Lymphoma & Plasma Cell Disorders

The Food and Drug Administration has added a warning about second-cancer risk to the label of lenalidomide, a widely used multiple myeloma drug, after a safety review lasting about 1 year.

Treatment with lenalidomide (Revlimid) for newly diagnosed multiple myeloma is associated with almost a threefold increased risk of developing secondary primary malignancies, the agency announced on May 7. The finding was based on three postapproval trials of lenalidomide as maintenance therapy in newly diagnosed patients.

"Specifically, these trials showed there was an increased risk of developing acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma," the FDA said. No increase was seen in incidence of nonmelanoma skin cancers and solid tumors.

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It noted that as of Feb. 28, 2011, a pooled analysis showed there were 65 second primary malignancies among 824 patients treated with lenalidomide vs. 19 second primary malignancies among 665 patients in treatment arms that did not include lenalidomide maintenance (7.9% vs. 2.8%, respectively; P less than .001). "The median time from start of Revlimid to a diagnosis of a second primary malignancy was two years," the agency said.

The three studies were designed to evaluate the effect of lenalidomide as maintenance therapy, compared with placebo, after patients with newly diagnosed multiple myeloma had received initial chemotherapy or chemotherapy plus a hematopoietic stem cell transplant. A thalidomide analogue, lenalidomide is approved in combination with dexamethasone to treat patients with multiple myeloma who have been treated previously.

The FDA also analyzed data from two clinical trials that were the basis of the approval in these patients – and it also found a higher incidence of second primary malignancies with lenalidomide plus dexamethasone, compared with dexamethasone alone. A higher incidence of nonmelanoma skin cancers accounted for most of this difference, however, and the agency said this was no longer significant after adjusting for the time on treatment.

The FDA recommends that clinicians monitor patients treated with lenalidomide for the development of secondary primary malignancies, and "take into account both the potential benefit of Revlimid and the risk of second primary malignancies when considering treatment with Revlimid."

The new safety information is being added to the warnings and precautions section of the label, and to the patient Medication Guide. Clinicians encourage patients treated with lenalidomide to read the Medication Guide, a handout that is distributed with each filled prescription, including refills, the FDA said, and patients should consult their health care professionals if they have any questions or concerns.

The FDA statement is available at http://www.fda.gov/Drugs/DrugSafety/ucm302939.htm. Adverse events associated with lenalidomide should be reported to the FDA’s MedWatch program at www.fda.gov/medwatch/ or 800-332-1088.

The Food and Drug Administration has added a warning about second-cancer risk to the label of lenalidomide, a widely used multiple myeloma drug, after a safety review lasting about 1 year.

Treatment with lenalidomide (Revlimid) for newly diagnosed multiple myeloma is associated with almost a threefold increased risk of developing secondary primary malignancies, the agency announced on May 7. The finding was based on three postapproval trials of lenalidomide as maintenance therapy in newly diagnosed patients.

"Specifically, these trials showed there was an increased risk of developing acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma," the FDA said. No increase was seen in incidence of nonmelanoma skin cancers and solid tumors.

----------------------------------------------------------------------------------------------

----------------------------------------------------------------------------------------------

It noted that as of Feb. 28, 2011, a pooled analysis showed there were 65 second primary malignancies among 824 patients treated with lenalidomide vs. 19 second primary malignancies among 665 patients in treatment arms that did not include lenalidomide maintenance (7.9% vs. 2.8%, respectively; P less than .001). "The median time from start of Revlimid to a diagnosis of a second primary malignancy was two years," the agency said.

The three studies were designed to evaluate the effect of lenalidomide as maintenance therapy, compared with placebo, after patients with newly diagnosed multiple myeloma had received initial chemotherapy or chemotherapy plus a hematopoietic stem cell transplant. A thalidomide analogue, lenalidomide is approved in combination with dexamethasone to treat patients with multiple myeloma who have been treated previously.

The FDA also analyzed data from two clinical trials that were the basis of the approval in these patients – and it also found a higher incidence of second primary malignancies with lenalidomide plus dexamethasone, compared with dexamethasone alone. A higher incidence of nonmelanoma skin cancers accounted for most of this difference, however, and the agency said this was no longer significant after adjusting for the time on treatment.

The FDA recommends that clinicians monitor patients treated with lenalidomide for the development of secondary primary malignancies, and "take into account both the potential benefit of Revlimid and the risk of second primary malignancies when considering treatment with Revlimid."

The new safety information is being added to the warnings and precautions section of the label, and to the patient Medication Guide. Clinicians encourage patients treated with lenalidomide to read the Medication Guide, a handout that is distributed with each filled prescription, including refills, the FDA said, and patients should consult their health care professionals if they have any questions or concerns.

The FDA statement is available at http://www.fda.gov/Drugs/DrugSafety/ucm302939.htm. Adverse events associated with lenalidomide should be reported to the FDA’s MedWatch program at www.fda.gov/medwatch/ or 800-332-1088.

The Food and Drug Administration has added a warning about second-cancer risk to the label of lenalidomide, a widely used multiple myeloma drug, after a safety review lasting about 1 year.

Treatment with lenalidomide (Revlimid) for newly diagnosed multiple myeloma is associated with almost a threefold increased risk of developing secondary primary malignancies, the agency announced on May 7. The finding was based on three postapproval trials of lenalidomide as maintenance therapy in newly diagnosed patients.

"Specifically, these trials showed there was an increased risk of developing acute myelogenous leukemia, myelodysplastic syndromes, and Hodgkin lymphoma," the FDA said. No increase was seen in incidence of nonmelanoma skin cancers and solid tumors.

----------------------------------------------------------------------------------------------

----------------------------------------------------------------------------------------------

It noted that as of Feb. 28, 2011, a pooled analysis showed there were 65 second primary malignancies among 824 patients treated with lenalidomide vs. 19 second primary malignancies among 665 patients in treatment arms that did not include lenalidomide maintenance (7.9% vs. 2.8%, respectively; P less than .001). "The median time from start of Revlimid to a diagnosis of a second primary malignancy was two years," the agency said.

The three studies were designed to evaluate the effect of lenalidomide as maintenance therapy, compared with placebo, after patients with newly diagnosed multiple myeloma had received initial chemotherapy or chemotherapy plus a hematopoietic stem cell transplant. A thalidomide analogue, lenalidomide is approved in combination with dexamethasone to treat patients with multiple myeloma who have been treated previously.

The FDA also analyzed data from two clinical trials that were the basis of the approval in these patients – and it also found a higher incidence of second primary malignancies with lenalidomide plus dexamethasone, compared with dexamethasone alone. A higher incidence of nonmelanoma skin cancers accounted for most of this difference, however, and the agency said this was no longer significant after adjusting for the time on treatment.

The FDA recommends that clinicians monitor patients treated with lenalidomide for the development of secondary primary malignancies, and "take into account both the potential benefit of Revlimid and the risk of second primary malignancies when considering treatment with Revlimid."

The new safety information is being added to the warnings and precautions section of the label, and to the patient Medication Guide. Clinicians encourage patients treated with lenalidomide to read the Medication Guide, a handout that is distributed with each filled prescription, including refills, the FDA said, and patients should consult their health care professionals if they have any questions or concerns.

The FDA statement is available at http://www.fda.gov/Drugs/DrugSafety/ucm302939.htm. Adverse events associated with lenalidomide should be reported to the FDA’s MedWatch program at www.fda.gov/medwatch/ or 800-332-1088.

Investigators in France have identified a profile that predicts longer survival for one in five patients with newly diagnosed multiple myeloma, according to a study published online April 30 in the Journal of Clinical Oncology.

The absence of three key chromosomal abnormalities in malignant plasma-cell samples, together with a low beta-2 microglobulin level, was seen in this subgroup of patients. In addition, patients younger than 55 years had longer progression-free and overall survival in a relatively young population that was limited to patients less than age 66 years.

The finding favoring younger age was unexpected and "to our knowledge, it has not been reported before," said Dr. Hervé Avet-Loiseau of the hematology laboratory, Biology Institute, University of Nantes (France), and his associates.

Whereas most prognostic studies are designed to identify myeloma patients with poorer outcomes, the researchers sought to identify patients with longer life expectancy. To that end, they updated and reanalyzed the data of patients treated in the IFM (Intergroupe Francophone du Myelome) 99-02 and 99-04 trials.

Sixty percent of the 520 patients studied did not carry any of the three high-risk genetic abnormalities. Those who also were younger than age 55 years and had beta-2 microglobulin levels less than 5.5 mg/l had an 8-year probability of survival of 75%. "This subgroup represented 20% of the entire patient population," the investigators noted.

Two of the chromosomal abnormalities – t(4;14) translocation and loss of the short arm of chromosome 17, or del(17p) – are known to be associated with a poor outcome and usually are assessed as part of risk stratification in patients with multiple myeloma. The third abnormality – a gain in chromosome 1q – has recently been recognized as a prognostic indicator but has not yet been added to the typical panel of genetic probes used to assess patient prognosis.

