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SAN FRANCISCO – With multiple therapies and refinements in diagnostic and staging criteria, risk stratification, and transplantation, “we have made dramatic improvements in survival” for malignant myeloma, Dr. Damian J. Green told attendees of the NCCN Annual Congress: Hematologic Malignancies. In fact, he said, these advances have propelled the field toward a once unthinkable question: Can myeloma be cured?
Diagnostic criteria
The criteria used to diagnose active myeloma recently changed, noted Dr. Green of the University of Washington, the Multiple Myeloma and Stem Cell Transplant Program at the Seattle Cancer Care Alliance, and the Fred Hutchinson Cancer Research Center, all in Seattle.
Long-used CRAB criteria (calcium elevation, renal failure, anemia, and bone lesions) have been updated to incorporate three additional biomarkers – a bone marrow plasma cell percentage of 60% or greater, a serum free light chain ratio of 100 or greater, and a skeletal MRI or CT showing more than one focal lesion – conferring a very high risk of progression (Lancet Oncol. 2014;15[12]:e538-48).
“Many of us are using these new, independently validated factors, I would say, in select cases, not all the time. But they are now becoming part of the accepted dogma for determining in whom you might initiate therapy,” he said.
This change is likely to affect the epidemiology of smoldering myeloma, he noted. “We are taking the people at highest risk of progression and shifting them now, potentially, into the active group. What that means is whoever remains in the smoldering group, their prognosis is actually going to be better in the future.”
Staging criteria
The criteria used to stage myeloma have also changed, just in the past few months. The International Staging System (ISS) is about 15 years old. “The problem is it predated the era of novel therapy, and it predated our understanding of high-risk cytogenetics. That has been a long-term criticism,” Dr. Green said.
The new revised system, termed R-ISS, incorporates cytogenetics – designating 17p deletion, translocation 4;14, and translocation 14;16 as high-risk cytogenetics – as well as lactate dehydrogenase (J Clin Oncol. 2015;33:2863-9).
“I think there’s going to be uniform acceptance of this change. It’s a big deal in terms of how we manage these folks and in terms of what tests need to be ordered,” he said. “But it’s going to change things because lots of our interpretation of prior data is based on the old [system].”
Primary therapy
Numerous regimens are effective as primary therapy in myeloma, with expert consensus favoring three drugs over two for fit patients. Triple combinations achieve a greater depth of response, and deeper responses – whether assessed with multiparameter high-sensitivity flow cytometry (Blood. 2015;125:1932-5) or deep sequencing (Blood. 2014;123:3073-9) – correlate with better outcomes.
“Now I don’t know if that is just telling us about the basic biology of the disease – you respond better, therefore you have a better outcome – or if three drugs are definitively better than two up front,” Dr. Green said. “But until we know that, I think the consensus from the myeloma community is, three drugs in patients who can tolerate that.”
Forthcoming data to be presented at the ASH meeting will likely shed more light on the comparative efficacy of various primary regimens, he said.
The therapeutic options also are likely to increase soon, as two or three new drugs are likely to be approved for multiple myeloma in the next 6 months, he added.
Risk-adapted management
Another area of rapid change has been therapy that is adapted to a patient’s risk of progression, Dr. Green said. “Because we have all these new agents, that keeps changing. Is it high risk or isn’t it high risk based on cytogenetics? Maybe it was yesterday and it’s not today because some new agent is improving outcomes for a specific subset of patients.”
There is some disagreement on where, exactly, certain cytogenetics fall. But 17p deletion is generally viewed as high risk, and a recent study suggested that the survival benefit of bortezomib (Velcade) induction followed by maintenance after stem cell transplant in newly diagnosed myeloma was especially pronounced among patients with this cytogenetic abnormality (J Clin Oncol. 2012;30:2946-55).
“Although there’s not a randomized trial powered to prove this directly, we are beginning to understand and see that difference clinically. Patients who have 17p disease should see proteasome inhibitor therapy up front and I believe as part of their maintenance, unless they can’t tolerate it or are resistant to it,” Dr. Green recommended.
Stem cell transplant
“The data continue to support the use of an autologous stem cell transplant up front in the management of patients with myeloma after induction,” he contended.
Studies establishing the efficacy of transplant were done before the era of novel therapies. “Some people said all these novel therapies make transplant less important, but that really hasn’t been borne out. That debate is sort of falling away because we now have some new studies that have come out demonstrating a continued benefit in survival for patients who are able to and undergo an autologous stem cell transplant as part of their care,” he said.
