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Molecular Pathogenesis of Multiple Myeloma

Panelists:Ajai Chari, MD, Mount Sinai Hospital; Sagar Lonial, MD, Emory University School of Medicine; Paul G. Richardson, MD, Harvard Medical School; Jatin J. Shah, MD, MD Anderson Cancer Center; Keith Stewart, MD, CHB, Mayo Clinic
Published: Tuesday, Jan 12, 2016


Transcript:

Keith Stewart, MB, CHB:
Hello, and thank you for joining this OncLive TV Peer Exchange. These are exciting times in the field of multiple myeloma, where treatment strategies continue to transform, both in the upfront and in the relapsed/refractory setting. However, even with the tremendous progress that has been made, and the advent of many novel therapies, most of our patients will not be cured of their disease even today.

Today I am joined by a group of thought leaders in multiple myeloma research who will provide perspective on the ever-growing opportunity we have to optimize treatment for individualized patients during today's program.

My name is Dr. Keith Stewart. I'm the Vasek and Anna Maria Polak Professor of Cancer Research at the Mayo Clinic. And joining me today are Dr. Ajai Chari, an associate professor of medicine for hematology and medical oncology at Mount Sinai Hospital in New York; Dr. Sagar Lonial, a professor and executive vice chair for the Department of Hematology and Medical Oncology and the chief medical officer at the Winship Cancer Institute of Emory University School of Medicine; Dr. Paul Richardson, clinical program leader and director of clinical research for the Jerome Lipper Multiple Myeloma Center, and the R.J. Corman Professor of Medicine at the Dana-Farber Cancer Institute at Harvard Medical School in Boston; and Dr. Jatin Shah, an associate professor of medicine and director of the Myeloma Clinical/Translational Research Program and program director for the Myeloma and Fellowship Department at the MD Anderson Cancer Center in Houston, Texas.

Thank you to each of you for joining us today. So let's get started.

Let's turn our attention first to the discussion of the molecular pathogenesis of multiple myeloma and what is new in that area. It seems to me, Dr. Lonial, that myeloma has never been shown to be a somewhat heterogeneous disease. Can you talk to us about it, what does that mean, and how does it impact our therapies?

Sagar Lonial, MD: Well, I think what we know about patients in the newly diagnosed setting is that, on average, they're a median of between 5 and 10 different subclones of myeloma that all have the same BDJ recombination, but have different genetic subtypes. And that means, in my view, that we need to think about combination therapy from the get-go because you may eliminate one or two clones, but the other three are still going to be there, and that's where the power of combination is really important.

Keith Stewart, MB, CHB: And does everybody subscribe to that theory? Dr. Chari, you believe that multiple clones require different drugs, is that true?

Ajai Chari, MD: You know, I think ideally we're going to get to a point where myeloma is going to be like lymphoma, where we have different histological types, different disease biologies, and then we'll be able to really tailor therapy to each particular disease category. I don't think we're there yet, but I think, clearly, the lack of cure for the vast majority of patients and yet a very heterogeneous outcome reflects a probably very diverse group of clones present at baseline.

Keith Stewart, MB, CHB: Well, maybe just for the audience, what do we mean by these different clones in myeloma? What are we talking about there?

Jatin J. Shah, MD: So, I think the challenge is that we can identify these multiple different clones that may have different mutations, but targeting those mutations becomes challenging at this point in time. And so I think that biologically it makes sense, where you identify these different clones, and clinically it makes sense to treat them with combination therapy because we're getting such nice high response rates.

But I think if you take it a step further and [ask], ‘Can we identify a specific subset of clones?’ and then treat it with specific therapy, we haven't got to that point yet. But I think that the progress we've made with combination therapies and the response that we've seen here really support that.

Sagar Lonial, MD: And I don't know that we ever will get to that. I mean, I've been sort of a skeptic of one-drug-one-disease concept. I think very few diseases are as straightforward as CML. And myeloma has got so much genetic, not just heterogeneity but complexity, that I think it's unlikely that one drug targeting a single mutation is going to have a long-term impact on that outcome.

Paul G. Richardson, MD: Yeah, I completely agree, Sagar. I think that the platform for combination therapy is now very well established. I think we've seen it in randomized trials supported in the relapsed-refractory setting, and now we have strong evidence in the randomized setting up front. And I think we have backbone drugs, such as immunomodulators and proteasome inhibitors, that combined are synergistic. And then we can rationally add next-generation novel agents to them to get to what Ajai is pointing out.

