Treatment of Relapsed/Refractory Myeloma: Novel Agents

Cristina Gasparetto, MD; Sagar Lonial, MD, FACP; Joseph Mikhael, MD; and Nina Shah, MD, discuss emerging agents available for the treatment of RRMM.

Keith Stewart, MD, ChB, MBA: I want to move on to some of the newer agents that are becoming available in relapse. We’re going to leave the BCMA-targeted drugs for now. Selinexor [Sarclisa] came up earlier. Sagar, I want to get your opinion on selinexor. We’ve heard from Cristina about the BOSTON trial, where selinexor was combined with bortezomib [Velcade]. We’ve heard it’s been combined with pomalidomide, and it’s FDA approved as a single agent. What are your thoughts on when to use selinexor, if you use it?

Sagar Lonial, MD, FACP: Selinexor is a great example of learning more about how to use a drug with more time. The twice-a-week dosing is almost impossible to give patients in a reliable, long-term way. The ones we’re dosing are in combination with bortezomib or carfilzomib or pomalidomide, or in the light setting. The BOSTON trial is an interesting trial that was a label-requiring trial for the drug. But from a practical perspective, if a patient is not seeing daratumumab, daratumumab is the backbone at first relapse and you’re going to add a PI [proteasome inhibitor] or you’re going to add an IMiD [immunomodulatory imide drug] to it. I don’t think it’s going to persuade anybody to say, “I’m going to use selinexor at first relapse.” But it does give you the comfort of knowing if you combine selinexor with a proteasome inhibitor, the adverse events are much lower. The GI [gastrointestinal] toxicity is much better. And that weekly dosing of bortezomib, for instance, is safe, and clearly very effective when you partner it with selinexor.

Keith Stewart, MD, ChB, MBA: Joe, I inherited some of your patients on selinexor. You’ve had some experience with it. What do you think about where it should be used?

Joseph Mikhael, MD: I agree with Sagar. This has come up routinely throughout the discussion, Keith. We’ve learned so much about these drugs over time. We use bortezomib differently now from how we did at the start. We use carfilzomib differently as well, and I agree with Cristina that our cardiac risk has gone down considerably as we’ve been more comfortable using it. I wonder if that may have even influenced some of the results of the ENDURANCE study that Nina described earlier. But selinexor is another perfect example that I’m sure we’ll talk about. Belantamab and other drugs are changing what we do too. I still will sometimes use it as the so-called single agent with dexamethasone [Ozurdex], twice weekly, but sparingly. It needs to be partnered and given once weekly. As Sagar stated, for bortezomib, it’s not the ideal partner in relapse myeloma because of the neuropathy and the challenges. We’re going to be using it much more with carfilzomib [Kyprolis]. It seems particularly effective in high-risk patients. We commented earlier, in early relapse, that I tend to try not to use pomalidomide as much in the high-risk setting. I’ll use isatuximab [Sarclisa], plus carfilzomib or daratumumab, plus carfilzomib. Now we’ll have another option, I think, with selinexor and carfilzomib. Remember, in the BOSTON study, half of those patients had high-risk sighted genetics. We’re going to be using selinexor more, now that it’s more comfortably used once weekly. But it will still be used with aggressive GI prophylaxis.

Keith Stewart, MD, ChB, MBA: There are many other options in first or second relapse. To me, in my own personal practices, selinexor stayed as an end-stage relapse drug. Nina, how about you? I’ll give you the last word on this 1.

Nina Shah, MD: I’m so happy that there’s another way to use Selinexor, because now we have more understanding of weekly usage with other drugs. I totally agree that the BOSTON trial itself isn’t going to make selinexor run into the second line as a standard therapy. But 1 of the analyses that I thought was very important was the 1 in ASH [American Society of Hematology annual meeting] that showed that prior prednisone inhibitor exposure did not negate the effect of the SVD—or XVD, as I call it now— selinexor, bortezomib, dexamethasone. As you were saying, people aren’t always more hesitant of refractory. They’re not always there—a refractory—if they got it in the front line. That’s something to consider later. We’re using the bortezomib if the patient isn’t previously bortezomib refractory, so we’re going to get more data from all the arms of STOMP. We’ll better understand how to use this with judicious GI support and other support.