“It is a standard of care and if you want proof of it, you can just look at the number of transplants we are doing of multiple myeloma in the United States every year,” he said. “It continues to increase and continues to be the No. 1 indication for transplant.”
Maintenance therapy post transplant
The best approach to maintenance therapy after transplant remains controversial, according to Dr. Green. Lenalidomide (Revlimid) is the standard of care in the United States based on three large trials, all of which showed a progression-free survival benefit of the drug, and one of which showed an overall survival benefit.
“That’s been the rationale for keeping patients on it,” he said, while noting that trials have differed with respect to patient populations and duration on the drug. However, patients with high-risk features may be good candidates for alternate agents.
Options for relapsed disease
Clonal evolution has become an area of interest as it pertains to treatment decisions in the relapsed myeloma setting. “Myeloma is a wily foe, it evolves over time: We find a good treatment against it and it evolves and there is progression,” Dr. Green said. For example, patients may be found to have a 17p deletion when they previously didn’t have one, which could tilt the treatment decision to bortezomib.
Hematologists should consider putting their patients with relapse on clinical trials testing salvage regimens, he said. “Only 4% of patients in the United States are enrolled in a clinical trial, and 40% of trials are closed due to low accrual. If you can get a patient on a trial, please do.”
A regimen that was successful previously in a given patient can be used again. And the roughly one dozen other options for relapsed disease now include the newcomers carfilzomib (Kyprolis), pomalidomide (Pomalyst), and panobinostat (Farydak).
The old drug melphalan (Alkeran) should not be overlooked either. “Melphalan should still be considered a part of salvage regimens for patients. If they have already undergone transplant or are not transplant candidates, at some point, they should receive melphalan, in my opinion,” he said.
Investigational agents
Various investigational agents are being evaluated in trials in myeloma. They include, for example, daratumumab, an anti-CD38 antibody that achieved a 36% response rate in patients with relapsed or relapsed, refractory disease (N Engl J Med. 2015;24;373[13]:1207-19), and elotuzumab, an anti-SLAM F7 antibody that when combined with lenalidomide and dexamethasone improved progression-free survival in patients with relapsed or refractory disease, both overall and among those with high-risk features (N Engl J Med. 2015;373[7]:621-31).
Chimeric antigen receptor (CAR) T cells also have been tested in myeloma (N Engl J Med. 2015;373[11]:1040-7). “I don’t think that this is going to be the home-run approach, but I do think it’s an interesting proof of principle,” Dr. Green said.
Taken together, data suggest that today, cure is within reach for at least a subset of patients with myeloma. For example, more than a third of those undergoing stem cell transplantation who have a complete response are still alive at 12 years, with some having long-term survival (Blood 2011;118:529-34).
“I’m betting that those are the patients who, if we were able to look back in time, we would have seen they had no evidence of minimal residual disease by looking with more of those technologies we now have available for depth of response,” proposed Dr. Green, who disclosed that he had no relevant conflicts of interest.
SAN FRANCISCO – With multiple therapies and refinements in diagnostic and staging criteria, risk stratification, and transplantation, “we have made dramatic improvements in survival” for malignant myeloma, Dr. Damian J. Green told attendees of the NCCN Annual Congress: Hematologic Malignancies. In fact, he said, these advances have propelled the field toward a once unthinkable question: Can myeloma be cured?
Diagnostic criteria
The criteria used to diagnose active myeloma recently changed, noted Dr. Green of the University of Washington, the Multiple Myeloma and Stem Cell Transplant Program at the Seattle Cancer Care Alliance, and the Fred Hutchinson Cancer Research Center, all in Seattle.
Long-used CRAB criteria (calcium elevation, renal failure, anemia, and bone lesions) have been updated to incorporate three additional biomarkers – a bone marrow plasma cell percentage of 60% or greater, a serum free light chain ratio of 100 or greater, and a skeletal MRI or CT showing more than one focal lesion – conferring a very high risk of progression (Lancet Oncol. 2014;15[12]:e538-48).
“Many of us are using these new, independently validated factors, I would say, in select cases, not all the time. But they are now becoming part of the accepted dogma for determining in whom you might initiate therapy,” he said.
This change is likely to affect the epidemiology of smoldering myeloma, he noted. “We are taking the people at highest risk of progression and shifting them now, potentially, into the active group. What that means is whoever remains in the smoldering group, their prognosis is actually going to be better in the future.”
