Multiple Myeloma

The use of pembrolizumab (Keytruda) in combination with dexamethasone and either lenalidomide or pomalidomide is associated with an increased risk of death in patients with multiple myeloma, according to an alert from the Food and Drug Administration.

The FDA issued the alert on Aug. 31 to inform the public, health care professionals, and oncology clinical investigators of the risk, which became apparent during the course of two now-halted clinical trials.

[email protected]

The use of pembrolizumab (Keytruda) in combination with dexamethasone and either lenalidomide or pomalidomide is associated with an increased risk of death in patients with multiple myeloma, according to an alert from the Food and Drug Administration.

The FDA issued the alert on Aug. 31 to inform the public, health care professionals, and oncology clinical investigators of the risk, which became apparent during the course of two now-halted clinical trials.

[email protected]

The use of pembrolizumab (Keytruda) in combination with dexamethasone and either lenalidomide or pomalidomide is associated with an increased risk of death in patients with multiple myeloma, according to an alert from the Food and Drug Administration.

The FDA issued the alert on Aug. 31 to inform the public, health care professionals, and oncology clinical investigators of the risk, which became apparent during the course of two now-halted clinical trials.

[email protected]

Photo courtesy of Janssen

Interim results of a phase 3 study suggest adding daratumumab to a 3-drug regimen can improve progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (MM).

In the phase 3 ALCYONE study, researchers are comparing daratumumab in combination with bortezomib, melphalan, and prednisone (VMP) to VMP alone in patients with newly diagnosed MM who are not considered candidates for autologous stem cell transplant.

Genmab A/S recently announced interim results from this trial and said additional data are expected to be submitted for presentation at an upcoming medical conference and for publication in a peer-reviewed journal.

The ALCYONE trial enrolled 706 patients who were randomized to receive 9 cycles of daratumumab plus VMP or VMP alone.

In the daratumumab arm, patients received 16 mg/kg of daratumumab once weekly for 6 weeks (cycle 1; 1 cycle = 42 days), followed by once every 3 weeks (cycles 2-9). After that, patients continued to receive 16 mg/kg of daratumumab once every 4 weeks until disease progression.

At the pre-planned interim analysis, the study’s primary endpoint was met. Treatment with daratumumab reduced the risk of disease progression or death by 50% when compared to VMP alone (hazard ratio=0.50; 95% CI 0.38-0.65; P<0.0001).

The median PFS has not been reached in the daratumumab arm but was an estimated 18.1 months for patients who received VMP alone.

Genmab said that, overall, the safety profile of daratumumab in combination with VMP is consistent with the known safety profile of the VMP regimen and the known safety profile of daratumumab.

Based on these results, an independent data monitoring committee recommended the data be unblinded. All patients will continue to be monitored for safety and overall survival.

Janssen Biotech, Inc., which licensed daratumumab from Genmab in 2012, said it will discuss with health authorities the potential for a regulatory submission for daratumumab in combination with VMP as a treatment for newly diagnosed MM.

Daratumumab is already approved in the US (as DARZALEX®) for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat MM patients who have received at least 1 prior therapy.

Daratumumab is also approved for use in combination with pomalidomide and dexamethasone to treat MM patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (PI).

And daratumumab is approved as monotherapy for MM patients who have received at least 3 prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.

Photo courtesy of Janssen

Interim results of a phase 3 study suggest adding daratumumab to a 3-drug regimen can improve progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (MM).

In the phase 3 ALCYONE study, researchers are comparing daratumumab in combination with bortezomib, melphalan, and prednisone (VMP) to VMP alone in patients with newly diagnosed MM who are not considered candidates for autologous stem cell transplant.

Genmab A/S recently announced interim results from this trial and said additional data are expected to be submitted for presentation at an upcoming medical conference and for publication in a peer-reviewed journal.

The ALCYONE trial enrolled 706 patients who were randomized to receive 9 cycles of daratumumab plus VMP or VMP alone.

In the daratumumab arm, patients received 16 mg/kg of daratumumab once weekly for 6 weeks (cycle 1; 1 cycle = 42 days), followed by once every 3 weeks (cycles 2-9). After that, patients continued to receive 16 mg/kg of daratumumab once every 4 weeks until disease progression.