To determine which prognostic indicators can be used to define shorter or longer survival, rather than just "poor outcome" or "better outcome," Dr. Avet-Loiseau and his colleagues included the assessment of 1q gains along with t(4:14) translocations and deletions of 17p in this large series.

For their study, Dr. Avet-Loiseau and his associates analyzed stored bone marrow and plasma samples of 520 patients who had all received the same induction regimen of vincristine, Adriamycin, and dexamethasone followed by high-dose melphalan. All the study subjects were younger than age 66 years. Median overall survival was 7.5 years.

A total of 11% of the cohort had t(4;14) translocations, 5.4% had del(17p), and 33% had 1q gains (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.36.5726]).

In contrast, patients who had two or more of these prognostic factors had a median overall survival of only 33 months. The findings indicate that assessment of 1q gains should be added to the panel of probes used routinely in determining prognosis in patients with multiple myeloma, the researchers said.

"The question now concerns the role of novel drugs in this prognostication," the authors wrote. None of the patients received bortezomib (Velcade) in first-line treatment, although most were given novel drugs upon progression.

As bortezomib may help to overcome the poor prognosis associated with t(4;14), long-term analysis of first-line trials are warranted, they said, noting, "However, such analyses will not be possible for 4-5 years, because the first trials testing this drug started in 2005."

Dr. Avet-Loiseau reported no financial conflicts of interest; one of his associates reported ties to Celgene and Janssen-Cilag.

Investigators in France have identified a profile that predicts longer survival for one in five patients with newly diagnosed multiple myeloma, according to a study published online April 30 in the Journal of Clinical Oncology.

The absence of three key chromosomal abnormalities in malignant plasma-cell samples, together with a low beta-2 microglobulin level, was seen in this subgroup of patients. In addition, patients younger than 55 years had longer progression-free and overall survival in a relatively young population that was limited to patients less than age 66 years.

The finding favoring younger age was unexpected and "to our knowledge, it has not been reported before," said Dr. Hervé Avet-Loiseau of the hematology laboratory, Biology Institute, University of Nantes (France), and his associates.

Whereas most prognostic studies are designed to identify myeloma patients with poorer outcomes, the researchers sought to identify patients with longer life expectancy. To that end, they updated and reanalyzed the data of patients treated in the IFM (Intergroupe Francophone du Myelome) 99-02 and 99-04 trials.

Sixty percent of the 520 patients studied did not carry any of the three high-risk genetic abnormalities. Those who also were younger than age 55 years and had beta-2 microglobulin levels less than 5.5 mg/l had an 8-year probability of survival of 75%. "This subgroup represented 20% of the entire patient population," the investigators noted.

Two of the chromosomal abnormalities – t(4;14) translocation and loss of the short arm of chromosome 17, or del(17p) – are known to be associated with a poor outcome and usually are assessed as part of risk stratification in patients with multiple myeloma. The third abnormality – a gain in chromosome 1q – has recently been recognized as a prognostic indicator but has not yet been added to the typical panel of genetic probes used to assess patient prognosis.

To determine which prognostic indicators can be used to define shorter or longer survival, rather than just "poor outcome" or "better outcome," Dr. Avet-Loiseau and his colleagues included the assessment of 1q gains along with t(4:14) translocations and deletions of 17p in this large series.

For their study, Dr. Avet-Loiseau and his associates analyzed stored bone marrow and plasma samples of 520 patients who had all received the same induction regimen of vincristine, Adriamycin, and dexamethasone followed by high-dose melphalan. All the study subjects were younger than age 66 years. Median overall survival was 7.5 years.

A total of 11% of the cohort had t(4;14) translocations, 5.4% had del(17p), and 33% had 1q gains (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.36.5726]).

In contrast, patients who had two or more of these prognostic factors had a median overall survival of only 33 months. The findings indicate that assessment of 1q gains should be added to the panel of probes used routinely in determining prognosis in patients with multiple myeloma, the researchers said.

"The question now concerns the role of novel drugs in this prognostication," the authors wrote. None of the patients received bortezomib (Velcade) in first-line treatment, although most were given novel drugs upon progression.

As bortezomib may help to overcome the poor prognosis associated with t(4;14), long-term analysis of first-line trials are warranted, they said, noting, "However, such analyses will not be possible for 4-5 years, because the first trials testing this drug started in 2005."

Dr. Avet-Loiseau reported no financial conflicts of interest; one of his associates reported ties to Celgene and Janssen-Cilag.

Investigators in France have identified a profile that predicts longer survival for one in five patients with newly diagnosed multiple myeloma, according to a study published online April 30 in the Journal of Clinical Oncology.

The absence of three key chromosomal abnormalities in malignant plasma-cell samples, together with a low beta-2 microglobulin level, was seen in this subgroup of patients. In addition, patients younger than 55 years had longer progression-free and overall survival in a relatively young population that was limited to patients less than age 66 years.

The finding favoring younger age was unexpected and "to our knowledge, it has not been reported before," said Dr. Hervé Avet-Loiseau of the hematology laboratory, Biology Institute, University of Nantes (France), and his associates.

Whereas most prognostic studies are designed to identify myeloma patients with poorer outcomes, the researchers sought to identify patients with longer life expectancy. To that end, they updated and reanalyzed the data of patients treated in the IFM (Intergroupe Francophone du Myelome) 99-02 and 99-04 trials.

Sixty percent of the 520 patients studied did not carry any of the three high-risk genetic abnormalities. Those who also were younger than age 55 years and had beta-2 microglobulin levels less than 5.5 mg/l had an 8-year probability of survival of 75%. "This subgroup represented 20% of the entire patient population," the investigators noted.

Two of the chromosomal abnormalities – t(4;14) translocation and loss of the short arm of chromosome 17, or del(17p) – are known to be associated with a poor outcome and usually are assessed as part of risk stratification in patients with multiple myeloma. The third abnormality – a gain in chromosome 1q – has recently been recognized as a prognostic indicator but has not yet been added to the typical panel of genetic probes used to assess patient prognosis.

To determine which prognostic indicators can be used to define shorter or longer survival, rather than just "poor outcome" or "better outcome," Dr. Avet-Loiseau and his colleagues included the assessment of 1q gains along with t(4:14) translocations and deletions of 17p in this large series.

For their study, Dr. Avet-Loiseau and his associates analyzed stored bone marrow and plasma samples of 520 patients who had all received the same induction regimen of vincristine, Adriamycin, and dexamethasone followed by high-dose melphalan. All the study subjects were younger than age 66 years. Median overall survival was 7.5 years.

A total of 11% of the cohort had t(4;14) translocations, 5.4% had del(17p), and 33% had 1q gains (J. Clin. Oncol. 2012 [doi:10.1200/JCO.2011.36.5726]).

In contrast, patients who had two or more of these prognostic factors had a median overall survival of only 33 months. The findings indicate that assessment of 1q gains should be added to the panel of probes used routinely in determining prognosis in patients with multiple myeloma, the researchers said.

"The question now concerns the role of novel drugs in this prognostication," the authors wrote. None of the patients received bortezomib (Velcade) in first-line treatment, although most were given novel drugs upon progression.

As bortezomib may help to overcome the poor prognosis associated with t(4;14), long-term analysis of first-line trials are warranted, they said, noting, "However, such analyses will not be possible for 4-5 years, because the first trials testing this drug started in 2005."

Dr. Avet-Loiseau reported no financial conflicts of interest; one of his associates reported ties to Celgene and Janssen-Cilag.

NEW YORK – Do not rush to biopsy every patient with Sjögren’s syndrome who presents with salivary gland enlargement, Dr. Steven E. Carsons said at a rheumatology meeting sponsored by New York University.

"My approach to lymphoma surveillance in Sjögren’s syndrome is to depend on clinical judgment, relying on the bedside exam coupled with basic laboratory measures," said Dr. Carsons, professor of medicine at the State University of New York at Stony Brook.

It’s important to remain cognizant of the fact that patients with Sjögren’s syndrome (SS) have a 16- to 40-fold increased relative risk of malignant non-Hodgkin’s lymphoma, commonly of the mucosa-associated lymphoid tissue (MALT) in the salivary glands. Given that half of patients with primary SS present with salivary gland enlargement at some point during their illness, it is impractical to biopsy them all.

Chronic inflammation of salivary and lachrymal glands is characteristic of SS. Salivary dysfunctions, such as dry mouth, salivary gland swelling, and abnormal scintigraphy or sialography, are key elements of the American-European Consensus Criteria for SS. In primary SS, enlargement of the salivary gland may be due to benign causes such as inflammation or blockage. Conditions other than SS to consider when evaluating swollen salivary glands are sialadenitis due to infection with hepatitis C or HIV, the presence of IgG4-related systemic disease, sarcoidosis, and amyloidosis or isolated salivary gland lymphoma or other neoplasms.

The risk of lymphoma is increased in SS patients. Cohort studies report that about 5%-10% of patients with primary SS develop malignant B cell non-Hodgkin’s lymphoma (Sjögren’s Syndrome, in "Kelley’s Textbook of Rheumatology," 8th ed., Saunders, 2009, pp. 1149-68). The cumulative risk has recently been estimated as ranging from 3.4% in the first 5 years to 9.8% at 15 years (Semin. Arthritis Rheum. 2011;41:415-23).