Staging criteria
The criteria used to stage myeloma have also changed, just in the past few months. The International Staging System (ISS) is about 15 years old. “The problem is it predated the era of novel therapy, and it predated our understanding of high-risk cytogenetics. That has been a long-term criticism,” Dr. Green said.
The new revised system, termed R-ISS, incorporates cytogenetics – designating 17p deletion, translocation 4;14, and translocation 14;16 as high-risk cytogenetics – as well as lactate dehydrogenase (J Clin Oncol. 2015;33:2863-9).
“I think there’s going to be uniform acceptance of this change. It’s a big deal in terms of how we manage these folks and in terms of what tests need to be ordered,” he said. “But it’s going to change things because lots of our interpretation of prior data is based on the old [system].”
Primary therapy
Numerous regimens are effective as primary therapy in myeloma, with expert consensus favoring three drugs over two for fit patients. Triple combinations achieve a greater depth of response, and deeper responses – whether assessed with multiparameter high-sensitivity flow cytometry (Blood. 2015;125:1932-5) or deep sequencing (Blood. 2014;123:3073-9) – correlate with better outcomes.
“Now I don’t know if that is just telling us about the basic biology of the disease – you respond better, therefore you have a better outcome – or if three drugs are definitively better than two up front,” Dr. Green said. “But until we know that, I think the consensus from the myeloma community is, three drugs in patients who can tolerate that.”
Forthcoming data to be presented at the ASH meeting will likely shed more light on the comparative efficacy of various primary regimens, he said.
The therapeutic options also are likely to increase soon, as two or three new drugs are likely to be approved for multiple myeloma in the next 6 months, he added.
Risk-adapted management
Another area of rapid change has been therapy that is adapted to a patient’s risk of progression, Dr. Green said. “Because we have all these new agents, that keeps changing. Is it high risk or isn’t it high risk based on cytogenetics? Maybe it was yesterday and it’s not today because some new agent is improving outcomes for a specific subset of patients.”
There is some disagreement on where, exactly, certain cytogenetics fall. But 17p deletion is generally viewed as high risk, and a recent study suggested that the survival benefit of bortezomib (Velcade) induction followed by maintenance after stem cell transplant in newly diagnosed myeloma was especially pronounced among patients with this cytogenetic abnormality (J Clin Oncol. 2012;30:2946-55).
“Although there’s not a randomized trial powered to prove this directly, we are beginning to understand and see that difference clinically. Patients who have 17p disease should see proteasome inhibitor therapy up front and I believe as part of their maintenance, unless they can’t tolerate it or are resistant to it,” Dr. Green recommended.
Stem cell transplant
“The data continue to support the use of an autologous stem cell transplant up front in the management of patients with myeloma after induction,” he contended.
Studies establishing the efficacy of transplant were done before the era of novel therapies. “Some people said all these novel therapies make transplant less important, but that really hasn’t been borne out. That debate is sort of falling away because we now have some new studies that have come out demonstrating a continued benefit in survival for patients who are able to and undergo an autologous stem cell transplant as part of their care,” he said.
“It is a standard of care and if you want proof of it, you can just look at the number of transplants we are doing of multiple myeloma in the United States every year,” he said. “It continues to increase and continues to be the No. 1 indication for transplant.”
Maintenance therapy post transplant
The best approach to maintenance therapy after transplant remains controversial, according to Dr. Green. Lenalidomide (Revlimid) is the standard of care in the United States based on three large trials, all of which showed a progression-free survival benefit of the drug, and one of which showed an overall survival benefit.
“That’s been the rationale for keeping patients on it,” he said, while noting that trials have differed with respect to patient populations and duration on the drug. However, patients with high-risk features may be good candidates for alternate agents.
Options for relapsed disease
Clonal evolution has become an area of interest as it pertains to treatment decisions in the relapsed myeloma setting. “Myeloma is a wily foe, it evolves over time: We find a good treatment against it and it evolves and there is progression,” Dr. Green said. For example, patients may be found to have a 17p deletion when they previously didn’t have one, which could tilt the treatment decision to bortezomib.
Hematologists should consider putting their patients with relapse on clinical trials testing salvage regimens, he said. “Only 4% of patients in the United States are enrolled in a clinical trial, and 40% of trials are closed due to low accrual. If you can get a patient on a trial, please do.”
A regimen that was successful previously in a given patient can be used again. And the roughly one dozen other options for relapsed disease now include the newcomers carfilzomib (Kyprolis), pomalidomide (Pomalyst), and panobinostat (Farydak).