Keith Stewart, MD, ChB, MBA: I have to go to Sagar for the next 1. We have lenalidomide, we have pomalidomide, and now we have iberdomide. Sagar, I know you’ve been the lead investigator on iberdomide studies. Are you excited about that? Do you think it’s an incremental improvement? What’s your thinking?

Sagar Lonial, MD, FACP: Iberdomide has a couple of strengths. The first is that it overcomes pomalidomide resistance and lenalidomide resistance, so it clearly has an activity of somewhere around 30%, in combination with dexamethasone in a highly resistant patient population. The second strength is that it’s tolerated better than all the other IMiDs [Immunomodulatory imide drugs], so it’s easier to keep people on iberdomide for a longer period of time. Iberdomide is much lower grade 3, grade 4 toxicity. Those 2 strengths are important, and iberdomide is a much more potent immune activator. Those 3 things make up why iberdomide is going to be a good drug.

Keith Stewart, MD, ChB, MBA: I tend to agree. There’s 1 more thing I want to get into. Cristina, have you had any experience or thoughts about the alkylating agent? Or improvement on the alkylating agent Melphalan, which is melflufen.

Cristina Gasparetto, MD: It’s a definitely another interesting drug. As you know, it’s a peptide link to an amino peptide. The alkylator is internalized. In a way, I see the drug not like an old-fashioned chemotherapy but more targeted because it penetrates and is internalized in the myeloma cells. That causes the cell to be more specific; it’s more targeted. No matter what, Melflufen was the first drug approved and introduced for treatment of myeloma, and we know that it’s a very effective alkylator in different situations. We’re still using it for transplant, of course, so it’s interesting to see the data on extramedullary disease. The responses weren’t phenomenal as a signal agent, but it’s also very convenient—given only once a month, in combination with dexamethasone—for patients with the extramedullary disease. Unfortunately, those are patients with very aggressive myeloma. Having a signal on this particular population—chemotherapy, at the end of the day, penetrates in the tissue—we can see some of these responses. We’ll see what’s happening with the different combinations. Can we combine it? There are clinical trials to combine Melflufen with daratumumab and bortezomib so we’ll see what’s happening over the next few years. But it’s another potential drug. If you think about, even older adults are nontransplant eligible. They want to be exposed, eventually, to chemotherapy. With the targeted therapy, the toxicity was a little similar to the Melflufen, with infection and a mild suppression.

Keith Stewart, MD, ChB, MBA: Thank you, Cristina. I’m going to turn to Sagar to close out this session. I understand that there was a press release…comparing Melflufen with pomalidomide and dexamethasone, vs Melflufen and dexamethasone, which didn’t meet the primary end point. Sagar, what are your comments on that? We haven’t seen the raw data yet.

Sagar Lonial, MD, FACP: Alkylators, as a class, have a certain utility and a certain function. Whether that alkylator is Melflufen, melphalan [Alkeran], or cyclophosphamide, they all have a role, and there’s no question about that. But it wasn’t until we got new targets that we started moving into the world of myeloma therapy. It doesn’t surprise me that it wasn’t better than pomalidomide-dexamethasone. It’s noninferiority if I remember correctly. Maybe my colleagues can correct that, but it is what it is.

Keith Stewart, MD, ChB, MBA: Do you think you’ll use it, as opposed to using melphalan alone?

Sagar Lonial, MD, FACP: We use oral cyclophosphamide, in combination with PIs, similar to your Canadian colleagues. We use it a fair amount in refractory myeloma, and that’s a pretty effective, easy drug to give.

Keith Stewart, MD, ChB, MBA: Sometimes it amazes me that people get through 4 or 5 lines of therapy without seeing an alkylator. I’m all for getting rid of chemotherapy, by the way, and we’re getting very close. We’ll talk about in the next session. We’ve covered a lot of ground in the last few minutes. The takeaway for the audience is that there are a lot of choices in relapse, which is excellent. Usually triple therapies are preferred. Sagar was the bluntest in saying that daratumumab is likely the cornerstone of first relapse. The question is whether you would combine that with carfilzomib or with 1 of these newer agents that we just discussed. Those questions are for another time and another date.

Transcript Edited for Clarity

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