Because it is impractical to biopsy every patient who presents with enlarged salivary glands, Dr. Carsons said that his clinical suspicions are raised when a patient develops enlargement of the salivary gland over time or when a firm nodule emerges, especially when the patient also develops lymphadenopathy, splenomegaly, weight loss, fever, or pulmonary infiltration. Loss of specific autoreactivities, such as antinuclear antibodies and anti-Sjögren’s syndrome A and B antibodies, may also indicate malignant transformation.

If any of these clinical findings are present, a biopsy is warranted, according to Dr. Carsons. The biopsy can be excisional, either by core needle or by excision of the node. Appropriate tissue analyses include immunoglobulin light-chain typing, hematoxylin and eosin staining, immunohistochemistry, and gene rearrangement studies. "I find pathology studies are not always conclusive," said Dr. Carsons. "Even the most prevalent rearrangements seen in [MALT] lymphomas are only present in 18% of cases." Intense glandular inflammation can produce histologic changes that may be difficult for pathologists to distinguish from lymphoma.

At this point, imaging studies may be considered, but Dr. Carsons noted that these results do not yield specific diagnoses. Even findings from PET imaging may show intermediate avidity in the presence of active inflammation. "Sometimes, there is still no conclusion at the end of the workup. Then we move back, reset the algorithm, and follow the patient clinically."

When the diagnosis of non-Hodgkin’s lymphoma is made, management strategies should take into account both the stage of the malignancy and the activity of extraglandular primary SS ("Sjögren’s Syndrome," Springer, 2011, pp. 345-55). According to Dr. Carsons, most MALT lymphomas are usually indolent, with a 5-year survival of 86%-95% regardless of whether the lymphoma is localized. Incidentally discovered non-Hodgkin’s lymphoma in patients with primary SS may not progress, even when untreated. For those reasons, if the lymphoma is asymptomatic and the primary SS disease activity is low, it is acceptable to follow a course of watchful waiting, and treatments should focus on the SS symptoms using medications, such as hydroxychloroquinolone or NSAIDs.

When the lymphoma is symptomatic but localized, and the SS activity is low, watchful waiting may still be appropriate or it may be time to begin treatment with low-dose radiation therapy for the lymphoma. Medications for SS should be continued.

If the lymphoma becomes symptomatic and/or disseminated and SS activity is high, rituximab should be initiated, with or without cyclophosphamide or a chemotherapy regimen consisting of cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine, and prednisone.

Rituximab may show promise for patients with primary Sjögren’s even in the absence of lymphoma. In a randomized, single-center trial of 30 patients with SS, a regimen of rituximab 1,000 mg twice a month stimulated salivary flow and significantly improved oral and ocular dryness as well as other Sjögren’s symptoms (Arthritis Rheum. 2010;62:960-8).

Dr. Carsons reported no relevant financial relationships.

NEW YORK – Do not rush to biopsy every patient with Sjögren’s syndrome who presents with salivary gland enlargement, Dr. Steven E. Carsons said at a rheumatology meeting sponsored by New York University.

"My approach to lymphoma surveillance in Sjögren’s syndrome is to depend on clinical judgment, relying on the bedside exam coupled with basic laboratory measures," said Dr. Carsons, professor of medicine at the State University of New York at Stony Brook.

It’s important to remain cognizant of the fact that patients with Sjögren’s syndrome (SS) have a 16- to 40-fold increased relative risk of malignant non-Hodgkin’s lymphoma, commonly of the mucosa-associated lymphoid tissue (MALT) in the salivary glands. Given that half of patients with primary SS present with salivary gland enlargement at some point during their illness, it is impractical to biopsy them all.

Chronic inflammation of salivary and lachrymal glands is characteristic of SS. Salivary dysfunctions, such as dry mouth, salivary gland swelling, and abnormal scintigraphy or sialography, are key elements of the American-European Consensus Criteria for SS. In primary SS, enlargement of the salivary gland may be due to benign causes such as inflammation or blockage. Conditions other than SS to consider when evaluating swollen salivary glands are sialadenitis due to infection with hepatitis C or HIV, the presence of IgG4-related systemic disease, sarcoidosis, and amyloidosis or isolated salivary gland lymphoma or other neoplasms.

The risk of lymphoma is increased in SS patients. Cohort studies report that about 5%-10% of patients with primary SS develop malignant B cell non-Hodgkin’s lymphoma (Sjögren’s Syndrome, in "Kelley’s Textbook of Rheumatology," 8th ed., Saunders, 2009, pp. 1149-68). The cumulative risk has recently been estimated as ranging from 3.4% in the first 5 years to 9.8% at 15 years (Semin. Arthritis Rheum. 2011;41:415-23).

Because it is impractical to biopsy every patient who presents with enlarged salivary glands, Dr. Carsons said that his clinical suspicions are raised when a patient develops enlargement of the salivary gland over time or when a firm nodule emerges, especially when the patient also develops lymphadenopathy, splenomegaly, weight loss, fever, or pulmonary infiltration. Loss of specific autoreactivities, such as antinuclear antibodies and anti-Sjögren’s syndrome A and B antibodies, may also indicate malignant transformation.

If any of these clinical findings are present, a biopsy is warranted, according to Dr. Carsons. The biopsy can be excisional, either by core needle or by excision of the node. Appropriate tissue analyses include immunoglobulin light-chain typing, hematoxylin and eosin staining, immunohistochemistry, and gene rearrangement studies. "I find pathology studies are not always conclusive," said Dr. Carsons. "Even the most prevalent rearrangements seen in [MALT] lymphomas are only present in 18% of cases." Intense glandular inflammation can produce histologic changes that may be difficult for pathologists to distinguish from lymphoma.

At this point, imaging studies may be considered, but Dr. Carsons noted that these results do not yield specific diagnoses. Even findings from PET imaging may show intermediate avidity in the presence of active inflammation. "Sometimes, there is still no conclusion at the end of the workup. Then we move back, reset the algorithm, and follow the patient clinically."

When the diagnosis of non-Hodgkin’s lymphoma is made, management strategies should take into account both the stage of the malignancy and the activity of extraglandular primary SS ("Sjögren’s Syndrome," Springer, 2011, pp. 345-55). According to Dr. Carsons, most MALT lymphomas are usually indolent, with a 5-year survival of 86%-95% regardless of whether the lymphoma is localized. Incidentally discovered non-Hodgkin’s lymphoma in patients with primary SS may not progress, even when untreated. For those reasons, if the lymphoma is asymptomatic and the primary SS disease activity is low, it is acceptable to follow a course of watchful waiting, and treatments should focus on the SS symptoms using medications, such as hydroxychloroquinolone or NSAIDs.

When the lymphoma is symptomatic but localized, and the SS activity is low, watchful waiting may still be appropriate or it may be time to begin treatment with low-dose radiation therapy for the lymphoma. Medications for SS should be continued.

If the lymphoma becomes symptomatic and/or disseminated and SS activity is high, rituximab should be initiated, with or without cyclophosphamide or a chemotherapy regimen consisting of cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine, and prednisone.

Rituximab may show promise for patients with primary Sjögren’s even in the absence of lymphoma. In a randomized, single-center trial of 30 patients with SS, a regimen of rituximab 1,000 mg twice a month stimulated salivary flow and significantly improved oral and ocular dryness as well as other Sjögren’s symptoms (Arthritis Rheum. 2010;62:960-8).

Dr. Carsons reported no relevant financial relationships.

NEW YORK – Do not rush to biopsy every patient with Sjögren’s syndrome who presents with salivary gland enlargement, Dr. Steven E. Carsons said at a rheumatology meeting sponsored by New York University.

"My approach to lymphoma surveillance in Sjögren’s syndrome is to depend on clinical judgment, relying on the bedside exam coupled with basic laboratory measures," said Dr. Carsons, professor of medicine at the State University of New York at Stony Brook.

It’s important to remain cognizant of the fact that patients with Sjögren’s syndrome (SS) have a 16- to 40-fold increased relative risk of malignant non-Hodgkin’s lymphoma, commonly of the mucosa-associated lymphoid tissue (MALT) in the salivary glands. Given that half of patients with primary SS present with salivary gland enlargement at some point during their illness, it is impractical to biopsy them all.

Chronic inflammation of salivary and lachrymal glands is characteristic of SS. Salivary dysfunctions, such as dry mouth, salivary gland swelling, and abnormal scintigraphy or sialography, are key elements of the American-European Consensus Criteria for SS. In primary SS, enlargement of the salivary gland may be due to benign causes such as inflammation or blockage. Conditions other than SS to consider when evaluating swollen salivary glands are sialadenitis due to infection with hepatitis C or HIV, the presence of IgG4-related systemic disease, sarcoidosis, and amyloidosis or isolated salivary gland lymphoma or other neoplasms.