The old drug melphalan (Alkeran) should not be overlooked either. “Melphalan should still be considered a part of salvage regimens for patients. If they have already undergone transplant or are not transplant candidates, at some point, they should receive melphalan, in my opinion,” he said.
Investigational agents
Various investigational agents are being evaluated in trials in myeloma. They include, for example, daratumumab, an anti-CD38 antibody that achieved a 36% response rate in patients with relapsed or relapsed, refractory disease (N Engl J Med. 2015;24;373[13]:1207-19), and elotuzumab, an anti-SLAM F7 antibody that when combined with lenalidomide and dexamethasone improved progression-free survival in patients with relapsed or refractory disease, both overall and among those with high-risk features (N Engl J Med. 2015;373[7]:621-31).
Chimeric antigen receptor (CAR) T cells also have been tested in myeloma (N Engl J Med. 2015;373[11]:1040-7). “I don’t think that this is going to be the home-run approach, but I do think it’s an interesting proof of principle,” Dr. Green said.
Taken together, data suggest that today, cure is within reach for at least a subset of patients with myeloma. For example, more than a third of those undergoing stem cell transplantation who have a complete response are still alive at 12 years, with some having long-term survival (Blood 2011;118:529-34).
“I’m betting that those are the patients who, if we were able to look back in time, we would have seen they had no evidence of minimal residual disease by looking with more of those technologies we now have available for depth of response,” proposed Dr. Green, who disclosed that he had no relevant conflicts of interest.
SAN FRANCISCO – With multiple therapies and refinements in diagnostic and staging criteria, risk stratification, and transplantation, “we have made dramatic improvements in survival” for malignant myeloma, Dr. Damian J. Green told attendees of the NCCN Annual Congress: Hematologic Malignancies. In fact, he said, these advances have propelled the field toward a once unthinkable question: Can myeloma be cured?
Diagnostic criteria
The criteria used to diagnose active myeloma recently changed, noted Dr. Green of the University of Washington, the Multiple Myeloma and Stem Cell Transplant Program at the Seattle Cancer Care Alliance, and the Fred Hutchinson Cancer Research Center, all in Seattle.
Long-used CRAB criteria (calcium elevation, renal failure, anemia, and bone lesions) have been updated to incorporate three additional biomarkers – a bone marrow plasma cell percentage of 60% or greater, a serum free light chain ratio of 100 or greater, and a skeletal MRI or CT showing more than one focal lesion – conferring a very high risk of progression (Lancet Oncol. 2014;15[12]:e538-48).
“Many of us are using these new, independently validated factors, I would say, in select cases, not all the time. But they are now becoming part of the accepted dogma for determining in whom you might initiate therapy,” he said.
This change is likely to affect the epidemiology of smoldering myeloma, he noted. “We are taking the people at highest risk of progression and shifting them now, potentially, into the active group. What that means is whoever remains in the smoldering group, their prognosis is actually going to be better in the future.”
Staging criteria
The criteria used to stage myeloma have also changed, just in the past few months. The International Staging System (ISS) is about 15 years old. “The problem is it predated the era of novel therapy, and it predated our understanding of high-risk cytogenetics. That has been a long-term criticism,” Dr. Green said.
The new revised system, termed R-ISS, incorporates cytogenetics – designating 17p deletion, translocation 4;14, and translocation 14;16 as high-risk cytogenetics – as well as lactate dehydrogenase (J Clin Oncol. 2015;33:2863-9).
“I think there’s going to be uniform acceptance of this change. It’s a big deal in terms of how we manage these folks and in terms of what tests need to be ordered,” he said. “But it’s going to change things because lots of our interpretation of prior data is based on the old [system].”
Primary therapy
Numerous regimens are effective as primary therapy in myeloma, with expert consensus favoring three drugs over two for fit patients. Triple combinations achieve a greater depth of response, and deeper responses – whether assessed with multiparameter high-sensitivity flow cytometry (Blood. 2015;125:1932-5) or deep sequencing (Blood. 2014;123:3073-9) – correlate with better outcomes.
“Now I don’t know if that is just telling us about the basic biology of the disease – you respond better, therefore you have a better outcome – or if three drugs are definitively better than two up front,” Dr. Green said. “But until we know that, I think the consensus from the myeloma community is, three drugs in patients who can tolerate that.”
Forthcoming data to be presented at the ASH meeting will likely shed more light on the comparative efficacy of various primary regimens, he said.
The therapeutic options also are likely to increase soon, as two or three new drugs are likely to be approved for multiple myeloma in the next 6 months, he added.
