal survey and should check urine and serum levels for protein every 6 months for the first year and then annually thereafter.
Patients with SMM are at an increased risk of progression to symptomatic MM compared with patients with MGUS (10% per year for the first 5 years, 3% per year for the next 5 years).13 Therefore, experts recommend physician visits and laboratory testing for M proteins every 2 to 3 months for the first year and then an evaluation every 6 to 12 months if the patient remains clinically stable.14 Additionally, there are new data to suggest that early therapy with lenalidomide plus dexamethasone for SMM can prolong time to disease progression as well as increase OS in individuals with SMM at high risk for progression.15
Patients With MM
All patients with a diagnosis of MM require immediate treatment. Initial choice of therapy is driven by whether a patient is eligible for an autologous stem cell transplant (ASCT), because certain agents, such as alkylating agents, should typically be avoided in those who are transplant eligible. Initial therapy for patients
with MM is also based on genetic risk stratification of the disease. Patients with high-risk disease require a complete response (CR) treatment for long-term OS
and thus benefit from an aggressive treatment strategy. Standard-risk patients have similar OS regardless of whether or not CR is achieved and thus can either
be treated with an aggressive approach or a sequential therapy approach.16
Transplant-Eligible Patients
All patients should be evaluated for transplant eligibility, because it results in superior progression-free survival (PFS) and OS in patients with MM compared
with standard chemotherapy. Transplant eligibility requirements differ, depending on the transplant center. There is no strict age limit in the U.S. for determining transplant eligibility. Physiological age and factors such as functional status and liver function are often considered before making a transplant decision.
For VA patients, transplants are generally considered in those aged < 65 years, and patients are referred to 1 of 3 transplant centers: VA Puget Sound Healthcare System in Seattle, Washington; Tennessee Valley Healthcare System in Nashville; or South Texas Veterans Healthcare System in San Antonio.17 All patients who are transplant eligible should receive induction therapy for 2 to 4 months before stem cell collection. This is to reduce tumor burden, for symptomatic management, as well as to lessen end organ damage. After stem cell collection, patients undergo either upfront ASCT or resume induction therapy and undergo a transplant after first relapse.
Bortezomib Regimens
Bortezomib is a proteasome inhibitor (PI) and has been used as upfront chemotherapy for transplant-eligible patients, traditionally to avoid alkylating agents that
could affect stem cell harvest. It is highly efficacious in the treatment of patients with MM. Two- or 3-drug regimens have been used. Common regimens include bortezomib, cyclophosphamide, dexamethasone; bortezomib, thalidomide, dexamethasone (VTD); bortezomib, lenalidomide, dexamethasone (VRD); bortezomib,
doxorubicin, dexamethasone; as well as bortezomib, dexamethasone.18 Dexamethasone is less expensive than VTD or VRD, well tolerated, and efficacious. It is
often used upfront for newly diagnosed MM.19 Threedrug regimens have shown to be more efficacious than 2-drug regimens in clinical trials (Table 5).20
Of note, bortezomib is not cleared through the kidney, which makes it an ideal choice for patients with renal function impairment. A significant potential AE with bortezomib is the onset of peripheral neuropathy. Bortezomib can be administered once or twice weekly. Twice-weekly administration of bortezomib is preferred when rapid results are needed, such as light chain cast nephropathy causing acute renal failure.21
Lenalidomide Plus Dexamethasone
Lenalidomide is a second-generation immunomodulating agent that is being increasingly used as initial therapy for MM. There is currently no data showing superiority of bortezomib-based regimens to lenalidomide plus dexamethasone in reference to OS. Bortezomib-based regimens seem to overcome the poor prognosis associated with t(4;14) translocation and thus should be considered in choosing initial chemotherapy treatment.22
Lenalidomide can affect stem cell collection; therefore, it is important to collect stem cells in transplanteligible patients who are aged < 65 years or for those who have received more than 4 cycles of treatment with this regimen.23,24 A major AE to lenalidomidecontaining regimens is the increased risk of thrombosis. All patients on lenalidomide require treatment with aspirin at a minimum; however, those at higher risk for thrombosis may require low-molecular weight heparin or warfarin.25
Carfilzomib Plus Lenalidomide Plus Dexamethasone
Carfilzomib is a recently approved PI that has shown promise in combination with lenalidomide and dexamethasone as initial therapy for MM. Several phase 2 trials
have reported favorable results with carfilzomib in combination with lenalidomide and dexamethasone in MM.26,27 More studies are needed to establish efficacy and
safety before this regimen is routinely used as upfront therapy.11
Thalidomide Plus Dexamethasone
Although there are no randomized controlled trials comparing lenalidomide plus dexamethasone with thalidomide plus dexamethasone, these regimens have been compared in retrospective studies. In these studies, lenalidomide plus dexamethasone showed both a higher response rate as well as an increased PFS and
OS compared with thalidomide plus dexamethasone. Additionally, lenalidomide’s AE profile was more favorable than that of thalidomide. In light of this, lenalidomide
plus dexamethasone is preferred to thalidomide plus dexamethasone in the management of MM, although the latter can be considered when lenalidomide is not available or when a patient does not tolerate lenalidomide.28
VDT-PACE
A multidrug combination that should be considered in select populations is the VDT-PACE regimen, which includes bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide. This regimen can be considered in those patients who have aggressive disease, such as those with plasma cell leukemia or with multiple extramedullary plasmacytomas.11
Autologous Stem Cell Transplant
Previous data suggest that ASCT improves OS in MM by 12 months.29 A more recent open-label, randomized trial comparing melphalan and ASCT to melphalanprednisone-lenalidomide showed significant prolonged PFS and OS among patients with MM.30 Although the role of ASCT may change as new drugs are
integrated into initial therapy of MM, ASCT is still the preferred approach in transplant-eligible patients. As such, all patients who are eligible should be considered
to receive a transplant.
There remains debate about whether ASCT should be performed early, after 2 to 4 cycles of induction therapy, or late after first relapse. Several randomized trials failed to show a difference in survival for early vs delayed ASCT approach.31 Generally, transplant can be delayed for patients with standard-risk MM who have responded well to therapy.11 Those patients who do not achieve a CR with their first ASCT may benefit from a second (tandem) ASCT.32 An allogeneic transplant is occasionally used in select populations and is the only potentially curative therapy for these patients. However, its high mortality rate precludes its everyday use.
Transplant-Ineligible Patients
For patients with newly diagnosed MM who are ineligible for ASCT due to age or other comorbidities, chemotherapy is the only option. Many patients will benefit
not only in survival, but also in quality of life. Immunomodulatory agents, such as lenalidomide and thalidomide, and PIs, such as bortezomib, are highly effective
and well tolerated. There has been a general shift to using these agents upfront in transplant-ineligible patients.
All previously mentioned regimens can also be used in transplant-ineligible patients. Although no longer the preferred treatment, melphalan can be considered
in resource-poor settings.11 Patients who are not transplant eligible are treated for a fixed period of 9 to 18 months, although lenalidomide plus dexamethasone is often continued until relapse.11,33
Melphalan Plus Prednisone Plus Bortezomib
The addition of bortezomib to melphalan and prednisone results in improved OS compared with that of melphalan and dexamethasone alone.34 Peripheral neuropathy is a significant AE and can be minimized by giving bortezomib once weekly.
Melphalan Plus Prednisone Plus Thalidomide
Melphalan plus prednisone plus thalidomide has shown an OS benefit compared with that of melphalan and prednisone alone. The regimen has a high toxicity rate (> 50%) and a deep vein thrombosis rate of 20%, so patients undergoing treatment with this regimen require thromboprophylaxis.35,36
Melphalan Plus Prednisone
Although melphalan plus prednisone has fallen out of favor due to the existence of more efficacious regimens, it may be useful in an elderly patient population who lack access to newer agents, such as lenalidomide, thalidomide, and bortezomib.
Assessing Treatment Response
The International Myeloma Working Group has established criteria for assessing disease response. Patient’s response to therapy should be assessed with a FLC assay
before each cycle with SPEP and UPEP and in those without measurable M protein levels. A bone marrow biopsy can be helpful in patients with immeasurable M protein levels and low FLC levels, as well as to establish that a CR is present.
A CR is defined as negative SPEP/UPEP, disappearance of soft tissue plamacytomas, and < 5% plasma cells in bone marrow. A very good partial response is defined as serum/urine M protein being present on immunofixation but not electrophoresis or reduction in serum M protein by 90% and urine M protein < 100 mg/d. For those without measurable M protein, a reduction in FLC ratio by 90% is required. A partial response is defined as > 50% reduction of the serum monoclonal protein and/or < 200 mg urinary M protein per 24 hours or > 90% reduction in urinary M protein. For those without M protein present, they should have > 50% decrease in FLC ratio.5
Maintenance Therapy
There is currently considerable debate about whether patients should be treated with maintenance therapy following induction chemotherapy or transplant. In patients treated with transplant, there have been several studies to investigate the use of maintenance therapy. Lenalidomide has been evaluated for maintenance therapy following stem cell transplant and has shown superior PFS with dexamethasone as post-ASCT maintenance; however, this is at the cost of increased secondary cancers.37
Thalidomide has also been studied as maintenance therapy and seems to have a modest improvement in PFS and OS but at the cost of increased toxicities, such as
neuropathy and thromboembolism.38,39 Still other studies compared bortezomib maintenance with thalidomide maintenance in posttransplant patients and was able to show improved OS. As a result, certain patients with intermediate- or high-risk disease may be eligible for bortezomib for maintenance following transplant.11 For transplant-ineligible patients, there is no clear role for maintenance therapy.
Refreactory/Relapsed Disease Treatments
1. Landgren O, Kyle R, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined
significance (MGUS) consistently precedes multiple myeloma: a prospective
study. Blood. 2009;113(22):5412-5417.
2. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed
multiple myeloma. Mayo Clin Proc. 2003;78(1):21-33.
3. Hutchison CA, Batuman V, Behrens J, et al; International Kidney and Monoclonal
Gammopathy Research Group. The pathogenesis and diagnosis of acute kidney
injury in multiple myeloma. Nat Review Nephrol. 2011;8(1):43-51.
4. Dimopoulous M, Kyle R, Fermand JP, et al; International Myeloma Workshop
Consensus Panel 3. Consensus recommendations for standard investigative workup:
report of the International Myeloma Workshop Consensus Panel 3. Blood.
2011;117(18):4701-4705.
5. Palumbo A, Rajkumar S, San Miguel JF, et al. International Melanoma Working
Group consensus statement for the management, treatment, and supportive care
of patients with myeloma not eligible for standard autologous stem-cell transplantation.
J Clin Oncol. 2014;32(6):587-600.
6. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working
Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol.
2014;15(12):e538-e548.
7. Dimopoulos MA, Kastritis E, Terpo E. Non-secretory myeloma: one, two, or more
entities? Oncology (Williston Park). 2013;27(9):930-932.
8. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation
of measured myeloma cell mass with presenting clinical features, response to
treatment, and survival. Cancer. 1975;36(3):842-854.
9. Griepp P, San Miguel J, Durie BG, et al. International staging system for multiple
myeloma. J Clin Oncol. 2005;23(15):3412-3420.
10. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival
in multiple myeloma: changes in early mortality and outcomes in older patients.
Leukemia. 2014; 28(5):1122-1128.
11. Rajkumar SV. Multiple myeloma: 2014 update on diagnosis, risk-stratification,
and management. Am J Hematol. 2014;89(10):999-1009.
12. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis
in monoclonal gammopathy of undetermined significance. N Engl J Med.
2002;346(8):564-569.
13. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering
(asymptomatic) multiple myeloma. N Engl J Med. 2007;356(25):2582-2590.
14. Landgren O. Monoclonal gammopathy of undetermined significance and smoldering
multiple myeloma: biological insights and early treatment strategies. Hematology
Am Soc Hematol Educ Program. 2013;2013(1):478-487.
15. Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone
for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369(5):438-447.
16. Haessler K, Shaughnessy JD Jr, Zhan F, et al. Benefit of complete response in multiple
myeloma limited to high-risk subgroup identified by gene expression profiling.
Clin Cancer Res. 2007;13(23):7073-7079.
17. Xiang Z, Mehta P. Management of multiple myeloma and its precursor syndromes.
Fed Pract. 2014;31(suppl 3):6S-13S.
18. National Comprehensive Cancer Network. NCCN clinical practice guidelines in
oncology: multiple myeloma. National Comprehensive Cancer Network Website.
http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf. Updated
March 10, 2015. Accessed July 8, 2015.
19. Kumar S, Flinn I, Richardson P, et al. Randomized, multicenter, phase 2 study
(EVOLUTION) of combinations of bortezomib, dexamethasone, cyclosphosphamide,
and lenalidomide in previously untreated multiple myeloma. Blood.
2012;119(19):4375-4382.
20. Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus
reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment
before autologous stem cell transplantation in newly diagnosed multiple
myeloma. Blood. 2011;118(22):5752-5758.
21. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous
administration of bortezomib in patients with relapsed multiple myeloma: a randomized,
phase 3, noninferiority study. Lancet Oncol. 2011;12(5):431-440.
22. Pineda-Roman M, Zangari M, Haessler J, et al. Sustained complete remissions in
multiple myeloma linked to bortezomib in total therapy 3: comparison with total
therapy 2. Br J Haematol. 2008;140(6):624-634.
23. Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem
cell mobilization and engraftment post-peripheral blood stem cell transplantation
in patients with newly diagnosed myeloma. Leukemia. 2007;21(9):2035-2042.
24. Kumar S, Giralt S, Stadtmauer EA, et al; International Myeloma Working Group.
Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell
collection following initial therapy with thalidomide-, lenalidomide-, or bortezomibcontaining
regimens. Blood. 2009;114(9):1729-1735.
25. Larocca A, Cavallo F, Bringhen S, et al. Aspirin or enoxaparin thromboprophylaxis
for patients with newly diagnosed multiple myeloma patients treated with
lenalidomide. Blood. 2012;119(4):933-939.
26. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in
combination with lenalidomide and low dose dexamethasone as a frontline treatment
for multiple myeloma. Blood. 2012;120(9):1801-1809.
27. Korde N, Zingone A, Kwok M, et al. Phase II clinical and correlative study of
carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide extended
dosing (CRD-R) induces high rates of MRD negativity in newly diagnosed
multiple myeloma patients [Abstract]. Blood. 2013;122(21):538.
28. Gay F, Hayman SR, Lacy MQ, et al. Lenalidomide plus dexamethasone versus thalidomide
plus dexamethasone in newly diagnosed multiple myeloma: a comparative
analysis of 411 patients. Blood. 2010;115(7):1343-1350.
29. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous
bone marrow transplantation and chemotherapy in multiple myeloma.
Intergroupe Français du Myélome. N Engl J Med. 1996;335(2):91-97.
30. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance
therapy in multiple myeloma. N Engl J Med. 2014;371(10):895-905.
31. Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous
stem cell transplantation in multiple myeloma: up-front or rescue treatment?
Results of a multicenter sequential randomized clinical trial. Blood.
1998;92(9):3131-3136.
32. Elice F, Raimondi R, Tosetto A, et al. Prolonged overall survival with second
on-demand autologous stem cell transplant in multiple myeloma. Am J Hematol.
2006;81(6):426-431.
33. Facon T, Dimopoulos MA, Dispenzieri A, et al. Initial phase 3 results of the
FIRST (frontline investigation of lenalidomide + dexamethasone versus standard
thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma
(NDMM) patients (pts) ineligible for stem cell transplantation (SCT). Blood.
2013;122(21):2.
34. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan
and prednisone for initial treatment of multiple myeloma. N Engl J Med.
2008;359(9):906-917.
35. Facon T, Mary JY, Hulin C, et al; Intergroupe Français du Myélome. Melphalan
and prednisone plus thalidomide versus melphalan and prednisone
alone or reduced-intensity autologous stem cell transplantation in
elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet.
2007;370(9594):1209-1218.
36. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide
in patients older than 75 years with newly diagnosed multiple myeloma.
IFM 01/01 trial. J Clin Oncol. 2009;27(22):3664-3670.
37. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stemcell
transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782-1791.
38. Attal M., Harousseau JL, Leyvraz S, et al; Inter-Groupe Francophone du Myélome
(IFM). Maintenance therapy with thalidomide improves survival in patients with
multiple myeloma. Blood. 2006;108(10):3289-3294.
39. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose
thalidomide and prednisolone prolongs the survival of multiple myeloma patients
undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol.
2009;27(11):1788-1793.
40. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and
maintenance treatment in patients with newly diagnosed multiple myeloma:
results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol.
2012;30(24):2946-2955.
41. Richardson PG, Sonneveld P, Schuster MW, et al; Assessment of Proteasome
Inhibition for Extending Remissions (APEX) Investigators. Bortezomib
or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med.
2005;352(24):2487-2498.
42. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated
liposomal doxorubicin plus bortezomib compared with bortezomib alone
in relapsed or refractory multiple myeloma: combination therapy improves time
to progression. J Clin Oncol. 2007;25(25):3892-3901.
43. Kumar SK, Lee JH, Lahuerta JJ, et al; International Myeloma Working Group.
Risk of progression and survival in multiple myeloma relapsing after therapy
with IMiDs and bortezomib: a multicenter international myeloma working group
study. Leukemia. 2012;26(1):149-157.
44. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus lowdose
dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol.
2009;27(30):5008-5014.
45. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single agent carfilzomib
(PX-171-003-A1) in patients with relapsed and refractory multiple myeloma.
Blood. 2012;120(14):2817-2825.
46. San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib
and dexamethasone versus placebo plus bortezomib and dexamethasone
in patients with relapsed or relapsed and refractory multiple
myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol.
2014;15(11):1195-1206.
1. Landgren O, Kyle R, Pfeiffer RM, et al. Monoclonal gammopathy of undetermined
significance (MGUS) consistently precedes multiple myeloma: a prospective
study. Blood. 2009;113(22):5412-5417.
2. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed
multiple myeloma. Mayo Clin Proc. 2003;78(1):21-33.
3. Hutchison CA, Batuman V, Behrens J, et al; International Kidney and Monoclonal
Gammopathy Research Group. The pathogenesis and diagnosis of acute kidney
injury in multiple myeloma. Nat Review Nephrol. 2011;8(1):43-51.
4. Dimopoulous M, Kyle R, Fermand JP, et al; International Myeloma Workshop
Consensus Panel 3. Consensus recommendations for standard investigative workup:
report of the International Myeloma Workshop Consensus Panel 3. Blood.
2011;117(18):4701-4705.
5. Palumbo A, Rajkumar S, San Miguel JF, et al. International Melanoma Working
Group consensus statement for the management, treatment, and supportive care
of patients with myeloma not eligible for standard autologous stem-cell transplantation.
J Clin Oncol. 2014;32(6):587-600.
6. Rajkumar SV, Dimopoulos MA, Palumbo A, et al. International Myeloma Working
Group updated criteria for the diagnosis of multiple myeloma. Lancet Oncol.
2014;15(12):e538-e548.
7. Dimopoulos MA, Kastritis E, Terpo E. Non-secretory myeloma: one, two, or more
entities? Oncology (Williston Park). 2013;27(9):930-932.
8. Durie BG, Salmon SE. A clinical staging system for multiple myeloma. Correlation
of measured myeloma cell mass with presenting clinical features, response to
treatment, and survival. Cancer. 1975;36(3):842-854.
9. Griepp P, San Miguel J, Durie BG, et al. International staging system for multiple
myeloma. J Clin Oncol. 2005;23(15):3412-3420.
10. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival
in multiple myeloma: changes in early mortality and outcomes in older patients.
Leukemia. 2014; 28(5):1122-1128.
11. Rajkumar SV. Multiple myeloma: 2014 update on diagnosis, risk-stratification,
and management. Am J Hematol. 2014;89(10):999-1009.
12. Kyle RA, Therneau TM, Rajkumar SV, et al. A long-term study of prognosis
in monoclonal gammopathy of undetermined significance. N Engl J Med.
2002;346(8):564-569.
13. Kyle RA, Remstein ED, Therneau TM, et al. Clinical course and prognosis of smoldering
(asymptomatic) multiple myeloma. N Engl J Med. 2007;356(25):2582-2590.
14. Landgren O. Monoclonal gammopathy of undetermined significance and smoldering
multiple myeloma: biological insights and early treatment strategies. Hematology
Am Soc Hematol Educ Program. 2013;2013(1):478-487.
15. Mateos MV, Hernández MT, Giraldo P, et al. Lenalidomide plus dexamethasone
for high-risk smoldering multiple myeloma. N Engl J Med. 2013;369(5):438-447.
16. Haessler K, Shaughnessy JD Jr, Zhan F, et al. Benefit of complete response in multiple
myeloma limited to high-risk subgroup identified by gene expression profiling.
Clin Cancer Res. 2007;13(23):7073-7079.
17. Xiang Z, Mehta P. Management of multiple myeloma and its precursor syndromes.
Fed Pract. 2014;31(suppl 3):6S-13S.
18. National Comprehensive Cancer Network. NCCN clinical practice guidelines in
oncology: multiple myeloma. National Comprehensive Cancer Network Website.
http://www.nccn.org/professionals/physician_gls/PDF/myeloma.pdf. Updated
March 10, 2015. Accessed July 8, 2015.