The risk of lymphoma is increased in SS patients. Cohort studies report that about 5%-10% of patients with primary SS develop malignant B cell non-Hodgkin’s lymphoma (Sjögren’s Syndrome, in "Kelley’s Textbook of Rheumatology," 8th ed., Saunders, 2009, pp. 1149-68). The cumulative risk has recently been estimated as ranging from 3.4% in the first 5 years to 9.8% at 15 years (Semin. Arthritis Rheum. 2011;41:415-23).

Because it is impractical to biopsy every patient who presents with enlarged salivary glands, Dr. Carsons said that his clinical suspicions are raised when a patient develops enlargement of the salivary gland over time or when a firm nodule emerges, especially when the patient also develops lymphadenopathy, splenomegaly, weight loss, fever, or pulmonary infiltration. Loss of specific autoreactivities, such as antinuclear antibodies and anti-Sjögren’s syndrome A and B antibodies, may also indicate malignant transformation.

If any of these clinical findings are present, a biopsy is warranted, according to Dr. Carsons. The biopsy can be excisional, either by core needle or by excision of the node. Appropriate tissue analyses include immunoglobulin light-chain typing, hematoxylin and eosin staining, immunohistochemistry, and gene rearrangement studies. "I find pathology studies are not always conclusive," said Dr. Carsons. "Even the most prevalent rearrangements seen in [MALT] lymphomas are only present in 18% of cases." Intense glandular inflammation can produce histologic changes that may be difficult for pathologists to distinguish from lymphoma.

At this point, imaging studies may be considered, but Dr. Carsons noted that these results do not yield specific diagnoses. Even findings from PET imaging may show intermediate avidity in the presence of active inflammation. "Sometimes, there is still no conclusion at the end of the workup. Then we move back, reset the algorithm, and follow the patient clinically."

When the diagnosis of non-Hodgkin’s lymphoma is made, management strategies should take into account both the stage of the malignancy and the activity of extraglandular primary SS ("Sjögren’s Syndrome," Springer, 2011, pp. 345-55). According to Dr. Carsons, most MALT lymphomas are usually indolent, with a 5-year survival of 86%-95% regardless of whether the lymphoma is localized. Incidentally discovered non-Hodgkin’s lymphoma in patients with primary SS may not progress, even when untreated. For those reasons, if the lymphoma is asymptomatic and the primary SS disease activity is low, it is acceptable to follow a course of watchful waiting, and treatments should focus on the SS symptoms using medications, such as hydroxychloroquinolone or NSAIDs.

When the lymphoma is symptomatic but localized, and the SS activity is low, watchful waiting may still be appropriate or it may be time to begin treatment with low-dose radiation therapy for the lymphoma. Medications for SS should be continued.

If the lymphoma becomes symptomatic and/or disseminated and SS activity is high, rituximab should be initiated, with or without cyclophosphamide or a chemotherapy regimen consisting of cyclophosphamide, hydroxydaunorubicin hydrochloride (doxorubicin hydrochloride), vincristine, and prednisone.

Rituximab may show promise for patients with primary Sjögren’s even in the absence of lymphoma. In a randomized, single-center trial of 30 patients with SS, a regimen of rituximab 1,000 mg twice a month stimulated salivary flow and significantly improved oral and ocular dryness as well as other Sjögren’s symptoms (Arthritis Rheum. 2010;62:960-8).

Dr. Carsons reported no relevant financial relationships.

Join community Oncology's Editor-in-Chief Dr. David Henry for an audio tour of the March issue, featuring Dr. Kenneth C. Anderson's review of targeted therapies in multiple myeloma, Dr. Stuart M. Lichtman's commentary on treating cancer in elderly patients, and Dr. Jame Abraham's Community Translation article on vemurafenib for melanoma with the BRAF V600E mutation.

Join community Oncology's Editor-in-Chief Dr. David Henry for an audio tour of the March issue, featuring Dr. Kenneth C. Anderson's review of targeted therapies in multiple myeloma, Dr. Stuart M. Lichtman's commentary on treating cancer in elderly patients, and Dr. Jame Abraham's Community Translation article on vemurafenib for melanoma with the BRAF V600E mutation.

Join community Oncology's Editor-in-Chief Dr. David Henry for an audio tour of the March issue, featuring Dr. Kenneth C. Anderson's review of targeted therapies in multiple myeloma, Dr. Stuart M. Lichtman's commentary on treating cancer in elderly patients, and Dr. Jame Abraham's Community Translation article on vemurafenib for melanoma with the BRAF V600E mutation.

DENVER – Electrocutaneous direct nerve stimulation via a device that scrambles "pain" and "no pain" signals reduced pain scores in preliminary studies involving patients with refractory chemotherapy-induced peripheral neuropathy, post-herpetic neuralgia, and other forms of chronic, disabling neuropathic pain.

"What I saw in our pilot study in patients with chemotherapy-induced peripheral neuropathy was about a 60% reduction in pain, and you knew right away – within the first 3 days – whether it was going to work," said Dr. Thomas J. Smith, professor of oncology and director of palliative care at Johns Hopkins University, Baltimore.

The device, known as the MC5-A Calmare Scrambler, received Food and Drug Administration clearance in February 2009 and has a Medicare payment code. The Scrambler has been used worldwide to treat more than 4,000 patients with no reported serious side effects. Yet few American physicians have heard of the therapy because Medicare fixed the payment so low (at $44) that there is little financial incentive to adopt it, according to Dr. Smith.

"There’s not much you can do in the hospital outpatient setting for $44. That barely covers the cost of the electrodes and maybe a technician’s time," he said at the annual meeting of the American Academy of Hospice and Palliative Care Medicine. "They set the reimbursement so low that it’s almost guaranteed not to be accepted by physicians until we get more evidence. But there are a significant number of studies in the works."

Chemotherapy-induced peripheral neuropathy affects up to 30%-40% of treated cancer patients. Dr. Smith’s pilot study involved 16 patients with refractory chemotherapy-induced peripheral neuropathy that lasted from 3 months to 8 years. The most common drugs involved were taxanes, platinum-based agents, and bortezomib (Velcade). Patients received hour-long Scrambler sessions daily on 10 consecutive working days.

Pain scores fell from a mean baseline score of 5.8 on a 10-point scale to 2.4 at the end of 10 days. Four patients had a pain score of 0, and 15 of the 16 patients had at least a 20% reduction in their pain score on day 10. There was no toxicity (J. Pain Symptom Manage. 2010;40:883-91).

"When you see that sort of effect size, you can’t believe it’s real," Dr. Smith observed. "That’s in fact what the first reviewer said of the article. He said, ‘I’ve never heard of this therapy, and I don’t believe it.’ I volunteered to give him the case reports."

Neuropathic pain reductions in the 60% range are what are seen with permanent implanted spinal cord stimulation devices, a therapy that runs about $40,000, he added.

Dr. Smith’s Scrambler pilot study results were confirmed in an Italian study involving 40 patients with refractory cancer and 33 with non–cancer-related pain. Their mean pretreatment pain scale score was 6.2, plunging to 1.6 after the 10th day of treatment, and rebounding to 2.9 at follow-up 2 weeks after the final treatment session. Again, there were no side effects (Support Care Cancer. 2012;20:405-12).

Separately, a group led by the Scrambler’s inventor, Giuseppe Marineo, Ph.D., of the University of Rome Tor Vergata, reported on a randomized but unblinded trial involving 52 patients with chronic failed back syndrome, post-herpetic neuralgia, or spinal cord stenosis. Subjects assigned to the control arm received pharmacotherapy according to European Federation of Neurological Societies guidelines (Eur. J. Neurol. 2010;17:1113-e88), while the intervention arm received 10 daily Scrambler sessions.

The pretreatment mean visual analog pain score fell in 1 month from 8.1 in a control group and 8.0 in a group treated with the Scrambler to 5.8 in controls and to 0.7 in the Scrambler group. At 2 and 3 months of follow-up, the mean pain scores were 1.4 and 2.0 points, respectively, in the Scrambler group but were still 5.7 and 5.9 points in controls. A marked and persistent reduction in allodynia was also documented in response to Scrambler therapy (J. Pain Symptom Manage. 2012;43:87-95).

With regard to post-herpetic neuralgia, Dr. Smith presented a series of 10 treated patients. Their mean pain scores dropped from 8 at baseline to less than 1 at 1 month, holding steady with a score of 2 at 2 and 3 months’ follow-up.

The Scrambler entails application of 16 ECG-like electrode pads placed along the dermatome above and below the site of pain. The Scrambler machine is designed to feed 16 different nerve potentials in rapid sequence, essentially in order to confuse a firing nerve. The electrical charge is individually adjusted to patient tolerance. It feels like a bee sting, according to Dr. Smith. The mechanism of benefit isn’t well defined as yet.

"It’s likely acting like direct spinal cord stimulation, raising the gate threshold," he continued. "My hypothesis – and the inventor’s hypothesis as well – is that the therapy resets the damaged nerves at several sites. You see some effect within the first 30 minutes, and that rapid onset suggests biochemical change. And the long-lasting nature of the pain relief suggests remodeling as well as adaptation to the pain."

