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High-Risk Smoldering Multiple Myeloma: Systemic Therapy

Insights From: Kenneth C. Anderson, MD, Dana-Farber Cancer Institute and Harvard Medical School; Rafael Fonseca, MD, Mayo Clinic; Noopur S. Raje, MD, Massachusetts General Hospital Cancer Center
Published: Wednesday, Feb 20, 2019



Transcript: 

Rafael Fonseca, MD: A number of clinical trials have started to address the possibility of treating smoldering multiple myeloma. One such example was a study that was presented from the group from Dana-Farber [Cancer Institute] that looks at the combination of ixazomib, lenalidomide, and dexamethasone. It’s still a small study.

This study, I would say not surprisingly, showed that these agents are active and there’s a high rate of response. And, of course, as we think about the potential of a treatment for patients with smoldering disease, the scope of who needs to be treated has greatly expanded. So I think we need to get in-depth information about this regimen, particularly if we still are not sure who’s going to progress. In this particular study, again, they address this combination. They have great results.

But I have to say we still have to wait for the larger studies in smoldering disease before we make recommendations about initiation of therapy. The road was paved by the studies of Dr Maria-Victoria Mateos, MD, PhD, from Spain, and studies that have been published and discussed elsewhere. For instance, even with simpler approaches like lenalidomide.

I think the remaining question, which is in some way hinted as by this particular study, is that if you’re going to “pull the trigger,” if you’re going to start therapy against a person who has a premalignant, almost malignant stage for the disease, do we do that with, “a gentle approach,” or do you go full-blown with all the extent of treatment options that are available in the idea of creating maximal reduction of the cells to prevent drug resistance and ultimately protection from future development of multiple myeloma?

Kenneth C. Anderson, MD: That particular trial of elotuzumab, lenalidomide, and dexamethasone in high-risk smoldering multiple myeloma actually came from our institution. Irene Ghobrial, MD, and many of us on her team treated patients who had high-risk smoldering myeloma who otherwise would not be treated. They had high-risk smoldering disease based on kappa/lambda ratios greater than 20, bone marrow plasma cells greater than 20% even though they didn’t have calcium, kidney, anemia, or bone disease. These patients, we know, will progress to myeloma in 18 months to 2 years if we don’t treat them. So we treated with the elotuzumab monoclonal antibody, lenalidomide, and dexamethasone in this group. And 84% of patients actually decreased their monoclonal protein and had a response that was very well tolerated. And with very early follow-up, patients have not progressed.

The study also includes genomic profiling. So before therapy is started and after therapy, or after progression occurs, in order to understand what might be the pathways that are implicated when a myeloma patient progresses from smoldering disease to active disease. And there is some early evidence that the MAP [mitogen-activated protein] kinase pathway may be implicated, for example.

It’s early days, but the concept that’s important is that a therapy such as elotuzumab, lenalidomide, and dexamethasone that is FDA approved to treat relapsed, more far advanced disease is now being used because it’s well tolerated earlier in the disease in smoldering myeloma with the view of delaying progression to active disease, or, someday, preventing progression to active disease.

Transcript Edited for Clarity
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Transcript: 

Rafael Fonseca, MD: A number of clinical trials have started to address the possibility of treating smoldering multiple myeloma. One such example was a study that was presented from the group from Dana-Farber [Cancer Institute] that looks at the combination of ixazomib, lenalidomide, and dexamethasone. It’s still a small study.

This study, I would say not surprisingly, showed that these agents are active and there’s a high rate of response. And, of course, as we think about the potential of a treatment for patients with smoldering disease, the scope of who needs to be treated has greatly expanded. So I think we need to get in-depth information about this regimen, particularly if we still are not sure who’s going to progress. In this particular study, again, they address this combination. They have great results.

But I have to say we still have to wait for the larger studies in smoldering disease before we make recommendations about initiation of therapy. The road was paved by the studies of Dr Maria-Victoria Mateos, MD, PhD, from Spain, and studies that have been published and discussed elsewhere. For instance, even with simpler approaches like lenalidomide.

I think the remaining question, which is in some way hinted as by this particular study, is that if you’re going to “pull the trigger,” if you’re going to start therapy against a person who has a premalignant, almost malignant stage for the disease, do we do that with, “a gentle approach,” or do you go full-blown with all the extent of treatment options that are available in the idea of creating maximal reduction of the cells to prevent drug resistance and ultimately protection from future development of multiple myeloma?

Kenneth C. Anderson, MD: That particular trial of elotuzumab, lenalidomide, and dexamethasone in high-risk smoldering multiple myeloma actually came from our institution. Irene Ghobrial, MD, and many of us on her team treated patients who had high-risk smoldering myeloma who otherwise would not be treated. They had high-risk smoldering disease based on kappa/lambda ratios greater than 20, bone marrow plasma cells greater than 20% even though they didn’t have calcium, kidney, anemia, or bone disease. These patients, we know, will progress to myeloma in 18 months to 2 years if we don’t treat them. So we treated with the elotuzumab monoclonal antibody, lenalidomide, and dexamethasone in this group. And 84% of patients actually decreased their monoclonal protein and had a response that was very well tolerated. And with very early follow-up, patients have not progressed.

The study also includes genomic profiling. So before therapy is started and after therapy, or after progression occurs, in order to understand what might be the pathways that are implicated when a myeloma patient progresses from smoldering disease to active disease. And there is some early evidence that the MAP [mitogen-activated protein] kinase pathway may be implicated, for example.

It’s early days, but the concept that’s important is that a therapy such as elotuzumab, lenalidomide, and dexamethasone that is FDA approved to treat relapsed, more far advanced disease is now being used because it’s well tolerated earlier in the disease in smoldering myeloma with the view of delaying progression to active disease, or, someday, preventing progression to active disease.

Transcript Edited for Clarity
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