19. Kumar S, Flinn I, Richardson P, et al. Randomized, multicenter, phase 2 study
(EVOLUTION) of combinations of bortezomib, dexamethasone, cyclosphosphamide,
and lenalidomide in previously untreated multiple myeloma. Blood.
2012;119(19):4375-4382.
20. Moreau P, Avet-Loiseau H, Facon T, et al. Bortezomib plus dexamethasone versus
reduced-dose bortezomib, thalidomide plus dexamethasone as induction treatment
before autologous stem cell transplantation in newly diagnosed multiple
myeloma. Blood. 2011;118(22):5752-5758.
21. Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous
administration of bortezomib in patients with relapsed multiple myeloma: a randomized,
phase 3, noninferiority study. Lancet Oncol. 2011;12(5):431-440.
22. Pineda-Roman M, Zangari M, Haessler J, et al. Sustained complete remissions in
multiple myeloma linked to bortezomib in total therapy 3: comparison with total
therapy 2. Br J Haematol. 2008;140(6):624-634.
23. Kumar S, Dispenzieri A, Lacy MQ, et al. Impact of lenalidomide therapy on stem
cell mobilization and engraftment post-peripheral blood stem cell transplantation
in patients with newly diagnosed myeloma. Leukemia. 2007;21(9):2035-2042.
24. Kumar S, Giralt S, Stadtmauer EA, et al; International Myeloma Working Group.
Mobilization in myeloma revisited: IMWG consensus perspectives on stem cell
collection following initial therapy with thalidomide-, lenalidomide-, or bortezomibcontaining
regimens. Blood. 2009;114(9):1729-1735.
25. Larocca A, Cavallo F, Bringhen S, et al. Aspirin or enoxaparin thromboprophylaxis
for patients with newly diagnosed multiple myeloma patients treated with
lenalidomide. Blood. 2012;119(4):933-939.
26. Jakubowiak AJ, Dytfeld D, Griffith KA, et al. A phase 1/2 study of carfilzomib in
combination with lenalidomide and low dose dexamethasone as a frontline treatment
for multiple myeloma. Blood. 2012;120(9):1801-1809.
27. Korde N, Zingone A, Kwok M, et al. Phase II clinical and correlative study of
carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide extended
dosing (CRD-R) induces high rates of MRD negativity in newly diagnosed
multiple myeloma patients [Abstract]. Blood. 2013;122(21):538.
28. Gay F, Hayman SR, Lacy MQ, et al. Lenalidomide plus dexamethasone versus thalidomide
plus dexamethasone in newly diagnosed multiple myeloma: a comparative
analysis of 411 patients. Blood. 2010;115(7):1343-1350.
29. Attal M, Harousseau JL, Stoppa AM, et al. A prospective, randomized trial of autologous
bone marrow transplantation and chemotherapy in multiple myeloma.
Intergroupe Français du Myélome. N Engl J Med. 1996;335(2):91-97.
30. Palumbo A, Cavallo F, Gay F, et al. Autologous transplantation and maintenance
therapy in multiple myeloma. N Engl J Med. 2014;371(10):895-905.
31. Fermand JP, Ravaud P, Chevret S, et al. High-dose therapy and autologous
stem cell transplantation in multiple myeloma: up-front or rescue treatment?
Results of a multicenter sequential randomized clinical trial. Blood.
1998;92(9):3131-3136.
32. Elice F, Raimondi R, Tosetto A, et al. Prolonged overall survival with second
on-demand autologous stem cell transplant in multiple myeloma. Am J Hematol.
2006;81(6):426-431.
33. Facon T, Dimopoulos MA, Dispenzieri A, et al. Initial phase 3 results of the
FIRST (frontline investigation of lenalidomide + dexamethasone versus standard
thalidomide) trial (MM-020/IFM 07 01) in newly diagnosed multiple myeloma
(NDMM) patients (pts) ineligible for stem cell transplantation (SCT). Blood.
2013;122(21):2.
34. San Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan
and prednisone for initial treatment of multiple myeloma. N Engl J Med.
2008;359(9):906-917.
35. Facon T, Mary JY, Hulin C, et al; Intergroupe Français du Myélome. Melphalan
and prednisone plus thalidomide versus melphalan and prednisone
alone or reduced-intensity autologous stem cell transplantation in
elderly patients with multiple myeloma (IFM 99-06): a randomised trial. Lancet.
2007;370(9594):1209-1218.
36. Hulin C, Facon T, Rodon P, et al. Efficacy of melphalan and prednisone plus thalidomide
in patients older than 75 years with newly diagnosed multiple myeloma.
IFM 01/01 trial. J Clin Oncol. 2009;27(22):3664-3670.
37. Attal M, Lauwers-Cances V, Marit G, et al. Lenalidomide maintenance after stemcell
transplantation for multiple myeloma. N Engl J Med. 2012;366(19):1782-1791.
38. Attal M., Harousseau JL, Leyvraz S, et al; Inter-Groupe Francophone du Myélome
(IFM). Maintenance therapy with thalidomide improves survival in patients with
multiple myeloma. Blood. 2006;108(10):3289-3294.
39. Spencer A, Prince HM, Roberts AW, et al. Consolidation therapy with low-dose
thalidomide and prednisolone prolongs the survival of multiple myeloma patients
undergoing a single autologous stem-cell transplantation procedure. J Clin Oncol.
2009;27(11):1788-1793.
40. Sonneveld P, Schmidt-Wolf IG, van der Holt B, et al. Bortezomib induction and
maintenance treatment in patients with newly diagnosed multiple myeloma:
results of the randomized phase III HOVON-65/GMMG-HD4 trial. J Clin Oncol.
2012;30(24):2946-2955.
41. Richardson PG, Sonneveld P, Schuster MW, et al; Assessment of Proteasome
Inhibition for Extending Remissions (APEX) Investigators. Bortezomib
or high-dose dexamethasone for relapsed multiple myeloma. N Engl J Med.
2005;352(24):2487-2498.
42. Orlowski RZ, Nagler A, Sonneveld P, et al. Randomized phase III study of pegylated
liposomal doxorubicin plus bortezomib compared with bortezomib alone
in relapsed or refractory multiple myeloma: combination therapy improves time
to progression. J Clin Oncol. 2007;25(25):3892-3901.
43. Kumar SK, Lee JH, Lahuerta JJ, et al; International Myeloma Working Group.
Risk of progression and survival in multiple myeloma relapsing after therapy
with IMiDs and bortezomib: a multicenter international myeloma working group
study. Leukemia. 2012;26(1):149-157.
44. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus lowdose
dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol.
2009;27(30):5008-5014.
45. Siegel DS, Martin T, Wang M, et al. A phase 2 study of single agent carfilzomib
(PX-171-003-A1) in patients with relapsed and refractory multiple myeloma.
Blood. 2012;120(14):2817-2825.
46. San-Miguel JF, Hungria VT, Yoon SS, et al. Panobinostat plus bortezomib
and dexamethasone versus placebo plus bortezomib and dexamethasone
in patients with relapsed or relapsed and refractory multiple
myeloma: a multicentre, randomised, double-blind phase 3 trial. Lancet Oncol.
2014;15(11):1195-1206.
Lenalidomide maintenance prolongs PFS, OS in MM
Lenalidomide maintenance can be considered a standard of care for multiple myeloma (MM) patients who have undergone hematopoietic stem cell transplant (HSCT), according to researchers.
A meta-analysis of data from 3 trials showed that lenalidomide maintenance extended both progression-free survival (PFS) and overall survival (OS) in these patients.
Philip L. McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York, and his colleagues reported results of the analysis in the Journal of Clinical Oncology.
The researchers analyzed data from 3 large, randomized trials conducted in the US, France, and Italy. The studies included patients with newly diagnosed MM who underwent autologous HSCT and then received continuous lenalidomide (n=605) or no maintenance/placebo (n=603).
Patient demographics and disease-related characteristics were generally balanced between the treatment groups.
The mean duration of maintenance was 28 months (range, 0-108) in the lenalidomide group and 22 months (range, 0-86) in the control group.
Fewer patients in the lenalidomide group (52.6%) started second-line anti-MM therapy than patients in the control group (70.8%). And the time to second-line anti-MM treatment was longer with lenalidomide than with control (hazard ratio [HR]=0.57; 95% CI, 0.49 to 0.66).
PFS and OS
Patients who received lenalidomide maintenance had significantly longer PFS and OS than patients in the control group.
The median PFS was 52.8 months and 23.5 months, respectively (HR=0.48; 95% CI, 0.41 to 0.55).
The median OS was not reached in the lenalidomide group and was 86.0 months in the control group (HR=0.75; 95% CI, 0.63 to 0.90; P=0.001),
At a median follow-up of 79.5 months, the OS rate was 64% in the lenalidomide group and 54% in the control group. The 7-year OS rates were 62% and 50%, respectively.
Safety
Safety data were not available for the Italian study. In the other 2 studies, 29.1% of patients in the lenalidomide group had treatment-emergent adverse events that led to discontinuation, as did 12.2% of patients in the control group.
Treatment-emergent adverse events leading to treatment discontinuation (in the lenalidomide and control groups, respectively) included neutropenia (2.3% vs 0.2%), thrombocytopenia (1.7% vs 1.1%), general disorders and administration site conditions (4.7% vs 1.5%), neoplasms (4.3% vs 1.0%), skin and subcutaneous tissue disorders (3.4% vs 1.9%), nervous system disorders (3.4% vs 1.7%), gastrointestinal disorders (3.4% vs 0.2%), infections and infestations (1.7% vs 0.8%), and musculoskeletal and connective tissue disorders (1.1% and 1.3%).
There was a higher frequency of second primary malignancies (SPMs) in the lenalidomide group than in the control group.
The incidence of hematologic SPMs occurring before disease progression was 5.3% and 0.8%, respectively. The incidence before and after progression was 6.1% and 2.8%, respectively.
The incidence of solid tumor SPMs occurring before disease progression was 5.8% and 2.0%, respectively. The incidence before and after progression was 7.3% and 4.2%, respectively.
“With this complete and mature data from 3 large, multinational studies, we now have clear evidence that ongoing treatment with lenalidomide can prevent disease progression and extend survival in patients with multiple myeloma who’ve received a stem cell transplant,” Dr McCarthy said.
“All the investigators wish to express enormous gratitude to the patients who took part in these trials. Many others will benefit from their role in this research.” 
Lenalidomide maintenance can be considered a standard of care for multiple myeloma (MM) patients who have undergone hematopoietic stem cell transplant (HSCT), according to researchers.
A meta-analysis of data from 3 trials showed that lenalidomide maintenance extended both progression-free survival (PFS) and overall survival (OS) in these patients.
Philip L. McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York, and his colleagues reported results of the analysis in the Journal of Clinical Oncology.
The researchers analyzed data from 3 large, randomized trials conducted in the US, France, and Italy. The studies included patients with newly diagnosed MM who underwent autologous HSCT and then received continuous lenalidomide (n=605) or no maintenance/placebo (n=603).
