Treatment Options in Triple-Class Refractory Multiple Myeloma - Episode 8

RRMM: Incorporating INN Melphalan Flufenamide Into Clinical Practice

Paul G. Richardson, MD: To some extent, we’ve already touched on a lot of the questions that arise about how this drug will be used in the context of approval. Its use in combination will be very important. Understanding long-term toxicities is going to be a crucial area of future research, and we will be very vigilant in that regard. It’s very encouraging that we have a drug that can be used once a month by infusion. It’s relatively simple to use and can be combined with other drugs. I’m also reminded of data from some years ago that led to the original premise of melflufen being very promising. That was the original FOCUS trial, where patients received either carfilzomib or an alkylator-based therapy as a salvage strategy. This was over 10 years ago. What was seen in that study was that if patients had multiple lines of prior virological therapy, PIs [proteasome inhibitors], and IMiDs [immunomodulatory drugs], there was a response rate seen in the cyclophosphamide-treated patients.

In the same vein, melflufen—recognizing that it’s really in a different league from cyclophosphamide in terms of its efficacy, its mechanism of action, and so forth—will provide us with a valuable new tool to offer patients as a targeted antibody-drug conjugate that exploits this particular vulnerability in the disease at this stage in patient’s illness.

In the context of relapsed/refractory disease that’s triple-class refractory, our challenges remain very substantial. I’m very pleased with the approval this year of isatuximab, belantamab mafodotin, and the full regulatory approval of selinexor in combination with bortezomib and dexamethasone. Hopefully melflufen will be approved soon too. That approval will be very important. We’re left in the situation where we have lots of options for our patients, but we must recognize that the challenge of highly resistant disease is that it is extremely resistant and very complex. While we might make incremental gains in certain respects, and these all add up and are valuable, we still have a lot of work to do.

I remain very impressed by the potential of cellular therapies and immune strategies. I’m particularly impressed by the bispecific T-cell engager [BiTE] data that we saw at the meeting [American Society of Hematology Annual Meeting]. It’s outstanding. But we also have to recognize that these are highly specialized approaches and that patient selection for these clinical trials has rightly been very careful and appropriate. In some ways, that’s a very selected population.

What I think is so exciting about some of these newer approvals is that they provide a very off-the-shelf, practical strategy that can be deployed for patients. It doesn’t in any way diminish that once myeloma has become highly relapsed and refractory and resistant—with a high mutational burden in terms of genetic or mutational load—we really face a major challenge. There’s going to be plenty of research still needed to deal with that therapeutically, but also, very importantly, wemust develop strategies in which we try to minimize that challenge. We are dealing with a problem once it’s become hugely challenging. If we can be smarter about what we do earlier, we might diminish this challenge as it emerges.

In terms of practical advice, agents that can be used in combination really are the key, along with recognizing that using less of each may amount to more. Combination strategies are everything, and realizing you can revisit classes of drugs—but combining them smartly with something else—can make the difference. The important point is that toxicology management is key: managing blood counts, hematologic reserve, minimizing infection, and controlling all the toxicities. That can really make an impact on quality of life.

At the same time, referral for clinical trials for the appropriate patient is vital because these really do provide hope and increasingly provide genuinely encouraging depths and rates of response, even in early phase trials, based on really smart preclinical development. There are some really important options there in clinical trials. For the patients who are not a candidate for clinical trials, obviously one could always do one’s very best to salvage patients and be creative.

There’s also the reality of recognizing when you’ve exhausted all reasonable options and making sure the patients’ needs and the families’ needs are always addressed. In particular for patients when treatment options have been exhausted, it’s important to take a very practical approach to symptom management and so forth because the relapsed/refractory population do face a really substantial challenge, and I’m acutely aware of how important that is.

Transcript Edited for Clarity