Risk-adapted management
Another area of rapid change has been therapy that is adapted to a patient’s risk of progression, Dr. Green said. “Because we have all these new agents, that keeps changing. Is it high risk or isn’t it high risk based on cytogenetics? Maybe it was yesterday and it’s not today because some new agent is improving outcomes for a specific subset of patients.”
There is some disagreement on where, exactly, certain cytogenetics fall. But 17p deletion is generally viewed as high risk, and a recent study suggested that the survival benefit of bortezomib (Velcade) induction followed by maintenance after stem cell transplant in newly diagnosed myeloma was especially pronounced among patients with this cytogenetic abnormality (J Clin Oncol. 2012;30:2946-55).
“Although there’s not a randomized trial powered to prove this directly, we are beginning to understand and see that difference clinically. Patients who have 17p disease should see proteasome inhibitor therapy up front and I believe as part of their maintenance, unless they can’t tolerate it or are resistant to it,” Dr. Green recommended.
Stem cell transplant
“The data continue to support the use of an autologous stem cell transplant up front in the management of patients with myeloma after induction,” he contended.
Studies establishing the efficacy of transplant were done before the era of novel therapies. “Some people said all these novel therapies make transplant less important, but that really hasn’t been borne out. That debate is sort of falling away because we now have some new studies that have come out demonstrating a continued benefit in survival for patients who are able to and undergo an autologous stem cell transplant as part of their care,” he said.
“It is a standard of care and if you want proof of it, you can just look at the number of transplants we are doing of multiple myeloma in the United States every year,” he said. “It continues to increase and continues to be the No. 1 indication for transplant.”
Maintenance therapy post transplant
The best approach to maintenance therapy after transplant remains controversial, according to Dr. Green. Lenalidomide (Revlimid) is the standard of care in the United States based on three large trials, all of which showed a progression-free survival benefit of the drug, and one of which showed an overall survival benefit.
“That’s been the rationale for keeping patients on it,” he said, while noting that trials have differed with respect to patient populations and duration on the drug. However, patients with high-risk features may be good candidates for alternate agents.
Options for relapsed disease
Clonal evolution has become an area of interest as it pertains to treatment decisions in the relapsed myeloma setting. “Myeloma is a wily foe, it evolves over time: We find a good treatment against it and it evolves and there is progression,” Dr. Green said. For example, patients may be found to have a 17p deletion when they previously didn’t have one, which could tilt the treatment decision to bortezomib.
Hematologists should consider putting their patients with relapse on clinical trials testing salvage regimens, he said. “Only 4% of patients in the United States are enrolled in a clinical trial, and 40% of trials are closed due to low accrual. If you can get a patient on a trial, please do.”
A regimen that was successful previously in a given patient can be used again. And the roughly one dozen other options for relapsed disease now include the newcomers carfilzomib (Kyprolis), pomalidomide (Pomalyst), and panobinostat (Farydak).
The old drug melphalan (Alkeran) should not be overlooked either. “Melphalan should still be considered a part of salvage regimens for patients. If they have already undergone transplant or are not transplant candidates, at some point, they should receive melphalan, in my opinion,” he said.
Investigational agents
Various investigational agents are being evaluated in trials in myeloma. They include, for example, daratumumab, an anti-CD38 antibody that achieved a 36% response rate in patients with relapsed or relapsed, refractory disease (N Engl J Med. 2015;24;373[13]:1207-19), and elotuzumab, an anti-SLAM F7 antibody that when combined with lenalidomide and dexamethasone improved progression-free survival in patients with relapsed or refractory disease, both overall and among those with high-risk features (N Engl J Med. 2015;373[7]:621-31).
Chimeric antigen receptor (CAR) T cells also have been tested in myeloma (N Engl J Med. 2015;373[11]:1040-7). “I don’t think that this is going to be the home-run approach, but I do think it’s an interesting proof of principle,” Dr. Green said.
Taken together, data suggest that today, cure is within reach for at least a subset of patients with myeloma. For example, more than a third of those undergoing stem cell transplantation who have a complete response are still alive at 12 years, with some having long-term survival (Blood 2011;118:529-34).
“I’m betting that those are the patients who, if we were able to look back in time, we would have seen they had no evidence of minimal residual disease by looking with more of those technologies we now have available for depth of response,” proposed Dr. Green, who disclosed that he had no relevant conflicts of interest.
EXPERT ANALYSIS FROM NCCN ANNUAL CONGRESS: HEMATOLOGIC MALIGNANCIES