Patient demographics and disease-related characteristics were generally balanced between the treatment groups.
The mean duration of maintenance was 28 months (range, 0-108) in the lenalidomide group and 22 months (range, 0-86) in the control group.
Fewer patients in the lenalidomide group (52.6%) started second-line anti-MM therapy than patients in the control group (70.8%). And the time to second-line anti-MM treatment was longer with lenalidomide than with control (hazard ratio [HR]=0.57; 95% CI, 0.49 to 0.66).
PFS and OS
Patients who received lenalidomide maintenance had significantly longer PFS and OS than patients in the control group.
The median PFS was 52.8 months and 23.5 months, respectively (HR=0.48; 95% CI, 0.41 to 0.55).
The median OS was not reached in the lenalidomide group and was 86.0 months in the control group (HR=0.75; 95% CI, 0.63 to 0.90; P=0.001),
At a median follow-up of 79.5 months, the OS rate was 64% in the lenalidomide group and 54% in the control group. The 7-year OS rates were 62% and 50%, respectively.
Safety
Safety data were not available for the Italian study. In the other 2 studies, 29.1% of patients in the lenalidomide group had treatment-emergent adverse events that led to discontinuation, as did 12.2% of patients in the control group.
Treatment-emergent adverse events leading to treatment discontinuation (in the lenalidomide and control groups, respectively) included neutropenia (2.3% vs 0.2%), thrombocytopenia (1.7% vs 1.1%), general disorders and administration site conditions (4.7% vs 1.5%), neoplasms (4.3% vs 1.0%), skin and subcutaneous tissue disorders (3.4% vs 1.9%), nervous system disorders (3.4% vs 1.7%), gastrointestinal disorders (3.4% vs 0.2%), infections and infestations (1.7% vs 0.8%), and musculoskeletal and connective tissue disorders (1.1% and 1.3%).
There was a higher frequency of second primary malignancies (SPMs) in the lenalidomide group than in the control group.
The incidence of hematologic SPMs occurring before disease progression was 5.3% and 0.8%, respectively. The incidence before and after progression was 6.1% and 2.8%, respectively.
The incidence of solid tumor SPMs occurring before disease progression was 5.8% and 2.0%, respectively. The incidence before and after progression was 7.3% and 4.2%, respectively.
“With this complete and mature data from 3 large, multinational studies, we now have clear evidence that ongoing treatment with lenalidomide can prevent disease progression and extend survival in patients with multiple myeloma who’ve received a stem cell transplant,” Dr McCarthy said.
“All the investigators wish to express enormous gratitude to the patients who took part in these trials. Many others will benefit from their role in this research.”
Lenalidomide maintenance can be considered a standard of care for multiple myeloma (MM) patients who have undergone hematopoietic stem cell transplant (HSCT), according to researchers.
A meta-analysis of data from 3 trials showed that lenalidomide maintenance extended both progression-free survival (PFS) and overall survival (OS) in these patients.
Philip L. McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, New York, and his colleagues reported results of the analysis in the Journal of Clinical Oncology.
The researchers analyzed data from 3 large, randomized trials conducted in the US, France, and Italy. The studies included patients with newly diagnosed MM who underwent autologous HSCT and then received continuous lenalidomide (n=605) or no maintenance/placebo (n=603).
Patient demographics and disease-related characteristics were generally balanced between the treatment groups.
The mean duration of maintenance was 28 months (range, 0-108) in the lenalidomide group and 22 months (range, 0-86) in the control group.
Fewer patients in the lenalidomide group (52.6%) started second-line anti-MM therapy than patients in the control group (70.8%). And the time to second-line anti-MM treatment was longer with lenalidomide than with control (hazard ratio [HR]=0.57; 95% CI, 0.49 to 0.66).
PFS and OS
Patients who received lenalidomide maintenance had significantly longer PFS and OS than patients in the control group.
The median PFS was 52.8 months and 23.5 months, respectively (HR=0.48; 95% CI, 0.41 to 0.55).
The median OS was not reached in the lenalidomide group and was 86.0 months in the control group (HR=0.75; 95% CI, 0.63 to 0.90; P=0.001),
At a median follow-up of 79.5 months, the OS rate was 64% in the lenalidomide group and 54% in the control group. The 7-year OS rates were 62% and 50%, respectively.
Safety
Safety data were not available for the Italian study. In the other 2 studies, 29.1% of patients in the lenalidomide group had treatment-emergent adverse events that led to discontinuation, as did 12.2% of patients in the control group.
Treatment-emergent adverse events leading to treatment discontinuation (in the lenalidomide and control groups, respectively) included neutropenia (2.3% vs 0.2%), thrombocytopenia (1.7% vs 1.1%), general disorders and administration site conditions (4.7% vs 1.5%), neoplasms (4.3% vs 1.0%), skin and subcutaneous tissue disorders (3.4% vs 1.9%), nervous system disorders (3.4% vs 1.7%), gastrointestinal disorders (3.4% vs 0.2%), infections and infestations (1.7% vs 0.8%), and musculoskeletal and connective tissue disorders (1.1% and 1.3%).
There was a higher frequency of second primary malignancies (SPMs) in the lenalidomide group than in the control group.
The incidence of hematologic SPMs occurring before disease progression was 5.3% and 0.8%, respectively. The incidence before and after progression was 6.1% and 2.8%, respectively.
The incidence of solid tumor SPMs occurring before disease progression was 5.8% and 2.0%, respectively. The incidence before and after progression was 7.3% and 4.2%, respectively.
“With this complete and mature data from 3 large, multinational studies, we now have clear evidence that ongoing treatment with lenalidomide can prevent disease progression and extend survival in patients with multiple myeloma who’ve received a stem cell transplant,” Dr McCarthy said.
“All the investigators wish to express enormous gratitude to the patients who took part in these trials. Many others will benefit from their role in this research.”
Post-approval trials for accelerated drugs fall short
New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.
Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.
“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“But we found that there were few differences in these key design features of the trials conducted before or after approval.”
Dr Kesselheim and his colleagues reported these findings in JAMA.
The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.
During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).
Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.
The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.
Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.
For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.
Study comparison
Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.
There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).
However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.
The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.
There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.
The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.
“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.
To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.
He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.
New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.
Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.
“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“But we found that there were few differences in these key design features of the trials conducted before or after approval.”
Dr Kesselheim and his colleagues reported these findings in JAMA.
The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.
During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).
Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.
The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.
Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.
For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.
Study comparison
Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.
There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).
However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.
The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.
There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.
The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.
“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.
To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.
He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.
New research has revealed shortcomings of post-approval studies for drugs granted accelerated approval in the US.
Researchers found that, for drugs granted accelerated approval from 2009 to 2013, both pre-approval and post-approval trials had limitations in their design and the endpoints used.
“One might expect accelerated approval confirmatory trials to be much more rigorous than the pre-approval trials,” said study author Aaron S. Kesselheim, MD, of Brigham and Women’s Hospital in Boston, Massachusetts.
“But we found that there were few differences in these key design features of the trials conducted before or after approval.”
Dr Kesselheim and his colleagues reported these findings in JAMA.
The researchers examined pre- and post-approval clinical trials of drugs granted accelerated approval by the US Food and Drug Administration (FDA) between 2009 and 2013.
During that time, the FDA granted 22 drugs accelerated approval for 24 indications (15 of them for hematologic disorders).
Fourteen of the indications were approved on the basis of single-intervention-group studies that enrolled a median of 132 patients.
The FDA ordered 38 post-approval studies to confirm the safety and efficacy of the drugs.
Three years after the last drug’s approval, half of those studies (n=19) were not complete. Eight (42%) of the incomplete studies were either terminated or delayed by more than 1 year.
For 14 of the 24 indications (58%), results from the post-approval studies were not available after a median of 5 years of follow-up.
Study comparison
Published reports were available for 18 of the 19 completed post-approval studies. The characteristics of these studies did not differ much from the 30 pre-approval studies.
There were no statistically significant differences with regard to median patient enrollment (P=0.17), the use of randomized (P=0.31) or double-blind trials (P=0.17), the use of placebo as a comparator (P=0.17), or the lack of a comparator (P=0.21).
However, there was a significant difference in the use of an active comparator (P=0.02), with more post-approval studies using an active comparator.
The researchers also found that 17 of the 18 post-approval trials still used surrogate measures of effect as primary endpoints.
There was no significant difference between pre- and post-approval trials when it came to the use of disease response (P=0.17) or most other surrogate measures (P=0.21) as the trials’ primary endpoint.
The same was true for overall survival (P=0.20), although significantly more post-approval studies used progression-free survival (P=0.001) as a primary endpoint.
“It is important to use clinical endpoints in testing investigational drugs whenever possible because there are numerous cases of drugs approved on the basis of a surrogate measure that turn out to later not effect actual clinical outcomes—or even make them worse,” Dr Kesselheim said.
To address these issues and improve the quality of confirmatory studies, Dr Kesselheim suggested the FDA clearly describe the limitations in the pre-approval data that will need to be addressed in post-approval studies.
He also suggested the agency work with manufacturers to ensure that post-approval studies are conducted using design features that will be optimally useful for confirming the efficacy of the drug.
Vitamin D level linked to post-alloSCT relapse risk in myeloma
Patients with myeloid malignancies who have vitamin D deficiency prior to an allogeneic stem cell transplant (alloSCT) are significantly more likely to experience a relapse and have worse overall survival after transplant than patients with adequate vitamin D levels at baseline, investigators have found.
Among 492 patients with lymphoid or myeloid malignancies who had an alloSCT at a single center, those with vitamin D deficiency had a risk of post-transplant relapse that was nearly double the risk of patients with sufficient vitamin D levels. Also, this relapse risk contributed to significantly worse overall survival for the vitamin D–deficient patients, reported Thomas Luft, MD, PhD, and his colleagues from the University of Heidelberg, Germany.
In multivariate analysis, the risk for relapse was limited to patients with myeloid rather than lymphatic disease, they reported in the Journal of Clinical Oncology.
“[O]ur study suggests that VitD deficiency might affect disease control after alloSCT, in particular, in patients allografted for myeloid malignancies. However, the question of whether improving VitD status before alloSCT has an impact on outcome can only be answered by clinical trial,” they wrote.
To see whether pre-transplant vitamin D deficiency – serum levels of 25-hydroxyvitamin D3 less than 20 ng/mL – might have prognostic significance, the investigators looked at a training cohort of 492 patients who underwent alloSCT at their center from 2002 through 2013, and a validation cohort consisting of 398 additional patients with myeloid malignancies treated at the University of Essen, Germany.
Overall survival for the 396 patients (80%) in the training cohort with vitamin D deficiency was significantly worse than for patients with adequate levels (hazard ratio, 1.78; P = .007) in a multivariate analysis adjusted for type of malignancy, disease stage, conditioning intensity, patient age, donor type, and recipient/donor sex match.
