Multiple Myeloma Treatment Sequencing and Selection, with Dr. Nikhil Munshi

DocWire News: Why is treatment sequencing a complex issue in multiple myeloma treatment?

Dr. Munshi: So, multiple myeloma treatment used to be quite simple, and I’m talking about 20 years ago. This is when we had three drugs, and it didn’t work very well, so we did what we could do. What has changed and made the treatment exciting but also complicated, is that we have 14 new drugs in last 15 years. So almost we have one new drug a year.

In last 12 months, we had three new drugs approved for myeloma, including a chimeric antigen receptor (CAR) T cell, a cellular therapy. So, first the element of complexities because we have so many good choices, and these are very effective drugs. Second thing is that we are beginning to understand the myeloma better biologically, genomically. So, that also helps us understand which patient would receive what. And, we are understanding better the prognostic factors in patients, high-risk myeloma, standard-risk myeloma, etc. And so, we are able to select appropriate treatment based on some of these features.

And the last element that makes the treatment complex is the combinations work of course, better than individual agents, and there are many, many studies done, which says that the three-drug combination is better than two. And now we are beginning to have four-drug combination, which works better than two and three. And what are those three or four-drug combinations? It includes a proteasome inhibitor, and there are three of them. It includes an immunomodulator, and there are three of them. And then it includes monoclonal antibody, and we have three monoclonal antibodies, two belonging to the same target CD38.

So, combining them together gives 100% response rate and almost 45–50% complete response rate. And so now when patients relapse, we would then utilize another three-drug combination. And you can see that with 13, 14 drugs available, there are permutations and combinations that one can utilize. And selecting them in the right sequence, and compressing various patient features, disease features, etc., brings about the complexity, and also at the same time, it also mixes responses, very meaningful in the subsequent line of treatment.

DW: New drug classes (CAR T, bispecific antibodies [BiTEs]) have been garnering attention. What are some considerations when selecting between new agents or autologous stem cell transplant (AHCT)?

Dr. Munshi: Well, so I think treatment selection in myeloma is dependent on various features, sometimes very patient-specific standard features. For example, frailty of the patient, age, status, disabilities, etc. Then we look at this is related morbidity, relapse this is a factor, renal failure, bone disease, etc. And then risk assessment: high risk, low risk, International Staging System [ISS] cytogenetics. And the patient’s lifestyle. But the most important feature that we consider, while including everything else in selecting some of these new agents, is patient’s treatment history. What did patients get last, and how well did the patient respond? And so based on that, one can pick the agents with lowest neurotoxicity, agents with less blood counts problem, etc. And so the selection partly depends on this.

The second component here in this newly-approved agents, is also the efficacy. How well these treatments work? Well do I get 80% response rate, 30% or less? And I think that is what is also utilized. And then the toxicity of this drug. If a particular drug has higher toxicity, then we would lean towards less toxicity. And so the risk benefit, benefit being the response rate, risk being the toxicity we are to balance, we try to get highest benefit, with as little as possible toxicity. And that goes into determining some of these secondary cells has brought about great excitement, partly because of the fact that it gives close to 80-plus percent responses at the target dose. However, CRS (cytokine release syndrome) is a toxicity that we have to be aware of, and we are to try and mitigate it and also keep in mind patient’s various features, including performance status and other things.

Now, the question you asked is, “How does this new choosing new agents and upfront autologous transplant come about?” So currently, all these new agents are approved for later line of treatment: third, fourth, and fifth line and beyond. However, because for example, CAR-T is so very effective, we are already investigating it in earlier line, first and second line, where there are planned studies to compare it with autologous transplant to see CAR-T gives similar depth of response as transplant does.

So currently, I think transplant has its place, but I think it’s going to be soon challenged by appropriate utilization of CAR-T cells in the right patients at an earlier time point. So I think what you should watch out now for this comparison between CAR-T versus transplant, and see which patients would benefit from which of these interventions. After saying that, I think transplant is still provides benefit, it still remains an important treatment to be considered for younger, newly diagnosed patients.