At the pre-planned interim analysis, the study’s primary endpoint was met. Treatment with daratumumab reduced the risk of disease progression or death by 50% when compared to VMP alone (hazard ratio=0.50; 95% CI 0.38-0.65; P<0.0001).

The median PFS has not been reached in the daratumumab arm but was an estimated 18.1 months for patients who received VMP alone.

Genmab said that, overall, the safety profile of daratumumab in combination with VMP is consistent with the known safety profile of the VMP regimen and the known safety profile of daratumumab.

Based on these results, an independent data monitoring committee recommended the data be unblinded. All patients will continue to be monitored for safety and overall survival.

Janssen Biotech, Inc., which licensed daratumumab from Genmab in 2012, said it will discuss with health authorities the potential for a regulatory submission for daratumumab in combination with VMP as a treatment for newly diagnosed MM.

Daratumumab is already approved in the US (as DARZALEX®) for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat MM patients who have received at least 1 prior therapy.

Daratumumab is also approved for use in combination with pomalidomide and dexamethasone to treat MM patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (PI).

And daratumumab is approved as monotherapy for MM patients who have received at least 3 prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.

Photo courtesy of Janssen

Interim results of a phase 3 study suggest adding daratumumab to a 3-drug regimen can improve progression-free survival (PFS) in patients with newly diagnosed multiple myeloma (MM).

In the phase 3 ALCYONE study, researchers are comparing daratumumab in combination with bortezomib, melphalan, and prednisone (VMP) to VMP alone in patients with newly diagnosed MM who are not considered candidates for autologous stem cell transplant.

Genmab A/S recently announced interim results from this trial and said additional data are expected to be submitted for presentation at an upcoming medical conference and for publication in a peer-reviewed journal.

The ALCYONE trial enrolled 706 patients who were randomized to receive 9 cycles of daratumumab plus VMP or VMP alone.

In the daratumumab arm, patients received 16 mg/kg of daratumumab once weekly for 6 weeks (cycle 1; 1 cycle = 42 days), followed by once every 3 weeks (cycles 2-9). After that, patients continued to receive 16 mg/kg of daratumumab once every 4 weeks until disease progression.

At the pre-planned interim analysis, the study’s primary endpoint was met. Treatment with daratumumab reduced the risk of disease progression or death by 50% when compared to VMP alone (hazard ratio=0.50; 95% CI 0.38-0.65; P<0.0001).

The median PFS has not been reached in the daratumumab arm but was an estimated 18.1 months for patients who received VMP alone.

Genmab said that, overall, the safety profile of daratumumab in combination with VMP is consistent with the known safety profile of the VMP regimen and the known safety profile of daratumumab.

Based on these results, an independent data monitoring committee recommended the data be unblinded. All patients will continue to be monitored for safety and overall survival.

Janssen Biotech, Inc., which licensed daratumumab from Genmab in 2012, said it will discuss with health authorities the potential for a regulatory submission for daratumumab in combination with VMP as a treatment for newly diagnosed MM.

Daratumumab is already approved in the US (as DARZALEX®) for use in combination with lenalidomide and dexamethasone, or bortezomib and dexamethasone, to treat MM patients who have received at least 1 prior therapy.

Daratumumab is also approved for use in combination with pomalidomide and dexamethasone to treat MM patients who have received at least 2 prior therapies, including lenalidomide and a proteasome inhibitor (PI).

And daratumumab is approved as monotherapy for MM patients who have received at least 3 prior lines of therapy, including a PI and an immunomodulatory agent, or who are double-refractory to a PI and an immunomodulatory agent.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

Image by Ed Uthman

An investigational antibody has demonstrated activity against acute myeloid leukemia (AML), multiple myeloma (MM), and non-Hodgkin lymphoma (NHL), according to researchers.

PF-06747143 is a humanized CXCR4 immunoglobulin G1 (IgG1) antibody that binds to CXCR4 and inhibits both CXCL12-mediated signaling pathways and cell migration.

Whether given alone or in combination with chemotherapy, PF-06747143 demonstrated efficacy in mouse models of NHL, MM, and AML.

Treatment involving PF-06747143—alone or in combination—eradicated more cancer cells than did standard treatment options.

These results were published in Blood Advances. The research was sponsored by Pfizer, Inc., the company developing PF-06747143.

“One of the major limitations we see in treating blood cancers is the failure to clear cancer cells from the bone marrow,” said study author Flavia Pernasetti, PhD, of Pfizer Oncology Research and Development.