Analysis also showed that the excess hazard was accounted for by higher risk of relapse than nonrelapse mortality (HR, 1.96; P = .006).
When the investigators looked at relapse risk by disease type, they found a significantly higher risk among vitamin D–deficient patients with myeloid malignancies (HR, 2.55; P = .014) but not with lymphoid malignancies.
The risk for relapse among patients with myeloid malignancies in the validation cohort was similarly high (HR, 2.60; P = .017).
“The growth inhibitory, pro-differentiation, and pro-apoptotic effects of VitD in vitro are well recognized, and low VitD levels have been shown to enhance clonal proliferation of leukemic cells. Therefore, with regard to treatment before alloSCT but also to conditioning, one might speculate that VitD deficiency facilitates resistance to chemotherapy,” the researchers wrote.
Low vitamin D levels have been associated in other studies with shorter relapse-free and overall survival in patients with acute myeloid leukemia apart from alloSCT.
The researchers recommend clinical trials to explore the possibility that vitamin D supplementation pre-transplant could improve post-transplant outcomes.
The study was supported by a grant from the BLUT Foundation and the European Union’s Seventh Framework Program. Dr. Luft disclosed consulting with Alexion and Jazz Pharmaceuticals, and institutional research funding and travel support from Medac, Neovii, and Jazz.
Patients with myeloid malignancies who have vitamin D deficiency prior to an allogeneic stem cell transplant (alloSCT) are significantly more likely to experience a relapse and have worse overall survival after transplant than patients with adequate vitamin D levels at baseline, investigators have found.
Among 492 patients with lymphoid or myeloid malignancies who had an alloSCT at a single center, those with vitamin D deficiency had a risk of post-transplant relapse that was nearly double the risk of patients with sufficient vitamin D levels. Also, this relapse risk contributed to significantly worse overall survival for the vitamin D–deficient patients, reported Thomas Luft, MD, PhD, and his colleagues from the University of Heidelberg, Germany.
In multivariate analysis, the risk for relapse was limited to patients with myeloid rather than lymphatic disease, they reported in the Journal of Clinical Oncology.
“[O]ur study suggests that VitD deficiency might affect disease control after alloSCT, in particular, in patients allografted for myeloid malignancies. However, the question of whether improving VitD status before alloSCT has an impact on outcome can only be answered by clinical trial,” they wrote.
To see whether pre-transplant vitamin D deficiency – serum levels of 25-hydroxyvitamin D3 less than 20 ng/mL – might have prognostic significance, the investigators looked at a training cohort of 492 patients who underwent alloSCT at their center from 2002 through 2013, and a validation cohort consisting of 398 additional patients with myeloid malignancies treated at the University of Essen, Germany.
Overall survival for the 396 patients (80%) in the training cohort with vitamin D deficiency was significantly worse than for patients with adequate levels (hazard ratio, 1.78; P = .007) in a multivariate analysis adjusted for type of malignancy, disease stage, conditioning intensity, patient age, donor type, and recipient/donor sex match.
Analysis also showed that the excess hazard was accounted for by higher risk of relapse than nonrelapse mortality (HR, 1.96; P = .006).
When the investigators looked at relapse risk by disease type, they found a significantly higher risk among vitamin D–deficient patients with myeloid malignancies (HR, 2.55; P = .014) but not with lymphoid malignancies.
The risk for relapse among patients with myeloid malignancies in the validation cohort was similarly high (HR, 2.60; P = .017).
“The growth inhibitory, pro-differentiation, and pro-apoptotic effects of VitD in vitro are well recognized, and low VitD levels have been shown to enhance clonal proliferation of leukemic cells. Therefore, with regard to treatment before alloSCT but also to conditioning, one might speculate that VitD deficiency facilitates resistance to chemotherapy,” the researchers wrote.
Low vitamin D levels have been associated in other studies with shorter relapse-free and overall survival in patients with acute myeloid leukemia apart from alloSCT.
The researchers recommend clinical trials to explore the possibility that vitamin D supplementation pre-transplant could improve post-transplant outcomes.
The study was supported by a grant from the BLUT Foundation and the European Union’s Seventh Framework Program. Dr. Luft disclosed consulting with Alexion and Jazz Pharmaceuticals, and institutional research funding and travel support from Medac, Neovii, and Jazz.
Patients with myeloid malignancies who have vitamin D deficiency prior to an allogeneic stem cell transplant (alloSCT) are significantly more likely to experience a relapse and have worse overall survival after transplant than patients with adequate vitamin D levels at baseline, investigators have found.
Among 492 patients with lymphoid or myeloid malignancies who had an alloSCT at a single center, those with vitamin D deficiency had a risk of post-transplant relapse that was nearly double the risk of patients with sufficient vitamin D levels. Also, this relapse risk contributed to significantly worse overall survival for the vitamin D–deficient patients, reported Thomas Luft, MD, PhD, and his colleagues from the University of Heidelberg, Germany.
In multivariate analysis, the risk for relapse was limited to patients with myeloid rather than lymphatic disease, they reported in the Journal of Clinical Oncology.
“[O]ur study suggests that VitD deficiency might affect disease control after alloSCT, in particular, in patients allografted for myeloid malignancies. However, the question of whether improving VitD status before alloSCT has an impact on outcome can only be answered by clinical trial,” they wrote.
To see whether pre-transplant vitamin D deficiency – serum levels of 25-hydroxyvitamin D3 less than 20 ng/mL – might have prognostic significance, the investigators looked at a training cohort of 492 patients who underwent alloSCT at their center from 2002 through 2013, and a validation cohort consisting of 398 additional patients with myeloid malignancies treated at the University of Essen, Germany.
Overall survival for the 396 patients (80%) in the training cohort with vitamin D deficiency was significantly worse than for patients with adequate levels (hazard ratio, 1.78; P = .007) in a multivariate analysis adjusted for type of malignancy, disease stage, conditioning intensity, patient age, donor type, and recipient/donor sex match.
Analysis also showed that the excess hazard was accounted for by higher risk of relapse than nonrelapse mortality (HR, 1.96; P = .006).
When the investigators looked at relapse risk by disease type, they found a significantly higher risk among vitamin D–deficient patients with myeloid malignancies (HR, 2.55; P = .014) but not with lymphoid malignancies.
The risk for relapse among patients with myeloid malignancies in the validation cohort was similarly high (HR, 2.60; P = .017).
“The growth inhibitory, pro-differentiation, and pro-apoptotic effects of VitD in vitro are well recognized, and low VitD levels have been shown to enhance clonal proliferation of leukemic cells. Therefore, with regard to treatment before alloSCT but also to conditioning, one might speculate that VitD deficiency facilitates resistance to chemotherapy,” the researchers wrote.
Low vitamin D levels have been associated in other studies with shorter relapse-free and overall survival in patients with acute myeloid leukemia apart from alloSCT.
The researchers recommend clinical trials to explore the possibility that vitamin D supplementation pre-transplant could improve post-transplant outcomes.
The study was supported by a grant from the BLUT Foundation and the European Union’s Seventh Framework Program. Dr. Luft disclosed consulting with Alexion and Jazz Pharmaceuticals, and institutional research funding and travel support from Medac, Neovii, and Jazz.
FROM JCO
Key clinical point: Vitamin D deficiency pre–allogenic stem cell transplant was associated with greater risk of relapse and lower survival for patients with myeloid malignancies.
Major finding: The hazard for relapse among patients with myeloid malignancies and low pre-transplant vitamin D was 2.55 (P = .014), compared with patients with adequate vitamin D.
Data source: Retrospective cohort study of 492 patients with myeloid or lymphoid malignancies, and a validation cohort of 398 patients.
Disclosures: The study was supported by a grant from the BLUT Foundation and the European Union’s Seventh Framework Program. Dr. Luft disclosed consulting with Alexion and Jazz Pharmaceuticals, and institutional research funding and travel support from Medac, Neovii, and Jazz.
Lenalidomide maintenance boosts survival in de novo myeloma after ASCT
Patients with newly diagnosed multiple myeloma who received lenalidomide as maintenance therapy following an autologous stem cell transplant (ASCT) had significantly better progression-free and overall survival, compared with patients who received placebo or observation after transplant, results of a meta-analysis showed.
Among 1,208 patients in an intention-to-treat analysis, the median progression-free survival (PFS) for patients who received lenalidomide maintenance was nearly double that of patients treated with placebo or observation alone after ASCT, and the median overall survival for patients on maintenance had not been reached after a median follow-up of 79.5 months, reported Phillip J McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, N.Y., and his colleagues.
“This study demonstrates a statistically significant and clinically meaningful improvement in OS with lenalidomide maintenance. With new, highly active, triplet induction regimens enhancing depth and duration of response, as well as ongoing studies evaluating the optimal timing of ASCT, the use of lenalidomide maintenance for transplantation-eligible patients can be considered a standard of care,” they wrote in the Journal of Clinical Oncology.
The authors drew on data from three randomized controlled trials in which patients with newly diagnosed multiple myeloma underwent ASCT followed by lenalidomide maintenance, placebo, or observation. The trials were the Cancer and Leukemia Group B (CALGB) 100104, Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) RV-MM-PI-209, and Intergroupe Francophone du Myelome (IFM) 2005-02.
Because all three studies had PFS as the primary endpoint and were not powered to detect an overall survival (OS) benefit, the investigators conducted a meta-analysis to get a better sense of the effect of maintenance on both PFS and OS.
The meta-analysis included 605 patients randomized to lenalidomide maintenance and 603 to placebo or observation.
The median PFS was 52.8 months with lenalidomide, vs. 23.5 months for placebo or observation (hazard ratio [HR] 0.48; 95% confidence interval, 0.41-0.55).
After a median follow-up of 79.5 months for all survivors, the median OS for patients on lenalidomide was not reached, compared with 86.0 months for placebo/observation (HR, 0.75, P = .001).
An analysis of safety data from the CALGB and IFM studies (GIMEMA data were not available) showed that second primary malignancies occurring before disease progression were more frequent in the lenalidomide maintenance group, at 5.3%, compared with 0.8%. In contrast, the cumulative incidence rates of progression, death, or myeloma-specific death were all higher with placebo or observation versus lenalidomide maintenance, the investigators found.
Although lenalidomide maintenance adds to the cost of care, the “costs of maintenance therapy should be weighed against the costs of shorter survival, earlier progression, and earlier use of subsequent lines of therapies for patients without maintenance,” the researchers wrote.
The study was supported by Celgene. Dr. McCarthy and multiple coauthors reported consulting/advisory roles, honoraria, travel support, and/or research support from the company.
