Selecting Treatment Regimens for Multiple Myeloma at First Relapse
Turning to the last module, expert panelists discuss the treatment armamentarium for patients experiencing early relapse in multiple myeloma.
Transcript:
Sagar Lonial, MD: Let’s get to all the new, exciting data, where the alphabet soup of myeloma is going to come out: in the context of relapsed myeloma. Let’s start with early relapse, which I’ve been describing for the last few years as the newly diagnosed myeloma. Our goal can be very long and durable remissions in that setting as well.
Timothy Schmidt, MD: It certainly can be. In today’s treatment landscape, most patients entering this early relapsed state are those who’ve been treated with a 3-drug induction regimen, with or without transplant, on lenalidomide maintenance. Maybe there have been some modifications. Sometimes patients come off their maintenance therapy for different reasons. Most patients who are entering this state are going to be exposed to an IMiD [immunomodulatory imide drug], a proteasome inhibitor, a steroid, and possibly an alkylating agent. Many are going to be refractory to at least 1 or 2 of those classes of therapy.
We’ve been talking about CD38 antibodies quite a bit in the newly diagnosed setting, but study after study—well-done phase 3 studies—has shown that in that early relapse setting, a CD38-containing triplet therapy is vastly superior to a doublet therapy, including with either an immunomodulatory drug or a proteasome inhibitor. We have a choice. There are many options to choose from in this setting. In terms of daratumumab, there are data to support combining this with lenalidomide-dexamethasone, bortezomib-dexamethasone, pomalidomide-dexamethasone, and carfilzomib-dexamethasone. For isatuximab, carfilzomib-dexamethasone and pomalidomide-dexamethasone. We tend to use a drug that we expect the patient to respond to, in terms of the adverse effect profile and what seems to make sense based on their medical history, comorbidities, and experience. We have a variety of choices. But we definitely [want to use] a triplet therapy in that first relapse.
The corollary to that is that now that we’re seeing CD38 antibodies incorporated into a newly diagnosed therapy, there are some patients who are starting to relapse who’ve received those. That’s a much more challenging group of patients because they’re relapsing faster and you don’t have that CD38 antibody, or at least you’re not as confident that it’s going to be as useful in that setting. In that case, combining next-generation PIs and IMiDs, such as carfilzomib and pomalidomide, are things we should be thinking about for those patients. But it’s definitely an area where there’s choice, with very good, very well-tolerated regimens for a lot of people.
Sagar Lonial, MD: On average, the median duration of remission is around 4 to 5 years. I don’t think many of those got CD38 as part of their induction.
Timothy Schmidt, MD: Not many, but some.
Sagar Lonial, MD: And that’s a high-risk cohort.
Samuel M. Rubinstein, MD: We feel that unmet need in our clinic because that’s who’s relapsing after quadruplet therapy.
Sagar Lonial, MD: Let’s ignore those folks for a moment and say that CD38 is where you’re going start. You’re going to partner it with a PI [proteasome inhibitor] or an IMiD. How do you make that choice in the context of first relapse?
Samuel M. Rubinstein, MD: It comes down to what they’re refractory to and how well they tolerated various drugs at previous points in their myeloma journey. Most patients with first relapse are relapsing on continuous lenalidomide maintenance, and usually it’s been 4 or 5 years since they’ve been treated with a proteasome inhibitor. My practice, unless there’s a limiting toxicity, is to use CD38 and proteasome inhibitor. I use carfilzomib in that setting more than bortezomib. We haven’t had direct comparisons of CD38 and Kd [carfilzomib, dexamethasone] or CD38 and Vd [bortezomib, dexamethasone] in this setting, but the progression-free survival [PFS] on the carfilzomib triplet trials is longer by meaningful amounts—periods of years—than with the bortezomib-based triplets. I don’t think it’s unreasonable to use bortezomib in that setting because it preserves carfilzomib for later lines. For immunotherapy qualification, we’re limited by how many prior lines of therapy patients have received. It’s not unreasonable to milk that a little in how you manage patients, but my general practice is CD38 and carfilzomib for a patient relapsing on lenalidomide maintenance.