Clearly, further studies need to be done – free of industry sponsorship, on larger numbers of patients, and with sham-treated controls – in order to fully assess the Scrambler therapy’s efficacy, mechanism of action, and optimal schedule.

"The Scrambler is one of several neurocutaneous direct nerve stimulation techniques that are interesting but absolutely require further testing," Dr. Smith said.

Dr. Charles L. Loprinzi, professor of oncology at the Mayo Clinic, Rochester, Minn., has started such studies, he noted. "He was at least as skeptical of this as I was, and he’s been impressed with results from this machine," Dr. Smith said, adding that Dr. Loprinzi’s research team is expected to present data later this year at the annual meeting of the American Society of Clinical Oncology.

Competitive Technologies Inc., based in Fairfield, Conn., has worldwide rights to the device. Dr. Smith reported having no financial conflicts.

DENVER – Electrocutaneous direct nerve stimulation via a device that scrambles "pain" and "no pain" signals reduced pain scores in preliminary studies involving patients with refractory chemotherapy-induced peripheral neuropathy, post-herpetic neuralgia, and other forms of chronic, disabling neuropathic pain.

"What I saw in our pilot study in patients with chemotherapy-induced peripheral neuropathy was about a 60% reduction in pain, and you knew right away – within the first 3 days – whether it was going to work," said Dr. Thomas J. Smith, professor of oncology and director of palliative care at Johns Hopkins University, Baltimore.

The device, known as the MC5-A Calmare Scrambler, received Food and Drug Administration clearance in February 2009 and has a Medicare payment code. The Scrambler has been used worldwide to treat more than 4,000 patients with no reported serious side effects. Yet few American physicians have heard of the therapy because Medicare fixed the payment so low (at $44) that there is little financial incentive to adopt it, according to Dr. Smith.

"There’s not much you can do in the hospital outpatient setting for $44. That barely covers the cost of the electrodes and maybe a technician’s time," he said at the annual meeting of the American Academy of Hospice and Palliative Care Medicine. "They set the reimbursement so low that it’s almost guaranteed not to be accepted by physicians until we get more evidence. But there are a significant number of studies in the works."

Chemotherapy-induced peripheral neuropathy affects up to 30%-40% of treated cancer patients. Dr. Smith’s pilot study involved 16 patients with refractory chemotherapy-induced peripheral neuropathy that lasted from 3 months to 8 years. The most common drugs involved were taxanes, platinum-based agents, and bortezomib (Velcade). Patients received hour-long Scrambler sessions daily on 10 consecutive working days.

Pain scores fell from a mean baseline score of 5.8 on a 10-point scale to 2.4 at the end of 10 days. Four patients had a pain score of 0, and 15 of the 16 patients had at least a 20% reduction in their pain score on day 10. There was no toxicity (J. Pain Symptom Manage. 2010;40:883-91).

"When you see that sort of effect size, you can’t believe it’s real," Dr. Smith observed. "That’s in fact what the first reviewer said of the article. He said, ‘I’ve never heard of this therapy, and I don’t believe it.’ I volunteered to give him the case reports."

Neuropathic pain reductions in the 60% range are what are seen with permanent implanted spinal cord stimulation devices, a therapy that runs about $40,000, he added.

Dr. Smith’s Scrambler pilot study results were confirmed in an Italian study involving 40 patients with refractory cancer and 33 with non–cancer-related pain. Their mean pretreatment pain scale score was 6.2, plunging to 1.6 after the 10th day of treatment, and rebounding to 2.9 at follow-up 2 weeks after the final treatment session. Again, there were no side effects (Support Care Cancer. 2012;20:405-12).

Separately, a group led by the Scrambler’s inventor, Giuseppe Marineo, Ph.D., of the University of Rome Tor Vergata, reported on a randomized but unblinded trial involving 52 patients with chronic failed back syndrome, post-herpetic neuralgia, or spinal cord stenosis. Subjects assigned to the control arm received pharmacotherapy according to European Federation of Neurological Societies guidelines (Eur. J. Neurol. 2010;17:1113-e88), while the intervention arm received 10 daily Scrambler sessions.

The pretreatment mean visual analog pain score fell in 1 month from 8.1 in a control group and 8.0 in a group treated with the Scrambler to 5.8 in controls and to 0.7 in the Scrambler group. At 2 and 3 months of follow-up, the mean pain scores were 1.4 and 2.0 points, respectively, in the Scrambler group but were still 5.7 and 5.9 points in controls. A marked and persistent reduction in allodynia was also documented in response to Scrambler therapy (J. Pain Symptom Manage. 2012;43:87-95).

With regard to post-herpetic neuralgia, Dr. Smith presented a series of 10 treated patients. Their mean pain scores dropped from 8 at baseline to less than 1 at 1 month, holding steady with a score of 2 at 2 and 3 months’ follow-up.

The Scrambler entails application of 16 ECG-like electrode pads placed along the dermatome above and below the site of pain. The Scrambler machine is designed to feed 16 different nerve potentials in rapid sequence, essentially in order to confuse a firing nerve. The electrical charge is individually adjusted to patient tolerance. It feels like a bee sting, according to Dr. Smith. The mechanism of benefit isn’t well defined as yet.

"It’s likely acting like direct spinal cord stimulation, raising the gate threshold," he continued. "My hypothesis – and the inventor’s hypothesis as well – is that the therapy resets the damaged nerves at several sites. You see some effect within the first 30 minutes, and that rapid onset suggests biochemical change. And the long-lasting nature of the pain relief suggests remodeling as well as adaptation to the pain."

Clearly, further studies need to be done – free of industry sponsorship, on larger numbers of patients, and with sham-treated controls – in order to fully assess the Scrambler therapy’s efficacy, mechanism of action, and optimal schedule.

"The Scrambler is one of several neurocutaneous direct nerve stimulation techniques that are interesting but absolutely require further testing," Dr. Smith said.

Dr. Charles L. Loprinzi, professor of oncology at the Mayo Clinic, Rochester, Minn., has started such studies, he noted. "He was at least as skeptical of this as I was, and he’s been impressed with results from this machine," Dr. Smith said, adding that Dr. Loprinzi’s research team is expected to present data later this year at the annual meeting of the American Society of Clinical Oncology.

Competitive Technologies Inc., based in Fairfield, Conn., has worldwide rights to the device. Dr. Smith reported having no financial conflicts.

DENVER – Electrocutaneous direct nerve stimulation via a device that scrambles "pain" and "no pain" signals reduced pain scores in preliminary studies involving patients with refractory chemotherapy-induced peripheral neuropathy, post-herpetic neuralgia, and other forms of chronic, disabling neuropathic pain.

"What I saw in our pilot study in patients with chemotherapy-induced peripheral neuropathy was about a 60% reduction in pain, and you knew right away – within the first 3 days – whether it was going to work," said Dr. Thomas J. Smith, professor of oncology and director of palliative care at Johns Hopkins University, Baltimore.

The device, known as the MC5-A Calmare Scrambler, received Food and Drug Administration clearance in February 2009 and has a Medicare payment code. The Scrambler has been used worldwide to treat more than 4,000 patients with no reported serious side effects. Yet few American physicians have heard of the therapy because Medicare fixed the payment so low (at $44) that there is little financial incentive to adopt it, according to Dr. Smith.

"There’s not much you can do in the hospital outpatient setting for $44. That barely covers the cost of the electrodes and maybe a technician’s time," he said at the annual meeting of the American Academy of Hospice and Palliative Care Medicine. "They set the reimbursement so low that it’s almost guaranteed not to be accepted by physicians until we get more evidence. But there are a significant number of studies in the works."

Chemotherapy-induced peripheral neuropathy affects up to 30%-40% of treated cancer patients. Dr. Smith’s pilot study involved 16 patients with refractory chemotherapy-induced peripheral neuropathy that lasted from 3 months to 8 years. The most common drugs involved were taxanes, platinum-based agents, and bortezomib (Velcade). Patients received hour-long Scrambler sessions daily on 10 consecutive working days.

Pain scores fell from a mean baseline score of 5.8 on a 10-point scale to 2.4 at the end of 10 days. Four patients had a pain score of 0, and 15 of the 16 patients had at least a 20% reduction in their pain score on day 10. There was no toxicity (J. Pain Symptom Manage. 2010;40:883-91).

"When you see that sort of effect size, you can’t believe it’s real," Dr. Smith observed. "That’s in fact what the first reviewer said of the article. He said, ‘I’ve never heard of this therapy, and I don’t believe it.’ I volunteered to give him the case reports."

Neuropathic pain reductions in the 60% range are what are seen with permanent implanted spinal cord stimulation devices, a therapy that runs about $40,000, he added.

Dr. Smith’s Scrambler pilot study results were confirmed in an Italian study involving 40 patients with refractory cancer and 33 with non–cancer-related pain. Their mean pretreatment pain scale score was 6.2, plunging to 1.6 after the 10th day of treatment, and rebounding to 2.9 at follow-up 2 weeks after the final treatment session. Again, there were no side effects (Support Care Cancer. 2012;20:405-12).