Patients with newly diagnosed multiple myeloma who received lenalidomide as maintenance therapy following an autologous stem cell transplant (ASCT) had significantly better progression-free and overall survival, compared with patients who received placebo or observation after transplant, results of a meta-analysis showed.
Among 1,208 patients in an intention-to-treat analysis, the median progression-free survival (PFS) for patients who received lenalidomide maintenance was nearly double that of patients treated with placebo or observation alone after ASCT, and the median overall survival for patients on maintenance had not been reached after a median follow-up of 79.5 months, reported Phillip J McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, N.Y., and his colleagues.
“This study demonstrates a statistically significant and clinically meaningful improvement in OS with lenalidomide maintenance. With new, highly active, triplet induction regimens enhancing depth and duration of response, as well as ongoing studies evaluating the optimal timing of ASCT, the use of lenalidomide maintenance for transplantation-eligible patients can be considered a standard of care,” they wrote in the Journal of Clinical Oncology.
The authors drew on data from three randomized controlled trials in which patients with newly diagnosed multiple myeloma underwent ASCT followed by lenalidomide maintenance, placebo, or observation. The trials were the Cancer and Leukemia Group B (CALGB) 100104, Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) RV-MM-PI-209, and Intergroupe Francophone du Myelome (IFM) 2005-02.
Because all three studies had PFS as the primary endpoint and were not powered to detect an overall survival (OS) benefit, the investigators conducted a meta-analysis to get a better sense of the effect of maintenance on both PFS and OS.
The meta-analysis included 605 patients randomized to lenalidomide maintenance and 603 to placebo or observation.
The median PFS was 52.8 months with lenalidomide, vs. 23.5 months for placebo or observation (hazard ratio [HR] 0.48; 95% confidence interval, 0.41-0.55).
After a median follow-up of 79.5 months for all survivors, the median OS for patients on lenalidomide was not reached, compared with 86.0 months for placebo/observation (HR, 0.75, P = .001).
An analysis of safety data from the CALGB and IFM studies (GIMEMA data were not available) showed that second primary malignancies occurring before disease progression were more frequent in the lenalidomide maintenance group, at 5.3%, compared with 0.8%. In contrast, the cumulative incidence rates of progression, death, or myeloma-specific death were all higher with placebo or observation versus lenalidomide maintenance, the investigators found.
Although lenalidomide maintenance adds to the cost of care, the “costs of maintenance therapy should be weighed against the costs of shorter survival, earlier progression, and earlier use of subsequent lines of therapies for patients without maintenance,” the researchers wrote.
The study was supported by Celgene. Dr. McCarthy and multiple coauthors reported consulting/advisory roles, honoraria, travel support, and/or research support from the company.
Patients with newly diagnosed multiple myeloma who received lenalidomide as maintenance therapy following an autologous stem cell transplant (ASCT) had significantly better progression-free and overall survival, compared with patients who received placebo or observation after transplant, results of a meta-analysis showed.
Among 1,208 patients in an intention-to-treat analysis, the median progression-free survival (PFS) for patients who received lenalidomide maintenance was nearly double that of patients treated with placebo or observation alone after ASCT, and the median overall survival for patients on maintenance had not been reached after a median follow-up of 79.5 months, reported Phillip J McCarthy, MD, of Roswell Park Cancer Institute in Buffalo, N.Y., and his colleagues.
“This study demonstrates a statistically significant and clinically meaningful improvement in OS with lenalidomide maintenance. With new, highly active, triplet induction regimens enhancing depth and duration of response, as well as ongoing studies evaluating the optimal timing of ASCT, the use of lenalidomide maintenance for transplantation-eligible patients can be considered a standard of care,” they wrote in the Journal of Clinical Oncology.
The authors drew on data from three randomized controlled trials in which patients with newly diagnosed multiple myeloma underwent ASCT followed by lenalidomide maintenance, placebo, or observation. The trials were the Cancer and Leukemia Group B (CALGB) 100104, Gruppo Italiano Malattie Ematologiche dell’Adulto (GIMEMA) RV-MM-PI-209, and Intergroupe Francophone du Myelome (IFM) 2005-02.
Because all three studies had PFS as the primary endpoint and were not powered to detect an overall survival (OS) benefit, the investigators conducted a meta-analysis to get a better sense of the effect of maintenance on both PFS and OS.
The meta-analysis included 605 patients randomized to lenalidomide maintenance and 603 to placebo or observation.
The median PFS was 52.8 months with lenalidomide, vs. 23.5 months for placebo or observation (hazard ratio [HR] 0.48; 95% confidence interval, 0.41-0.55).
After a median follow-up of 79.5 months for all survivors, the median OS for patients on lenalidomide was not reached, compared with 86.0 months for placebo/observation (HR, 0.75, P = .001).
An analysis of safety data from the CALGB and IFM studies (GIMEMA data were not available) showed that second primary malignancies occurring before disease progression were more frequent in the lenalidomide maintenance group, at 5.3%, compared with 0.8%. In contrast, the cumulative incidence rates of progression, death, or myeloma-specific death were all higher with placebo or observation versus lenalidomide maintenance, the investigators found.
Although lenalidomide maintenance adds to the cost of care, the “costs of maintenance therapy should be weighed against the costs of shorter survival, earlier progression, and earlier use of subsequent lines of therapies for patients without maintenance,” the researchers wrote.
The study was supported by Celgene. Dr. McCarthy and multiple coauthors reported consulting/advisory roles, honoraria, travel support, and/or research support from the company.
FROM JCO
Key clinical point: Lenalidomide maintenance after stem cell transplant in patients with newly diagnosed multiple myeloma is associated with better progression-free and overall survival.
Major finding: Median overall survival was not reached with lenalidomide after a median 79.5 months’ follow-up, vs. 86 months for placebo/observation.
Data source: A meta-analysis of data from three randomized controlled trials, with a total of 1,208 patients with newly diagnosed multiple myeloma.
Disclosures: The study was supported by Celgene. Dr. McCarthy and multiple coauthors reported consulting/advisory roles, honoraria, travel support, and/or research support from the company.
Cancer patients perceive their abilities differently than caregivers do
New research suggests older cancer patients and their caregivers often differ in their assessment of the patients’ abilities.
In this study, patients generally rated their physical and mental function higher than caregivers did.
The study also showed the differences in assessment of patients’ physical abilities were associated with greater caregiver burden.
This research was published in The Oncologist.
“Caregivers are such an important part of our healthcare system, particularly for older adults with cancer,” said study author Arti Hurria, MD, of City of Hope National Medical Center in Duarte, California.
“We wanted to further understand the factors that are associated with caregiver burden.”
One factor Dr Hurria and her colleagues thought might be important is differences in assessments of patient health and physical abilities between patients and their caregivers.
“In daily practice, we sometimes see a disconnect between what the patient perceives their general health and abilities to be in comparison to what the caregiver thinks,” Dr Hurria said. “We wanted to see whether this disconnect impacted caregiver burden.”
To do this, Dr Hurria and her colleagues questioned 100 older cancer patients and their caregivers.
Subjects were asked about the patients’ general health and physical function, meaning their ability to perform everyday activities. The researchers then compared the answers given by the patients and their respective caregivers.
The researchers also assessed the level of caregiver burden (defined as a subjective feeling of stress caused by being overwhelmed by the demands of caring) by administering a standard questionnaire on topics such as sleep disturbance, physical effort, and patient behavior.
The 100 cancer patients, ages 65 to 91, were suffering from a variety of cancers. The most common were lymphoma (n=26), breast cancer (n=19), and gastrointestinal cancers (n=15). Twelve patients had leukemia, and 10 had myeloma.
The ages of the caregivers ranged from 28 to 85, and the majority were female (73%). They were mainly either the spouse of the patient (68%) or an adult child (18%).
Results
There was no significant difference in patient and caregiver accounts of the patients’ comorbidities (P=0.68), falls in the last 6 months (P=0.71), or percent weight change in the last 6 months (P=0.21).
However, caregivers consistently rated patients as having poorer physical function and mental health and requiring more social support than the patients themselves did.
There was a significant difference (P<0.05) in caregiver and patient accounts when it came to the following measures:
- Need for help with instrumental activities of daily living
- Karnofsky Performance Status
- Medical Outcomes Study-Physical Function
- Medical Outcomes Study-Social Support Survey
- Mental Health Inventory.
Only the disparity in the assessment of physical function was significantly associated with greater caregiver burden (P<0.001). What is still unclear is the cause of this disparity.
“I think there are 2 possible explanations,” said study author Tina Hsu, MD, of the University of Ottawa in Ontario, Canada.
“One is that older adults with cancer either don’t appreciate how much help they require or, more likely, they are able preserve their sense of independence and dignity through a perception that they feel they can do more than they really can.”
“Alternatively, it is possible that caregivers who are more stressed out perceive their loved one to require more help than they actually do need. Most likely, the truth of how much help the patient actually needs lies somewhere between what patients and caregivers report.”
Based on their findings, Drs Hsu and Hurria and their colleagues advise that clinicians consider assessing caregiver burden in those caregivers who report the patient as being more dependent than the patient does themselves.
“Caregivers play an essential role in supporting older adults with cancer,” Dr Hsu said. “We plan to further explore factors associated with caregiver burden in this population, particularly in those who are frailer and thus require even more hands-on support. We also hope to explore what resources caregivers of older adults with cancer feel they need to better help them with their role.”
New research suggests older cancer patients and their caregivers often differ in their assessment of the patients’ abilities.
In this study, patients generally rated their physical and mental function higher than caregivers did.
The study also showed the differences in assessment of patients’ physical abilities were associated with greater caregiver burden.
This research was published in The Oncologist.
“Caregivers are such an important part of our healthcare system, particularly for older adults with cancer,” said study author Arti Hurria, MD, of City of Hope National Medical Center in Duarte, California.
“We wanted to further understand the factors that are associated with caregiver burden.”
One factor Dr Hurria and her colleagues thought might be important is differences in assessments of patient health and physical abilities between patients and their caregivers.
“In daily practice, we sometimes see a disconnect between what the patient perceives their general health and abilities to be in comparison to what the caregiver thinks,” Dr Hurria said. “We wanted to see whether this disconnect impacted caregiver burden.”
To do this, Dr Hurria and her colleagues questioned 100 older cancer patients and their caregivers.
Subjects were asked about the patients’ general health and physical function, meaning their ability to perform everyday activities. The researchers then compared the answers given by the patients and their respective caregivers.
The researchers also assessed the level of caregiver burden (defined as a subjective feeling of stress caused by being overwhelmed by the demands of caring) by administering a standard questionnaire on topics such as sleep disturbance, physical effort, and patient behavior.
The 100 cancer patients, ages 65 to 91, were suffering from a variety of cancers. The most common were lymphoma (n=26), breast cancer (n=19), and gastrointestinal cancers (n=15). Twelve patients had leukemia, and 10 had myeloma.