We can hopefully get to a point where we have an antibody plus a platform of a proteasome inhibitor and an immunomodulator that give us the best chance of putting a net around the disease in any individual patient in a way in which, frankly, the toxicity is also manageable, because then it becomes a very important parameter, as well.
                                                                                                                                                                                                                                                                                                              
Transcript Edited for Clarity
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Transcript:

Keith Stewart, MB, CHB:
Hello, and thank you for joining this OncLive TV Peer Exchange. These are exciting times in the field of multiple myeloma, where treatment strategies continue to transform, both in the upfront and in the relapsed/refractory setting. However, even with the tremendous progress that has been made, and the advent of many novel therapies, most of our patients will not be cured of their disease even today.

Today I am joined by a group of thought leaders in multiple myeloma research who will provide perspective on the ever-growing opportunity we have to optimize treatment for individualized patients during today's program.

My name is Dr. Keith Stewart. I'm the Vasek and Anna Maria Polak Professor of Cancer Research at the Mayo Clinic. And joining me today are Dr. Ajai Chari, an associate professor of medicine for hematology and medical oncology at Mount Sinai Hospital in New York; Dr. Sagar Lonial, a professor and executive vice chair for the Department of Hematology and Medical Oncology and the chief medical officer at the Winship Cancer Institute of Emory University School of Medicine; Dr. Paul Richardson, clinical program leader and director of clinical research for the Jerome Lipper Multiple Myeloma Center, and the R.J. Corman Professor of Medicine at the Dana-Farber Cancer Institute at Harvard Medical School in Boston; and Dr. Jatin Shah, an associate professor of medicine and director of the Myeloma Clinical/Translational Research Program and program director for the Myeloma and Fellowship Department at the MD Anderson Cancer Center in Houston, Texas.

Thank you to each of you for joining us today. So let's get started.

Let's turn our attention first to the discussion of the molecular pathogenesis of multiple myeloma and what is new in that area. It seems to me, Dr. Lonial, that myeloma has never been shown to be a somewhat heterogeneous disease. Can you talk to us about it, what does that mean, and how does it impact our therapies?

Sagar Lonial, MD: Well, I think what we know about patients in the newly diagnosed setting is that, on average, they're a median of between 5 and 10 different subclones of myeloma that all have the same BDJ recombination, but have different genetic subtypes. And that means, in my view, that we need to think about combination therapy from the get-go because you may eliminate one or two clones, but the other three are still going to be there, and that's where the power of combination is really important.

Keith Stewart, MB, CHB: And does everybody subscribe to that theory? Dr. Chari, you believe that multiple clones require different drugs, is that true?

Ajai Chari, MD: You know, I think ideally we're going to get to a point where myeloma is going to be like lymphoma, where we have different histological types, different disease biologies, and then we'll be able to really tailor therapy to each particular disease category. I don't think we're there yet, but I think, clearly, the lack of cure for the vast majority of patients and yet a very heterogeneous outcome reflects a probably very diverse group of clones present at baseline.

Keith Stewart, MB, CHB: Well, maybe just for the audience, what do we mean by these different clones in myeloma? What are we talking about there?

Jatin J. Shah, MD: So, I think the challenge is that we can identify these multiple different clones that may have different mutations, but targeting those mutations becomes challenging at this point in time. And so I think that biologically it makes sense, where you identify these different clones, and clinically it makes sense to treat them with combination therapy because we're getting such nice high response rates.

But I think if you take it a step further and [ask], ‘Can we identify a specific subset of clones?’ and then treat it with specific therapy, we haven't got to that point yet. But I think that the progress we've made with combination therapies and the response that we've seen here really support that.

Sagar Lonial, MD: And I don't know that we ever will get to that. I mean, I've been sort of a skeptic of one-drug-one-disease concept. I think very few diseases are as straightforward as CML. And myeloma has got so much genetic, not just heterogeneity but complexity, that I think it's unlikely that one drug targeting a single mutation is going to have a long-term impact on that outcome.

Paul G. Richardson, MD: Yeah, I completely agree, Sagar. I think that the platform for combination therapy is now very well established. I think we've seen it in randomized trials supported in the relapsed-refractory setting, and now we have strong evidence in the randomized setting up front. And I think we have backbone drugs, such as immunomodulators and proteasome inhibitors, that combined are synergistic. And then we can rationally add next-generation novel agents to them to get to what Ajai is pointing out.

We can hopefully get to a point where we have an antibody plus a platform of a proteasome inhibitor and an immunomodulator that give us the best chance of putting a net around the disease in any individual patient in a way in which, frankly, the toxicity is also manageable, because then it becomes a very important parameter, as well.
                                                                                                                                                                                                                                                                                                              
Transcript Edited for Clarity
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