“Because the bone marrow allows the cancer cells to flourish, removing these cells is an essential step in treating these malignancies effectively.”

With this goal in mind, Dr Pernasetti and her colleagues looked to the mechanisms that control the movement of cells into the bone marrow (BM) in the first place—the chemokine receptor CXCR4 and its ligand CXCL12.

The researchers created PF-06747143, which attacks and kills cancer cells directly but also removes cancer cells from the BM so they can be killed by other treatments.

Results in NHL

The researchers first tested PF-06747143 in an NHL Ramos xenograft model. Mice received PF-06747143 or a control IgG1 antibody at 10 mg/kg on days 1 and 8.

PF-06747143 significantly inhibited tumor growth compared to the control antibody (P<0.0001). Seventy percent of PF-06747143-treated mice had tumor volumes below their initial size at the end of the study.

PF-06747143 produced a dose-dependent response that was sustained until the end of the study, even after treatment was stopped.

Results in MM

The researchers tested PF-06747143 in a disseminated MM model, in which the OPM2-Luc tumor cells were implanted intravenously and migrated spontaneously to the BM.

Mice received PF-06747143 or IgG1 control at 10 mg/kg weekly for 5 doses. Other mice received melphalan at 1 mg/kg twice a week for a total of 4 cycles.

On day 30, PF-06747143 had significantly inhibited BM tumor growth compared to the control antibody or melphalan (P<0.0001).

PF-06747143-treated mice also had a significant survival benefit. The median survival was 33.5 days for mice that received the control antibody and 36 days for mice treated with melphalan. However, there were no deaths in the PF-06747143-treated mice by day 50, which marked the end of the study (P<0.0001).

The researchers also tested PF-06747143 at a lower dose (1 mg/kg weekly for a total of 7 doses), both alone and in combination with bortezomib (0.5 mg/kg twice a week for a total of 4 cycles).

The median survival was 34 days in the control mice, 44 days in mice that received bortezomib alone, and 47 days in mice that received PF-06747143 alone. However, there were no deaths in the combination arm at day 51, which was the end of the study (P<0.0003).

Results in AML

The researchers tested PF-06747143 in an AML disseminated tumor model using MV4-11 cells.

They compared PF-06747143 (given at 0.1, 1, or 10 mg/kg weekly for 4 doses) to the chemotherapeutic agent daunorubicin (2 mg/kg on days 1, 3, and 5), the FLT3 inhibitor crenolanib (7.5 mg/kg twice a day, on days 11-15 and 25-29), and a control IgG1 antibody (10 mg/kg weekly for 4 doses).

PF-06747143 (at 10 mg/kg), daunorubicin, and crenolanib all significantly reduced the number of tumor cells in the peripheral blood and BM when compared with the control antibody (P<0.05).

PF-06746143 treatment (at 10 mg/kg) reduced the number of AML cells in the BM by 95.9%, while daunorubicin reduced them by 84.5% and crenolanib by 80.5%.

The median survival was 36 days for mice that received PF-06747143 at 0.1 mg/kg, 41 days for mice that received the control antibody, 47 days for mice that received PF-06747143 at 1 mg/kg, and 63 days for mice that received PF-06747143 at 10 mg/kg.

The researchers also found that PF-06747143 had a “strong combinatorial effect” with daunorubicin and cytarabine in a chemotherapy-resistant model of AML. The team noted that only 36% of BM cells are positive for CXCR4 in this model.

Treatment with PF-06747143 alone reduced the percentage of AML cells in the BM to 80%, combination daunorubicin and cytarabine reduced it to 27%, and combination PF-06747143, daunorubicin, and cytarabine reduced the percentage of AML cells in the BM to 0.3%.

“Our preliminary preclinical results are encouraging,” Dr Pernasetti said, “and we are very excited to see how our antibody fares in clinical testing.”

PF-06747143 is currently being evaluated in a phase 1 trial of AML patients.

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.

Photo courtesy of Celgene

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.”

Photo courtesy of Celgene

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.”

Photo courtesy of Celgene

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.”

Photo by Steven Harbour

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.

Photo by Steven Harbour

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.

Photo by Steven Harbour

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.

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.

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.

Photo by Rhoda Baer

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.”

Photo by Rhoda Baer

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.”

Photo by Rhoda Baer

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.”