The ages of the caregivers ranged from 28 to 85, and the majority were female (73%). They were mainly either the spouse of the patient (68%) or an adult child (18%).
Results
There was no significant difference in patient and caregiver accounts of the patients’ comorbidities (P=0.68), falls in the last 6 months (P=0.71), or percent weight change in the last 6 months (P=0.21).
However, caregivers consistently rated patients as having poorer physical function and mental health and requiring more social support than the patients themselves did.
There was a significant difference (P<0.05) in caregiver and patient accounts when it came to the following measures:
- Need for help with instrumental activities of daily living
- Karnofsky Performance Status
- Medical Outcomes Study-Physical Function
- Medical Outcomes Study-Social Support Survey
- Mental Health Inventory.
Only the disparity in the assessment of physical function was significantly associated with greater caregiver burden (P<0.001). What is still unclear is the cause of this disparity.
“I think there are 2 possible explanations,” said study author Tina Hsu, MD, of the University of Ottawa in Ontario, Canada.
“One is that older adults with cancer either don’t appreciate how much help they require or, more likely, they are able preserve their sense of independence and dignity through a perception that they feel they can do more than they really can.”
“Alternatively, it is possible that caregivers who are more stressed out perceive their loved one to require more help than they actually do need. Most likely, the truth of how much help the patient actually needs lies somewhere between what patients and caregivers report.”
Based on their findings, Drs Hsu and Hurria and their colleagues advise that clinicians consider assessing caregiver burden in those caregivers who report the patient as being more dependent than the patient does themselves.
“Caregivers play an essential role in supporting older adults with cancer,” Dr Hsu said. “We plan to further explore factors associated with caregiver burden in this population, particularly in those who are frailer and thus require even more hands-on support. We also hope to explore what resources caregivers of older adults with cancer feel they need to better help them with their role.”
New research suggests older cancer patients and their caregivers often differ in their assessment of the patients’ abilities.
In this study, patients generally rated their physical and mental function higher than caregivers did.
The study also showed the differences in assessment of patients’ physical abilities were associated with greater caregiver burden.
This research was published in The Oncologist.
“Caregivers are such an important part of our healthcare system, particularly for older adults with cancer,” said study author Arti Hurria, MD, of City of Hope National Medical Center in Duarte, California.
“We wanted to further understand the factors that are associated with caregiver burden.”
One factor Dr Hurria and her colleagues thought might be important is differences in assessments of patient health and physical abilities between patients and their caregivers.
“In daily practice, we sometimes see a disconnect between what the patient perceives their general health and abilities to be in comparison to what the caregiver thinks,” Dr Hurria said. “We wanted to see whether this disconnect impacted caregiver burden.”
To do this, Dr Hurria and her colleagues questioned 100 older cancer patients and their caregivers.
Subjects were asked about the patients’ general health and physical function, meaning their ability to perform everyday activities. The researchers then compared the answers given by the patients and their respective caregivers.
The researchers also assessed the level of caregiver burden (defined as a subjective feeling of stress caused by being overwhelmed by the demands of caring) by administering a standard questionnaire on topics such as sleep disturbance, physical effort, and patient behavior.
The 100 cancer patients, ages 65 to 91, were suffering from a variety of cancers. The most common were lymphoma (n=26), breast cancer (n=19), and gastrointestinal cancers (n=15). Twelve patients had leukemia, and 10 had myeloma.
The ages of the caregivers ranged from 28 to 85, and the majority were female (73%). They were mainly either the spouse of the patient (68%) or an adult child (18%).
Results
There was no significant difference in patient and caregiver accounts of the patients’ comorbidities (P=0.68), falls in the last 6 months (P=0.71), or percent weight change in the last 6 months (P=0.21).
However, caregivers consistently rated patients as having poorer physical function and mental health and requiring more social support than the patients themselves did.
There was a significant difference (P<0.05) in caregiver and patient accounts when it came to the following measures:
- Need for help with instrumental activities of daily living
- Karnofsky Performance Status
- Medical Outcomes Study-Physical Function
- Medical Outcomes Study-Social Support Survey
- Mental Health Inventory.
Only the disparity in the assessment of physical function was significantly associated with greater caregiver burden (P<0.001). What is still unclear is the cause of this disparity.
“I think there are 2 possible explanations,” said study author Tina Hsu, MD, of the University of Ottawa in Ontario, Canada.
“One is that older adults with cancer either don’t appreciate how much help they require or, more likely, they are able preserve their sense of independence and dignity through a perception that they feel they can do more than they really can.”
“Alternatively, it is possible that caregivers who are more stressed out perceive their loved one to require more help than they actually do need. Most likely, the truth of how much help the patient actually needs lies somewhere between what patients and caregivers report.”
Based on their findings, Drs Hsu and Hurria and their colleagues advise that clinicians consider assessing caregiver burden in those caregivers who report the patient as being more dependent than the patient does themselves.
“Caregivers play an essential role in supporting older adults with cancer,” Dr Hsu said. “We plan to further explore factors associated with caregiver burden in this population, particularly in those who are frailer and thus require even more hands-on support. We also hope to explore what resources caregivers of older adults with cancer feel they need to better help them with their role.”
VSTs can treat 5 different viral infections after HSCT
New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).
The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).
Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.
“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”
“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.
“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”
The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.
“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.
“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”
“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”
Patients
The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).
These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).
Response
The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.
Six weeks after the first VST infusion, the overall response rate was 91.9%.
Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).
Two patients received VSTs for EBV, and both achieved a virologic CR.
Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.
Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.
Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).
All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.
A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.
Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.
Toxicity
One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.
One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.
Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.
One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).
Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.
“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”
New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).
The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).
Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.
“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”
“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.
“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”
The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.
“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.
“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”
“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”
Patients
The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).
These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).
Response
The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.
Six weeks after the first VST infusion, the overall response rate was 91.9%.
Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).
Two patients received VSTs for EBV, and both achieved a virologic CR.
Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.
Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.
Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).
All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.
A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.
Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.
Toxicity
One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.
One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.
Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.
One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).
Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.
“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”
New research suggests virus-specific T cells (VSTs) can protect patients from severe viral infections that sometimes occur after hematopoietic stem cell transplant (HSCT).
The VSTs proved effective against 5 different viruses—Epstein-Barr virus (EBV), adenovirus (AdV), cytomegalovirus (CMV), BK virus (BKV), and human herpesvirus 6 (HHV-6).
Ifigeneia Tzannou, MD, of Baylor College of Medicine in Houston, Texas, and her colleagues reported these findings in the Journal of Clinical Oncology.
“In this study, we continued our previous work . . . in which we showed that patients who had developed an Epstein-Barr virus infection after a transplant . . . could be helped by receiving immune cells specialized in eliminating that particular virus,” Dr Tzannou said. “Then, we and others successfully targeted other viruses—namely, adenoviruses and cytomegalovirus.”
“The novel contribution of this study is that we have targeted additional viruses, the BK virus and the HHV-6 virus, which had not been targeted this way before,” added study author Bilal Omer, MD, of Baylor College of Medicine.
“This is important because the BK virus does not have an effective treatment, and the complications are significant, including severe pain and bleeding. These patients are in the hospital for weeks, months sometimes, and, now, we have a treatment option.”
The researchers tested their VSTs in a phase 2 trial of 38 HSCT recipients with at least 1 of the aforementioned viruses.
“[To prepare the VSTs,] we take blood from healthy donors who have already been exposed to these viruses and who we have confirmed have immune cells that can fight the infections,” Dr Tzannou said.
“We isolate the cells and let them multiply in culture. The final product is a mixture of cells that, together, can target all 5 viruses. We prepared 59 sets of virus-specific cells from different donors following this procedure.”
“Our strategy is to prepare a number of sets of virus-specific cells ahead of time and store them in a freezer, ready to use when a patient needs them,” Dr Omer noted. “To match patient and donor, we use elaborate matching algorithms.”
Patients
The trial included 38 patients who had undergone HSCT to treat acute myeloid leukemia/myelodysplastic syndromes (n=20), acute lymphoblastic leukemia (n=9), lymphoma/myeloma (n=3), or nonmalignant disorders (n=6).
These 38 patients had a total of 45 infections—CMV (n=17), EBV (n=2), AdV (n=7), BKV (n=16), and HHV-6 (n=3).
Response
The researchers monitored virus levels and other clinical responses in the 37 evaluable patients.
Six weeks after the first VST infusion, the overall response rate was 91.9%.
Seventeen patients received VSTs for persistent CMV. Sixteen of these patients (94.1%) responded, 6 with complete responses (CRs) and 10 with partial responses (PRs).
Two patients received VSTs for EBV, and both achieved a virologic CR.
Seven patients received VSTs for persistent AdV. The response rate was 71.4%. Four patients achieved a CR, 1 had a PR, and 2 patients did not respond.
Three patients received VSTs to treat HHV-6 reactivations. The response rate was 67%. Two patients had a PR, and 1 was not evaluable.
Sixteen patients received VSTs for BKV-associated hemorrhagic cystitis (n= 14) or BKV-associated nephritis (n=2).
All 16 patients responded. One had a clinical and virologic CR. Six had a clinical CR but a virologic PR. Seven had a virologic and clinical PR. And 2 patients had only a virologic PR.
A total of 15 patients received a second VST infusion—1 due to lack of response, 7 who had a PR, and 7 due to recurrence. Ten of these patients responded to the second infusion—1 with a CR and 9 with a PR.
Four patients received a third infusion of VSTs. Two achieved a CR, 1 had a PR, and 1 did not respond.
Toxicity
One patient developed an isolated fever within 24 hours of VST infusion, but the researchers did not observe any other immediate toxicities.
One of the patients with BKV-associated hemorrhagic cystitis experienced transient hydronephrosis and a decrease in renal function associated with a concomitant bacterial urinary tract infection.
Nineteen patients had prior grade 2 to 4 graft-versus-host disease (GVHD)—15 with grade 2 and 4 with grade 3. All GVHD was quiescent at the time of VST infusion.
One patient developed recurrent grade 3 gastrointestinal GVHD after VST infusion and rapid corticosteroid taper. Five patients developed recurrent (n=3) or de novo (n=2) grade 1 to 2 skin GVHD, which resolved with topical treatment (n=4) and reinitiation of corticosteroid treatment (n=1).
Two patients had a flare of upper-gastrointestinal GVHD, which resolved after a brief corticosteroid course.
“We didn’t have any significant toxicities,” Dr Tzannou said. “Taken together, the results of this trial suggest that it is reasonable to consider this treatment as an early option for these patients. We hope that the results of a future multicenter, phase 3 clinical trial will help raise awareness in both physicians and patients that this treatment, which is safe and effective, is available.”
Researchers find higher opioid use among cancer survivors
A study of residents in Ontario, Canada, showed that opioid prescription use was more common in cancer survivors than in individuals without a history of cancer.
This was true even among survivors who were 10 or more years past their cancer diagnosis.
