MM and Regimens for First- and Second-Line Treatment

Joshua Richter, MD, and Roy Beveridge, MD, explain the role triplet regimens play in MM treatment and how physician decision-making has been impacted since the NCCN guidelines have expanded the list of acceptable first- and second-line treatment options.

Ryan Haumschild, PharmD, MS, MBA: Josh, can you discuss the combination regimens? Muhamed said something in terms of looking at some of the quadruplet vs triplet therapies. Maybe you can hit on that, and then we can transition into some patient-specific reasons why you’d pick some of these different regimens and why we’re seeing quadruplet and triplet therapy. Then talk about how it’s becoming more patient specific in terms of the combination and choices of regimens.

Joshua Richter, MD: We’ve had a dozen of approvals across the last decade with these drugs. The only thing that we could say as a definitive statement in 2022 is that 1 drug is better than 0, 2 is better than 1, 3 is better than 2, and in certain situations 4 may be better than 3. Which drugs to plug in there—that’s the big mystery, but we know combinations are better. The main reason combinations are better has to do with the subclonal nature of myeloma. At the time of diagnosis, for most patients with myeloma, it’s not 1 disease. They already have around 4 to 6 subclones of disease, and you may need drug A to kill this clone and drug B to kill that and the synergy of those 2 to kill another. Plus, we know depth of response correlates with duration of response.

There’s this wonderful paper from awhile back that showed that each log reduction in minimal residual disease that you achieve correlates to about a year improvement in median overall survival. We know that the deeper you get, the more durable it is. Well, how do we get deeper? We get deeper by killing more subclones. How do we achieve the kill of more subclones? Multiple mechanisms of action [MOAs]. Muhamed wasn’t talking about classical chemotherapy drugs like etoposide and methotrexate and having to cull together 3- and 4-drug combinations of toxic drugs. He’s talking about novel agents, we’re able to combine 3 and 4 combination drugs with therapies in these things that we put together. And we’re able to do it without tremendous toxicity. When you get 3 or 4 MOAs together, they kill more subclones. The more subclones you kill, the deeper the remission. The deeper the remission, the more durable the remission.

How do we piece together for an individual which drug is better? We always talk about the 3 factors in choosing myeloma therapy: patient-related factors, disease-related factors, and treatment-related factors. Patient related—are they old, young, fit, or frail? [Do they have] comorbidities? Disease-related factors—is it high risk, standard risk, extramedullary, plasma cell leukemia, big plasmacytomas pushing somewhere? And treatment related. We know our drugs, and if we give somebody an IMiD [immunomodulatory imide drug] and they don’t respond well, a second-generation IMiD is probably not going to be the next course of action. We may need to dramatically switch the MOA. I share the excitement from you and Muhamed about all these drugs that we have and that we’re going to have pretty soon in our armamentarium.

Ryan Haumschild, PharmD, MS, MBA: That was a great summary. I took away a lot of things. You shared a lot of great data on where things are heading, but it’s also patient specific in some of the selection: we need to maximize outcomes and know the patient and their treatment history. It plays a unique role when you start combination therapy. Roy, I’m going to pitch the next question to you because we’ve had a good setting of the landscape in terms of some of the therapy has to be patient-specific. I think about the way that the list of treatment options have been expanded with the NCCN [National Comprehensive Cancer Network] Guidelines for first- and second-line treatment. In your opinion, how does route of administration, whether it’s oral or injectable, weigh into treatment selection besides just treatment history and how a patient has responded? Does this affect a patient’s preference and access to certain medications within their benefit design?

Roy Beveridge, MD: From a payer’s perspective, when they see the diagnosis of myeloma, they recognize that that’s going to be 1 of 2 most expensive diseases that they’re going to be responsible for in terms of payment for the next number of years. Muhamed has talked about what is almost an embarrassment of riches in terms of the opportunities that we have. And Josh eloquently says 4 is probably better than 3, 3 is probably better than 2, and 2 is better than 1. From a payer perspective, you sit there and you scratch your head and you go, “Which doublet, which triplet, which quad is better?” The patient is very interested in this in terms of efficacy but also cost. Sometimes they’re looking at the data slightly differently from all the very bright people in academic centers. If you’ve got an older patient with a poor performance status, how are they going to tolerate things? Orals tend to be easier for most people.

If you’re asking about the drug design in terms of benefit management, all these products hit the maximum out-of-pocket for a patient almost immediately. If you’re in Revlimid [lenalidomide], you’ve hit your doughnut hole, and you’re past the doughnut hole even at the accelerated rate by cycle 1. After that, they’ve reached their maximum out of pocket, so it becomes a relative choice of preference. Cost becomes a huge issue because they’ve already hit it, usually in the first cycle. People are looking less in terms of whether an oral or an IV [intravenous] vs what’s the toxicity, both short and long term. All these drugs still have toxicities. Revlimid still has toxicities. All these drugs have short and longer-term toxicities.

Ryan Haumschild, PharmD, MS, MBA: It’s interesting because you’re right about the toxicity profile. One thing that causes patients to be successful in these therapies over time is adherence and good adherence. We know when patients experience that peripheral neuropathy, maybe they had some bortezomib. Maybe they had some other agents like heart pills, and over time it wears on them. You want to think, “How can I have this patient be successful?” We know that proportion of days covered is important. A patient could be prescribed Revlimid or Pomalyst [pomalidomide], but if they’re not taking it appropriately, they’re not going to see the clinical results we’ve seen in our trials. That’s 1 thing that we want to think about: access and adherence as we start to make coverage determinations.

This transcript has been edited for clarity.

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