Separately, a group led by the Scrambler’s inventor, Giuseppe Marineo, Ph.D., of the University of Rome Tor Vergata, reported on a randomized but unblinded trial involving 52 patients with chronic failed back syndrome, post-herpetic neuralgia, or spinal cord stenosis. Subjects assigned to the control arm received pharmacotherapy according to European Federation of Neurological Societies guidelines (Eur. J. Neurol. 2010;17:1113-e88), while the intervention arm received 10 daily Scrambler sessions.

The pretreatment mean visual analog pain score fell in 1 month from 8.1 in a control group and 8.0 in a group treated with the Scrambler to 5.8 in controls and to 0.7 in the Scrambler group. At 2 and 3 months of follow-up, the mean pain scores were 1.4 and 2.0 points, respectively, in the Scrambler group but were still 5.7 and 5.9 points in controls. A marked and persistent reduction in allodynia was also documented in response to Scrambler therapy (J. Pain Symptom Manage. 2012;43:87-95).

With regard to post-herpetic neuralgia, Dr. Smith presented a series of 10 treated patients. Their mean pain scores dropped from 8 at baseline to less than 1 at 1 month, holding steady with a score of 2 at 2 and 3 months’ follow-up.

The Scrambler entails application of 16 ECG-like electrode pads placed along the dermatome above and below the site of pain. The Scrambler machine is designed to feed 16 different nerve potentials in rapid sequence, essentially in order to confuse a firing nerve. The electrical charge is individually adjusted to patient tolerance. It feels like a bee sting, according to Dr. Smith. The mechanism of benefit isn’t well defined as yet.

"It’s likely acting like direct spinal cord stimulation, raising the gate threshold," he continued. "My hypothesis – and the inventor’s hypothesis as well – is that the therapy resets the damaged nerves at several sites. You see some effect within the first 30 minutes, and that rapid onset suggests biochemical change. And the long-lasting nature of the pain relief suggests remodeling as well as adaptation to the pain."

Clearly, further studies need to be done – free of industry sponsorship, on larger numbers of patients, and with sham-treated controls – in order to fully assess the Scrambler therapy’s efficacy, mechanism of action, and optimal schedule.

"The Scrambler is one of several neurocutaneous direct nerve stimulation techniques that are interesting but absolutely require further testing," Dr. Smith said.

Dr. Charles L. Loprinzi, professor of oncology at the Mayo Clinic, Rochester, Minn., has started such studies, he noted. "He was at least as skeptical of this as I was, and he’s been impressed with results from this machine," Dr. Smith said, adding that Dr. Loprinzi’s research team is expected to present data later this year at the annual meeting of the American Society of Clinical Oncology.

Competitive Technologies Inc., based in Fairfield, Conn., has worldwide rights to the device. Dr. Smith reported having no financial conflicts.

MIAMI – Patients who are diagnosed with multiple myeloma can expect to live longer than in the past, but their symptom burden remains considerable for at least 10 years after diagnosis, a prospective, population-based, Dutch study has concluded.

"The symptom burden is not only caused by the disease itself but also by the new aggressive treatments," said Floortje Mols, Ph.D., of Tilburg (the Netherlands) University at the annual conference of the American Psychosocial Oncology Society.

Dr. Mols and her coauthors identified multiple myeloma patients in the Eindhoven (the Netherlands) Cancer Registry who had been diagnosed during 1999-2010 in that country. They surveyed the survivors twice – at baseline and a year later – along with an age- and sex-matched population-based cohort.

At baseline, 156 survivors reported significantly lower scores than did the control group on every subscale of the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire), a validated instrument that has been used in more than 3,000 published studies. No significant differences were seen in symptom and quality of life scores between short-term (defined as up to 5 years) and long-term (more than 5 years) survivors, she reported.

Physical functioning, fatigue, and dyspnea scores diverged from those in the controls most strikingly, but the difference was statistically significant for every subscale with P scores of less than 0.01 and beyond, said Dr. Mols, a medical psychologist at the university’s center of research on psychology in somatic diseases and the Comprehensive Cancer Centre South, Eindhoven.

In addition, multiple myeloma survivors reported a high rate of disease-specific symptoms, including tingling and numbness, pain, and drowsiness – even years beyond diagnosis. Peripheral neuropathy is a common side effect of therapy for multiple myeloma.

At baseline, 37% of short- and long-term survivors reported worrying about their health during the previous week, 34% reported worrying about their disease, and 21% reported worrying "very much or quite a bit" about dying.

In the second round, at a 1-year follow-up, 80 survivors (including some diagnosed more recently) responded to the same questionnaire. Over that time, quality of life had diminished further for 74% of respondents (mean score, 55 vs. 68; P less than .001).

Half of the patients reported more fatigue, 71% more nausea and vomiting, 59% more pain, and 66% more dyspnea than at baseline. The most bothersome symptoms cited in the follow-up survey included tingling of the hands and feet (32%), back pain (28%), bone aches and pain (26%), pain in the arms and shoulders (19%), and drowsiness (18%).

"Maximizing disease control while minimizing these symptoms with supportive care for the entire survivorship trajectory is, I think, one of the major challenges of multiple myeloma treatment," said Dr. Mols.

She recommended referral of survivors to specific cancer survivorship care programs for management of symptoms that extend beyond the active phase of their treatment.

Improvement – and Side Effects

Dr. William I. Bensinger, who was not affiliated with the study, said following the meeting that the results were "not surprising."

"We have made great strides in the management of multiple myeloma, and patients are clearly living longer. Some of these improved treatments, however, come with the risk of significant side effects," said Dr. Bensinger, professor of medicine at the University of Washington and Fred Hutchinson Cancer Research Center in Seattle.

Dr. Bensinger called the results "a wake-up call to my fellow oncologists that we need to do a better job of proactively managing symptoms of treatment in order to improve our patients’ quality of life."

Ebb and Flow in QOL

Another multiple myeloma specialist, Dr. Jayesh Mehta, a professor of medicine at Northwestern University in Chicago, said that quality of life may ebb and flow over the course of many years in survivors.

"What we see in a typical patient is somewhat impaired quality of life at baseline that may worsen or remain stable in the short term, but improves by a year after diagnosis, remains good for a few years – say, 3 to 5 – worsens somewhat when there is relapse due to disease and therapy, stabilizes as the disease responds, and then worsens again when the disease returns."

Funding for the study was provided by the Netherlands Organization for Scientific Research, the Dutch Cancer Society, the Jonker-Driessen Foundation, ZonMW (the Netherlands organization for health research and development), and PHAROS (Population-Based Haematological Registry for Observational Studies).

MIAMI – Patients who are diagnosed with multiple myeloma can expect to live longer than in the past, but their symptom burden remains considerable for at least 10 years after diagnosis, a prospective, population-based, Dutch study has concluded.

"The symptom burden is not only caused by the disease itself but also by the new aggressive treatments," said Floortje Mols, Ph.D., of Tilburg (the Netherlands) University at the annual conference of the American Psychosocial Oncology Society.

Dr. Mols and her coauthors identified multiple myeloma patients in the Eindhoven (the Netherlands) Cancer Registry who had been diagnosed during 1999-2010 in that country. They surveyed the survivors twice – at baseline and a year later – along with an age- and sex-matched population-based cohort.

At baseline, 156 survivors reported significantly lower scores than did the control group on every subscale of the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire), a validated instrument that has been used in more than 3,000 published studies. No significant differences were seen in symptom and quality of life scores between short-term (defined as up to 5 years) and long-term (more than 5 years) survivors, she reported.

Physical functioning, fatigue, and dyspnea scores diverged from those in the controls most strikingly, but the difference was statistically significant for every subscale with P scores of less than 0.01 and beyond, said Dr. Mols, a medical psychologist at the university’s center of research on psychology in somatic diseases and the Comprehensive Cancer Centre South, Eindhoven.

In addition, multiple myeloma survivors reported a high rate of disease-specific symptoms, including tingling and numbness, pain, and drowsiness – even years beyond diagnosis. Peripheral neuropathy is a common side effect of therapy for multiple myeloma.

At baseline, 37% of short- and long-term survivors reported worrying about their health during the previous week, 34% reported worrying about their disease, and 21% reported worrying "very much or quite a bit" about dying.

In the second round, at a 1-year follow-up, 80 survivors (including some diagnosed more recently) responded to the same questionnaire. Over that time, quality of life had diminished further for 74% of respondents (mean score, 55 vs. 68; P less than .001).

Half of the patients reported more fatigue, 71% more nausea and vomiting, 59% more pain, and 66% more dyspnea than at baseline. The most bothersome symptoms cited in the follow-up survey included tingling of the hands and feet (32%), back pain (28%), bone aches and pain (26%), pain in the arms and shoulders (19%), and drowsiness (18%).

"Maximizing disease control while minimizing these symptoms with supportive care for the entire survivorship trajectory is, I think, one of the major challenges of multiple myeloma treatment," said Dr. Mols.