Rinku Sutradhar, PhD, of the University of Toronto in Ontario, Canada, and her colleagues reported these findings in Cancer.
The researchers said little is known about prescribing opioids to relieve pain in individuals who have survived cancer.
To investigate, the team looked at opioid prescribing among residents of Ontario, Canada, with and without a history of cancer.
The study included 8601 adults who were at least 5 years past a cancer diagnosis. These subjects were were matched with 8601 individuals without a prior cancer diagnosis. The subjects were matched based on sex and calendar year of birth.
The researchers looked for opioid prescriptions filled at a pharmacy during the observation period. Follow-up was stopped at any indication of cancer recurrence, second malignancy, or new cancer diagnosis.
The rate of opioid prescribing was 1.22 times higher among cancer survivors than corresponding matched controls.
Over a 36-month period, the average number of opioid prescriptions filled by cancer survivors was 7.7, compared with 6.3 for controls.
This increased rate of opioid prescribing was also seen among survivors who were 10 or more years past their cancer diagnosis.
Individuals with lower income and those who were younger, from rural neighborhoods, and with more comorbidities had significantly higher prescribing rates. Sex was not associated with prescribing rates.
“Our research findings raise concerns about the diagnosis and management of chronic pain problems among survivors stemming from their cancer diagnosis or treatment,” Dr Sutradhar said. “Physicians providing primary care to cancer survivors should consider close examination of reasons for continued opioid use to differentiate chronic pain from dependency.”
A study of residents in Ontario, Canada, showed that opioid prescription use was more common in cancer survivors than in individuals without a history of cancer.
This was true even among survivors who were 10 or more years past their cancer diagnosis.
Rinku Sutradhar, PhD, of the University of Toronto in Ontario, Canada, and her colleagues reported these findings in Cancer.
The researchers said little is known about prescribing opioids to relieve pain in individuals who have survived cancer.
To investigate, the team looked at opioid prescribing among residents of Ontario, Canada, with and without a history of cancer.
The study included 8601 adults who were at least 5 years past a cancer diagnosis. These subjects were were matched with 8601 individuals without a prior cancer diagnosis. The subjects were matched based on sex and calendar year of birth.
The researchers looked for opioid prescriptions filled at a pharmacy during the observation period. Follow-up was stopped at any indication of cancer recurrence, second malignancy, or new cancer diagnosis.
The rate of opioid prescribing was 1.22 times higher among cancer survivors than corresponding matched controls.
Over a 36-month period, the average number of opioid prescriptions filled by cancer survivors was 7.7, compared with 6.3 for controls.
This increased rate of opioid prescribing was also seen among survivors who were 10 or more years past their cancer diagnosis.
Individuals with lower income and those who were younger, from rural neighborhoods, and with more comorbidities had significantly higher prescribing rates. Sex was not associated with prescribing rates.
“Our research findings raise concerns about the diagnosis and management of chronic pain problems among survivors stemming from their cancer diagnosis or treatment,” Dr Sutradhar said. “Physicians providing primary care to cancer survivors should consider close examination of reasons for continued opioid use to differentiate chronic pain from dependency.”
A study of residents in Ontario, Canada, showed that opioid prescription use was more common in cancer survivors than in individuals without a history of cancer.
This was true even among survivors who were 10 or more years past their cancer diagnosis.
Rinku Sutradhar, PhD, of the University of Toronto in Ontario, Canada, and her colleagues reported these findings in Cancer.
The researchers said little is known about prescribing opioids to relieve pain in individuals who have survived cancer.
To investigate, the team looked at opioid prescribing among residents of Ontario, Canada, with and without a history of cancer.
The study included 8601 adults who were at least 5 years past a cancer diagnosis. These subjects were were matched with 8601 individuals without a prior cancer diagnosis. The subjects were matched based on sex and calendar year of birth.
The researchers looked for opioid prescriptions filled at a pharmacy during the observation period. Follow-up was stopped at any indication of cancer recurrence, second malignancy, or new cancer diagnosis.
The rate of opioid prescribing was 1.22 times higher among cancer survivors than corresponding matched controls.
Over a 36-month period, the average number of opioid prescriptions filled by cancer survivors was 7.7, compared with 6.3 for controls.
This increased rate of opioid prescribing was also seen among survivors who were 10 or more years past their cancer diagnosis.
Individuals with lower income and those who were younger, from rural neighborhoods, and with more comorbidities had significantly higher prescribing rates. Sex was not associated with prescribing rates.
“Our research findings raise concerns about the diagnosis and management of chronic pain problems among survivors stemming from their cancer diagnosis or treatment,” Dr Sutradhar said. “Physicians providing primary care to cancer survivors should consider close examination of reasons for continued opioid use to differentiate chronic pain from dependency.”
Tests can produce confusing results after HSCT in MM
Tests used to assess treatment response in multiple myeloma (MM) may often produce confusing results after patients have undergone hematopoietic stem cell transplant (HSCT), a new study suggests.
The tests—serum protein electrophoresis/serum immunofixation electrophoresis (SPEP/SIFE) and serum free light chain assay (SFLCA)—can sometimes produce an oligoclonal pattern that can be mistaken for an M spike and suggest disease recurrence.
The study showed that this confusing result was significantly more likely to occur after patients underwent HSCT than after they received chemotherapy.
Gurmukh Singh, MD, PhD, of Augusta University in Augusta, Georgia, reported these findings in the Journal of Clinical Medicine Research.
For this study, Dr Singh looked at lab and clinical data on 251 MM patients treated from January 2010 to December 2016. One hundred and fifty-nine of those patients received autologous HSCTs.
Dr Singh compared results of SPEP/SIFE and/or SFLCA in patients who underwent HSCT and patients who did not. Each patient had at least 3 tests, and, for HSCT recipients, at least 2 of the tests occurred after transplant.
The incidence of oligoclonal patterns was significantly higher in HSCT recipients than in patients who had chemotherapy alone—57.9% and 8.8%, respectively (P=0.000003).
Only 5 of the 159 HSCT recipients had an oligoclonal pattern before treatment, but 92 of them had one afterward.
More than half of the oligoclonal patterns developed within the first year of HSCT. The earliest pattern was detected at 2 months—as soon as the first post-transplant tests were done—and a few occurred as late as 5 years later.
“We want to emphasize that oligoclonal bands should mostly be recognized as a response to treatment and not be mistaken as a recurrence of the original tumor,” Dr Singh said.
He explained that the key clarifier appears to be the location of the M spike when the diagnosis is made compared to the location of new spikes that may show up after HSCT.
“If the original peak was at location A, now the peak is location B, that allows us to determine that it is not the same abnormal, malignant antibody,” he said. “If it’s in a different location, it’s not the same protein. [T]his is just a normal response of recovery of the bone marrow that could be mistaken for recurrence of the disease.”
Tests used to assess treatment response in multiple myeloma (MM) may often produce confusing results after patients have undergone hematopoietic stem cell transplant (HSCT), a new study suggests.
The tests—serum protein electrophoresis/serum immunofixation electrophoresis (SPEP/SIFE) and serum free light chain assay (SFLCA)—can sometimes produce an oligoclonal pattern that can be mistaken for an M spike and suggest disease recurrence.
The study showed that this confusing result was significantly more likely to occur after patients underwent HSCT than after they received chemotherapy.
Gurmukh Singh, MD, PhD, of Augusta University in Augusta, Georgia, reported these findings in the Journal of Clinical Medicine Research.
For this study, Dr Singh looked at lab and clinical data on 251 MM patients treated from January 2010 to December 2016. One hundred and fifty-nine of those patients received autologous HSCTs.
Dr Singh compared results of SPEP/SIFE and/or SFLCA in patients who underwent HSCT and patients who did not. Each patient had at least 3 tests, and, for HSCT recipients, at least 2 of the tests occurred after transplant.
The incidence of oligoclonal patterns was significantly higher in HSCT recipients than in patients who had chemotherapy alone—57.9% and 8.8%, respectively (P=0.000003).
Only 5 of the 159 HSCT recipients had an oligoclonal pattern before treatment, but 92 of them had one afterward.
More than half of the oligoclonal patterns developed within the first year of HSCT. The earliest pattern was detected at 2 months—as soon as the first post-transplant tests were done—and a few occurred as late as 5 years later.
“We want to emphasize that oligoclonal bands should mostly be recognized as a response to treatment and not be mistaken as a recurrence of the original tumor,” Dr Singh said.
He explained that the key clarifier appears to be the location of the M spike when the diagnosis is made compared to the location of new spikes that may show up after HSCT.
“If the original peak was at location A, now the peak is location B, that allows us to determine that it is not the same abnormal, malignant antibody,” he said. “If it’s in a different location, it’s not the same protein. [T]his is just a normal response of recovery of the bone marrow that could be mistaken for recurrence of the disease.”
Tests used to assess treatment response in multiple myeloma (MM) may often produce confusing results after patients have undergone hematopoietic stem cell transplant (HSCT), a new study suggests.
The tests—serum protein electrophoresis/serum immunofixation electrophoresis (SPEP/SIFE) and serum free light chain assay (SFLCA)—can sometimes produce an oligoclonal pattern that can be mistaken for an M spike and suggest disease recurrence.
The study showed that this confusing result was significantly more likely to occur after patients underwent HSCT than after they received chemotherapy.
Gurmukh Singh, MD, PhD, of Augusta University in Augusta, Georgia, reported these findings in the Journal of Clinical Medicine Research.
For this study, Dr Singh looked at lab and clinical data on 251 MM patients treated from January 2010 to December 2016. One hundred and fifty-nine of those patients received autologous HSCTs.
Dr Singh compared results of SPEP/SIFE and/or SFLCA in patients who underwent HSCT and patients who did not. Each patient had at least 3 tests, and, for HSCT recipients, at least 2 of the tests occurred after transplant.
The incidence of oligoclonal patterns was significantly higher in HSCT recipients than in patients who had chemotherapy alone—57.9% and 8.8%, respectively (P=0.000003).
Only 5 of the 159 HSCT recipients had an oligoclonal pattern before treatment, but 92 of them had one afterward.
More than half of the oligoclonal patterns developed within the first year of HSCT. The earliest pattern was detected at 2 months—as soon as the first post-transplant tests were done—and a few occurred as late as 5 years later.
“We want to emphasize that oligoclonal bands should mostly be recognized as a response to treatment and not be mistaken as a recurrence of the original tumor,” Dr Singh said.
He explained that the key clarifier appears to be the location of the M spike when the diagnosis is made compared to the location of new spikes that may show up after HSCT.
“If the original peak was at location A, now the peak is location B, that allows us to determine that it is not the same abnormal, malignant antibody,” he said. “If it’s in a different location, it’s not the same protein. [T]his is just a normal response of recovery of the bone marrow that could be mistaken for recurrence of the disease.”