Sequencing Monoclonal Antibodies in Myeloma

Transcript:James R. Berenson, MD: Myeloma today is very different than 10 years ago. There are a multitude of options—it becomes very complex. I like to say it’s no longer a sprint race, it’s a marathon. We also like to say it’s better to run 10-minute miles and finish the marathon, rather than run 5-minute miles and have a good 5-mile time, but you don’t finish the race. To prove that, my assistant made me run the marathon. I did 20-minute miles but I didn’t do 10; I didn’t have such a good time. But, I did finish. But, in that regard I’m a true believer that you need to take your time in many patients. And you need to think about the long-term goals here. You’ve got to keep the patient in the race. You’ve got to keep them well enough that they can avail themselves the opportunity of the newer drugs. And the newer drugs that are now in clinical development, they won’t be able to get them. They may be curative, and curative in a way that will allow them to live their life. Whereas if you beat on them, they may not be in a position to take them or tolerate them in a manner that will allow them to live their life.

So, I’m a firm believer that you can take it slow and you can take a breath. There are subgroups of patients you can’t do that in—those patients who come in with kidney failure, with lots of plasma cells in the blood, sickle plasma cell leukemia, terrible blood counts, and people who have gotten disease outside the bone marrow, so it’s in the liver, the lung. That’s bad. Then, you got to go after it. But, that’s a minority of what we see. I’m not a big believer and a big hammer. I’m a big believer that you need to be smarter. As my good friend Geo, who’s on our board at the Institute says, “It’s not about more, it’s about being more specific.” And I think that that not only applies to acting, it applies to taking care of myeloma patients today.

Ivan Marques Borrello, MD: Monoclonal antibodies in myeloma clearly are new. Both daratumumab and elotuzumab were FDA-approved in November of 2015, and I think we’re still trying to understand how to integrate these into the therapy and into the treatment paradigms that exist now that we have many drugs. In terms of the mSMART criteria, the recommendations that are given is that they should be integrated at least after the second line of therapy. I would venture to say that in light of hopefully more positive data coming out from different clinical trials, including the upfront setting, that these drugs will clearly, in the near future, move closer and closer to frontline therapy to develop the equivalent of an R-CHOP approach that is currently existing in lymphomas in the myeloma setting.

Jatin P. Shah, MD: One of the important questions that comes up now in clinical practice is sequencing strategies. How do you sequence and how do you best or optimally use these drugs? It’s important to really understand where this question comes from. I think, historically, when we had limited therapeutic options, we would talk about using three drugs versus two drugs, or saving options for patients down the road, because we had limited therapeutic options. And that was an important concept, I think historically, in myeloma. But, that’s changed nowadays with the multiple therapeutic options that we have. And so, it’s important as you get all these different combinations, really as you try to understand how to best sequence them, let’s come back to our core principles in oncology and help use that to guide how we use these combinations.

One of the core principles that we’ve seen now, consistently, is use your best drugs upfront. We see this in myeloma, we’ve seen this in solid tumors, and we’ve seen this in hematologic malignancies broadly. Use your best, most effective therapies upfront, don’t save them for later. And I think that sometimes we get caught in that in myeloma, because that’s how we’re used to thinking about it: let me use drug A, and then let me use drug B later, because I think drug B can salvage drug A. Even though I think drug B is a better drug, I’m going to save it for later or sequence it later down the road. I think that it’s important to get away from that concept. Let’s stick with our true oncologic principles, that’s well defined now over the last 50 years across all tumor types, which is, use your best, most effective therapies upfront. I think if you do that, that helps you understand sequencing.

So, when you start thinking about that, it’s important also to use your three-drug combinations now earlier in the lines of therapy, as well as in relapsed myeloma. I think that’s important. That’s been consistently shown now across multiple phase III trials, that three drugs are better than two drugs. And so, that’s the new standard of care as well. I think if we stick with those two oncologic principles, and principles that we’ve now learned, that becomes very helpful. As you start getting down into more of the details now, and, for example, if you think about the aggressive or nonaggressive relapse, then it’s very helpful to start thinking about combinations in that setting as well. For example, the phase III trial of lenalidomide/dexamethasone plus elotuzumab becomes an important option for those patients with an earlier or indolent nonaggressive relapse, or for older patients. Because, really when you look at the addition of elotuzumab and you look at the phase III studies, the difference in the side effects was really identical between the two arms.

Essentially what you end up getting with, for example, with elotuzumab, is the addition of a third drug, the benefit of a third drug, and the long-term disease control with an immuno-stimulatory component, with minimal to no additional toxicity. So, I think that becomes an important option where you get the benefit of a third drug without the “cost or side effect of a third drug.” And you get, with an immuno-stimulatory component, long-term disease control as well. For those patients with an indolent and early relapse who don’t need aggressive therapy to reverse their end-organ damage right away, that might be an important option for those patients as well when looking at that. That’s one example of how you would use sequencing strategies, and identifying patients that may benefit from a combination.

Transcript Edited for Clarity