She recommended referral of survivors to specific cancer survivorship care programs for management of symptoms that extend beyond the active phase of their treatment.

Improvement – and Side Effects

Dr. William I. Bensinger, who was not affiliated with the study, said following the meeting that the results were "not surprising."

"We have made great strides in the management of multiple myeloma, and patients are clearly living longer. Some of these improved treatments, however, come with the risk of significant side effects," said Dr. Bensinger, professor of medicine at the University of Washington and Fred Hutchinson Cancer Research Center in Seattle.

Dr. Bensinger called the results "a wake-up call to my fellow oncologists that we need to do a better job of proactively managing symptoms of treatment in order to improve our patients’ quality of life."

Ebb and Flow in QOL

Another multiple myeloma specialist, Dr. Jayesh Mehta, a professor of medicine at Northwestern University in Chicago, said that quality of life may ebb and flow over the course of many years in survivors.

"What we see in a typical patient is somewhat impaired quality of life at baseline that may worsen or remain stable in the short term, but improves by a year after diagnosis, remains good for a few years – say, 3 to 5 – worsens somewhat when there is relapse due to disease and therapy, stabilizes as the disease responds, and then worsens again when the disease returns."

Funding for the study was provided by the Netherlands Organization for Scientific Research, the Dutch Cancer Society, the Jonker-Driessen Foundation, ZonMW (the Netherlands organization for health research and development), and PHAROS (Population-Based Haematological Registry for Observational Studies).

MIAMI – Patients who are diagnosed with multiple myeloma can expect to live longer than in the past, but their symptom burden remains considerable for at least 10 years after diagnosis, a prospective, population-based, Dutch study has concluded.

"The symptom burden is not only caused by the disease itself but also by the new aggressive treatments," said Floortje Mols, Ph.D., of Tilburg (the Netherlands) University at the annual conference of the American Psychosocial Oncology Society.

Dr. Mols and her coauthors identified multiple myeloma patients in the Eindhoven (the Netherlands) Cancer Registry who had been diagnosed during 1999-2010 in that country. They surveyed the survivors twice – at baseline and a year later – along with an age- and sex-matched population-based cohort.

At baseline, 156 survivors reported significantly lower scores than did the control group on every subscale of the EORTC QLQ-C30 (European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire), a validated instrument that has been used in more than 3,000 published studies. No significant differences were seen in symptom and quality of life scores between short-term (defined as up to 5 years) and long-term (more than 5 years) survivors, she reported.

Physical functioning, fatigue, and dyspnea scores diverged from those in the controls most strikingly, but the difference was statistically significant for every subscale with P scores of less than 0.01 and beyond, said Dr. Mols, a medical psychologist at the university’s center of research on psychology in somatic diseases and the Comprehensive Cancer Centre South, Eindhoven.

In addition, multiple myeloma survivors reported a high rate of disease-specific symptoms, including tingling and numbness, pain, and drowsiness – even years beyond diagnosis. Peripheral neuropathy is a common side effect of therapy for multiple myeloma.

At baseline, 37% of short- and long-term survivors reported worrying about their health during the previous week, 34% reported worrying about their disease, and 21% reported worrying "very much or quite a bit" about dying.

In the second round, at a 1-year follow-up, 80 survivors (including some diagnosed more recently) responded to the same questionnaire. Over that time, quality of life had diminished further for 74% of respondents (mean score, 55 vs. 68; P less than .001).

Half of the patients reported more fatigue, 71% more nausea and vomiting, 59% more pain, and 66% more dyspnea than at baseline. The most bothersome symptoms cited in the follow-up survey included tingling of the hands and feet (32%), back pain (28%), bone aches and pain (26%), pain in the arms and shoulders (19%), and drowsiness (18%).

"Maximizing disease control while minimizing these symptoms with supportive care for the entire survivorship trajectory is, I think, one of the major challenges of multiple myeloma treatment," said Dr. Mols.

She recommended referral of survivors to specific cancer survivorship care programs for management of symptoms that extend beyond the active phase of their treatment.

Improvement – and Side Effects

Dr. William I. Bensinger, who was not affiliated with the study, said following the meeting that the results were "not surprising."

"We have made great strides in the management of multiple myeloma, and patients are clearly living longer. Some of these improved treatments, however, come with the risk of significant side effects," said Dr. Bensinger, professor of medicine at the University of Washington and Fred Hutchinson Cancer Research Center in Seattle.

Dr. Bensinger called the results "a wake-up call to my fellow oncologists that we need to do a better job of proactively managing symptoms of treatment in order to improve our patients’ quality of life."

Ebb and Flow in QOL

Another multiple myeloma specialist, Dr. Jayesh Mehta, a professor of medicine at Northwestern University in Chicago, said that quality of life may ebb and flow over the course of many years in survivors.

"What we see in a typical patient is somewhat impaired quality of life at baseline that may worsen or remain stable in the short term, but improves by a year after diagnosis, remains good for a few years – say, 3 to 5 – worsens somewhat when there is relapse due to disease and therapy, stabilizes as the disease responds, and then worsens again when the disease returns."

Funding for the study was provided by the Netherlands Organization for Scientific Research, the Dutch Cancer Society, the Jonker-Driessen Foundation, ZonMW (the Netherlands organization for health research and development), and PHAROS (Population-Based Haematological Registry for Observational Studies).

Patients with juvenile idiopathic arthritis have an increased rate of malignancy, compared with unaffected children, according to a report published online Feb. 13 in Arthritis & Rheumatism.

The increased cancer incidence, which ranged from 1.4 to 4.5 times higher than that in comparison groups of children with other chronic diseases, is not significantly associated with JIA treatments, including tumor necrosis factor–inhibiting agents, said Dr. Timothy Beukelman of the division of pediatric rheumatology, University of Alabama at Birmingham, and his associates.

The Food and Drug Administration issued a black box warning on TNF inhibitors in 2009, cautioning that there was an increased risk of malignancy (particularly lymphoma) in pediatric patients who used the drugs, based on reports to the Adverse Event Reporting System. But critics argued that the warning was premature because of the limited data on the background rate of malignancy in this patient population.

"Chronic autoimmune inflammatory conditions such as JIA may be associated with an increased risk of malignancy irrespective of specific therapeutic agents. For example, an increased risk of lymphoma has been observed among adults with rheumatoid arthritis, particularly among those with a high burden of inflammatory activity," De. Beukelman and his colleagues noted.

Moreover, most JIA patients who are treated with TNF inhibitors also receive other drugs, including methotrexate, which may themselves contribute to a higher cancer risk.

The investigators assessed the background rate of malignancy in JIA by using the Medicaid Analytic eXtract (MAX) administrative database, hoping that such a large source would contain sufficient numbers to allow study of two rare disorders: JIA and childhood cancer. The MAX database includes the medical and pharmacy records of all low-income children who receive government medical assistance.

The study assessed 7,812 JIA patients who were followed for approximately 2 years, for a total follow-up time of 12, 614 person-years.

For an "internal" comparison, the researchers also assessed the background cancer rate among children in the database who had two other chronic conditions: asthma (652,234 subjects) and attention-deficit/hyperactivity disorder (321,821 subjects). For an "external" comparison, they obtained population-based estimates of cancer rates from the SEER (Surveillance Epidemiology and End Results) database.

The JIA patients’ medication exposures were divided into three categories by drug class: methotrexate or leflunomide; TNF inhibitors (etanercept, infliximab, or adalimumab); and other immunomodulatory agents (abatacept, alefacept, anakinra, azathioprine, cyclophosphamide, cyclosporine, efalizumab, 6-mercaptopurine, mycophenolate mofetil, rituximab, or tacrolimus).

A total of 3,423 JIA patients (44%) had taken methotrexate or leflunomide; 1,484 (19%) had taken TNF inhibitors; 398 (5%) had taken other immunomodulatory agents; and 2,507 (32%) had not taken any of these drugs.

Only 10 cancers were identified in the JIA patients. Six of them (three brain malignancies, one leukemia, one soft tissue cancer, and one gastrointestinal cancer) developed in the children who had not been exposed to any of the drugs. Three malignancies (two leukemias and one soft tissue cancer) developed in children who had taken methotrexate but not TNF inhibitors. And one malignancy (uterine cancer) developed in a child who had taken TNF inhibitors.

Thus, there was no association between TNF inhibitors and cancer, and there were no cases of lymphoma in any of the children who had JIA, the investigators said (Arthritis Rheum. 2012 Feb. 13 [doi:10.1002/art.34348]).

Compared with the study subjects who had asthma or ADHD, the JIA group had an overall cancer rate that was 1.4-4.5 times higher. The findings were similar when the analysis was restricted only to hematologic cancers.

"The SEER external comparator standardized malignancy rates were significantly lower than the ADHD and asthma internal comparator rates," the researchers noted. This means that study subjects with JIA had even higher rates of cancer, regardless of the treatments they received, than would be expected in the general population based on SEER data.

There are several reasons why JIA might be associated with an increased risk of cancer. Rheumatoid arthritis is known to raise the risk of malignancy, particularly lymphoma. And arthritis medications suppress the immune system, although "we also found an increased rate of malignancies among children not treated with systemic immunosuppression."