Sagar Lonial, MD: Is anybody starting off with an IMiD as a first partner?
Timothy Schmidt, MD: It depends.
Sandy Wong, MD: It depends. For a standard-risk patient in first relapse, if you redo their marrow and they’re still standard risk, daratumumab-pomalidomide is a great combination, obviously with dexamethasone. If someone is standard risk, I do a marrow at relapse, and if they have a deletion of 17p, then I would definitely need to use carfilzomib with daratumumab. I use the cytogenetic risk, specifically, to have an idea if their myeloma changed in terms of the ability to resist therapies.
Then you have the functional high-risk patients who relapse. It seems that people define functional high-risk patients a little differently depending on the trial. We expect 3 years or so. If they relapse in a year, that’s functional high risk, and I don’t care what their cytogenetics look like. They’re going to get daratumumab-carfilzomib. That’s the way I think about it. The caveat is that with daratumumab-carfilzomib, there’s going to be a bit more toxicity compared with daratumumab-pomalidomide.
Samuel M. Rubinstein, MD: I’ll push back just a little. The typical limiting toxicity for this patient, who’s relapsing after lenalidomide-maintenance, is marrow suppression. There may be a little more of that with pomalidomide than carfilzomib in many cases. But in terms of functional toxicities, carfilzomib is a harder drug to tolerate than pomalidomide.
Caitlin Costello, MD: And to receive it. We’ve talked a lot about frailty. But regardless of whether you’re fit or unfit, to get twice-a-week carfilzomib is challenging, especially if it’s for the long run. Carfilzomib is a very good drug. For high-risk patients, I agree. Many of these patients have been on lenalidomide maintenance, and there are data to support giving pomalidomide after lenalidomide. But my bias is that I want a drug class switch. Many patients relapsing today haven’t received CD38 monoclonal antibody. My go-to is daratumumab, carfilzomib, and dexamethasone unless, for some reason, I have worries about the toxicity or the inconvenience about the carfilzomib or the patient does. Then pomalidomide is my go-to. With daratumumab-pomalidomide-dexamethasone, none of us can get it to 4 mg, right? I don’t even start at 4 mg. We all start at 2 mg. Then you’re managing having them come in to get their growth factor to manage the neutropenia on top of it. You have to have that conversation to understand the biology of the disease, the toxicity of the drugs, and the comorbidities of the patient.
Sagar Lonial, MD: At our center [Winship Cancer Institute], Dr [Nisha] Joseph looked back at our experience. Because we’ve been using daratumumab-pomalidomide for a long time. We looked at the number of people who get dose reduced from 4 mg, and it was less than 50%. We start at 4 mg. In our practice, each of us is more or less intense about maintaining 4 mg. What Dr Joseph looked at, in a couple of hundred patients, was time from diagnosis to relapse. If it was less than 3 years, the benefit of pomalidomide-daratumumab was less. It was maybe 7 months. With those folks, we clearly agree that CAR [chimeric antigen receptor T-cell therapy] is probably the better partner. In patients whose time from diagnosis was more than 3 years, the daratumumab-pomalidomide PFS is really good—over 40 months. The hard part with the early relapse trials is comparing the CAR partner with the pomalidomide partner trials. Because the median number of lines of therapy in both of the carfilzomib-CD38 trials was 1 to 2, and in the pomalidomide trial, it’s 2 to 3. Some of that accounts for the numerical difference we’re seeing in PFS, but there’s probably a risk, as Dr Costello brought up.
Samuel M. Rubinstein, MD: Fundamentally, the strategies we’re all using and advocating for haven’t been directly compared with one another, nor are they likely to be. Many of these answers are correct in and of themselves.
Caitlin Costello, MD: Options.
Timothy Schmidt, MD: Options.
Transcript edited for clarity.