It is also possible that JIA patients are more carefully screened for cancer because of the extensive contact they have with the health care system. And finally, some malignancies, especially acute leukemias, may initially be misdiagnosed as JIA, Dr. Beukelman and his colleagues said.

This study was supported by the Agency for Healthcare Research and Quality, the FDA, and the National Institutes of Health. No financial conflicts of interest were reported by the researchers.

Patients with juvenile idiopathic arthritis have an increased rate of malignancy, compared with unaffected children, according to a report published online Feb. 13 in Arthritis & Rheumatism.

The increased cancer incidence, which ranged from 1.4 to 4.5 times higher than that in comparison groups of children with other chronic diseases, is not significantly associated with JIA treatments, including tumor necrosis factor–inhibiting agents, said Dr. Timothy Beukelman of the division of pediatric rheumatology, University of Alabama at Birmingham, and his associates.

The Food and Drug Administration issued a black box warning on TNF inhibitors in 2009, cautioning that there was an increased risk of malignancy (particularly lymphoma) in pediatric patients who used the drugs, based on reports to the Adverse Event Reporting System. But critics argued that the warning was premature because of the limited data on the background rate of malignancy in this patient population.

"Chronic autoimmune inflammatory conditions such as JIA may be associated with an increased risk of malignancy irrespective of specific therapeutic agents. For example, an increased risk of lymphoma has been observed among adults with rheumatoid arthritis, particularly among those with a high burden of inflammatory activity," De. Beukelman and his colleagues noted.

Moreover, most JIA patients who are treated with TNF inhibitors also receive other drugs, including methotrexate, which may themselves contribute to a higher cancer risk.

The investigators assessed the background rate of malignancy in JIA by using the Medicaid Analytic eXtract (MAX) administrative database, hoping that such a large source would contain sufficient numbers to allow study of two rare disorders: JIA and childhood cancer. The MAX database includes the medical and pharmacy records of all low-income children who receive government medical assistance.

The study assessed 7,812 JIA patients who were followed for approximately 2 years, for a total follow-up time of 12, 614 person-years.

For an "internal" comparison, the researchers also assessed the background cancer rate among children in the database who had two other chronic conditions: asthma (652,234 subjects) and attention-deficit/hyperactivity disorder (321,821 subjects). For an "external" comparison, they obtained population-based estimates of cancer rates from the SEER (Surveillance Epidemiology and End Results) database.

The JIA patients’ medication exposures were divided into three categories by drug class: methotrexate or leflunomide; TNF inhibitors (etanercept, infliximab, or adalimumab); and other immunomodulatory agents (abatacept, alefacept, anakinra, azathioprine, cyclophosphamide, cyclosporine, efalizumab, 6-mercaptopurine, mycophenolate mofetil, rituximab, or tacrolimus).

A total of 3,423 JIA patients (44%) had taken methotrexate or leflunomide; 1,484 (19%) had taken TNF inhibitors; 398 (5%) had taken other immunomodulatory agents; and 2,507 (32%) had not taken any of these drugs.

Only 10 cancers were identified in the JIA patients. Six of them (three brain malignancies, one leukemia, one soft tissue cancer, and one gastrointestinal cancer) developed in the children who had not been exposed to any of the drugs. Three malignancies (two leukemias and one soft tissue cancer) developed in children who had taken methotrexate but not TNF inhibitors. And one malignancy (uterine cancer) developed in a child who had taken TNF inhibitors.

Thus, there was no association between TNF inhibitors and cancer, and there were no cases of lymphoma in any of the children who had JIA, the investigators said (Arthritis Rheum. 2012 Feb. 13 [doi:10.1002/art.34348]).

Compared with the study subjects who had asthma or ADHD, the JIA group had an overall cancer rate that was 1.4-4.5 times higher. The findings were similar when the analysis was restricted only to hematologic cancers.

"The SEER external comparator standardized malignancy rates were significantly lower than the ADHD and asthma internal comparator rates," the researchers noted. This means that study subjects with JIA had even higher rates of cancer, regardless of the treatments they received, than would be expected in the general population based on SEER data.

There are several reasons why JIA might be associated with an increased risk of cancer. Rheumatoid arthritis is known to raise the risk of malignancy, particularly lymphoma. And arthritis medications suppress the immune system, although "we also found an increased rate of malignancies among children not treated with systemic immunosuppression."

It is also possible that JIA patients are more carefully screened for cancer because of the extensive contact they have with the health care system. And finally, some malignancies, especially acute leukemias, may initially be misdiagnosed as JIA, Dr. Beukelman and his colleagues said.

This study was supported by the Agency for Healthcare Research and Quality, the FDA, and the National Institutes of Health. No financial conflicts of interest were reported by the researchers.

Patients with juvenile idiopathic arthritis have an increased rate of malignancy, compared with unaffected children, according to a report published online Feb. 13 in Arthritis & Rheumatism.

The increased cancer incidence, which ranged from 1.4 to 4.5 times higher than that in comparison groups of children with other chronic diseases, is not significantly associated with JIA treatments, including tumor necrosis factor–inhibiting agents, said Dr. Timothy Beukelman of the division of pediatric rheumatology, University of Alabama at Birmingham, and his associates.

The Food and Drug Administration issued a black box warning on TNF inhibitors in 2009, cautioning that there was an increased risk of malignancy (particularly lymphoma) in pediatric patients who used the drugs, based on reports to the Adverse Event Reporting System. But critics argued that the warning was premature because of the limited data on the background rate of malignancy in this patient population.

"Chronic autoimmune inflammatory conditions such as JIA may be associated with an increased risk of malignancy irrespective of specific therapeutic agents. For example, an increased risk of lymphoma has been observed among adults with rheumatoid arthritis, particularly among those with a high burden of inflammatory activity," De. Beukelman and his colleagues noted.

Moreover, most JIA patients who are treated with TNF inhibitors also receive other drugs, including methotrexate, which may themselves contribute to a higher cancer risk.

The investigators assessed the background rate of malignancy in JIA by using the Medicaid Analytic eXtract (MAX) administrative database, hoping that such a large source would contain sufficient numbers to allow study of two rare disorders: JIA and childhood cancer. The MAX database includes the medical and pharmacy records of all low-income children who receive government medical assistance.

The study assessed 7,812 JIA patients who were followed for approximately 2 years, for a total follow-up time of 12, 614 person-years.

For an "internal" comparison, the researchers also assessed the background cancer rate among children in the database who had two other chronic conditions: asthma (652,234 subjects) and attention-deficit/hyperactivity disorder (321,821 subjects). For an "external" comparison, they obtained population-based estimates of cancer rates from the SEER (Surveillance Epidemiology and End Results) database.

The JIA patients’ medication exposures were divided into three categories by drug class: methotrexate or leflunomide; TNF inhibitors (etanercept, infliximab, or adalimumab); and other immunomodulatory agents (abatacept, alefacept, anakinra, azathioprine, cyclophosphamide, cyclosporine, efalizumab, 6-mercaptopurine, mycophenolate mofetil, rituximab, or tacrolimus).

A total of 3,423 JIA patients (44%) had taken methotrexate or leflunomide; 1,484 (19%) had taken TNF inhibitors; 398 (5%) had taken other immunomodulatory agents; and 2,507 (32%) had not taken any of these drugs.

Only 10 cancers were identified in the JIA patients. Six of them (three brain malignancies, one leukemia, one soft tissue cancer, and one gastrointestinal cancer) developed in the children who had not been exposed to any of the drugs. Three malignancies (two leukemias and one soft tissue cancer) developed in children who had taken methotrexate but not TNF inhibitors. And one malignancy (uterine cancer) developed in a child who had taken TNF inhibitors.

Thus, there was no association between TNF inhibitors and cancer, and there were no cases of lymphoma in any of the children who had JIA, the investigators said (Arthritis Rheum. 2012 Feb. 13 [doi:10.1002/art.34348]).

Compared with the study subjects who had asthma or ADHD, the JIA group had an overall cancer rate that was 1.4-4.5 times higher. The findings were similar when the analysis was restricted only to hematologic cancers.

"The SEER external comparator standardized malignancy rates were significantly lower than the ADHD and asthma internal comparator rates," the researchers noted. This means that study subjects with JIA had even higher rates of cancer, regardless of the treatments they received, than would be expected in the general population based on SEER data.

There are several reasons why JIA might be associated with an increased risk of cancer. Rheumatoid arthritis is known to raise the risk of malignancy, particularly lymphoma. And arthritis medications suppress the immune system, although "we also found an increased rate of malignancies among children not treated with systemic immunosuppression."

It is also possible that JIA patients are more carefully screened for cancer because of the extensive contact they have with the health care system. And finally, some malignancies, especially acute leukemias, may initially be misdiagnosed as JIA, Dr. Beukelman and his colleagues said.

This study was supported by the Agency for Healthcare Research and Quality, the FDA, and the National Institutes of Health. No financial conflicts of interest were reported by the researchers.