Recent Advances in the Treatment of Relapsed/Refractory Multiple Myeloma - Episode 6
Sagar Lonial, MD; Joshua Richter, MD; and Ola Landgren, MD, PhD, comment on the selection of the appropriate treatment regimen at first relapse, including CD38-based, non-CD38–based and non-PI–based treatment regimens for multiple myeloma, and discuss their approach to assessing treatment response.
Nina Shah, MD: Sagar, I want to flesh this out a bit. This is happening more, where people are getting anti-CD38 therapy up front. Would you ever reuse anti-CD38 therapy? If so, when? Particularly in thinking about the first relapse.
Sagar Lonial, MD, FACP: When daratumumab is used as part of the induction, as it is in standard-risk patients treated at our place, we don’t give it continuously. We give it for the first of 4 cycles of induction, then consolidate with a transplant, and then go on to risk-adapted maintenance. In that patient, while they’re exposed, they’re still daratumumab sensitive, so I wouldn’t have an issue reusing an anti-CD38 antibody. But if they’re getting continuous daratumumab or they’re getting daratumumab as part of the maintenance, then it’s a different discussion.
There are a number of non-CD38–based salvage therapies, typically including both a PI [proteasome inhibitor], like carfilzomib, bortezomib, or even ixazomib, and an IMiD [immunomodulatory imide drug], typically using pomalidomide. KPd [carfilzomib, pomalidomide, dexamethasone] has 2 small phase 2 studies that support its activity. The carfilzomib dose in KPd [carfilzomib, pomalidomide, dexamethasone] is lower than the dose that you’re seeing in combination with CD38 antibodies, and that might give you the opportunity to use carfilzomib again later on at a higher dose to try to overcome resistance potentially. Ixazomib-pomalidomide-dexamethasone has data, and bortezomib-pomalidomide-dexamethasone has data.
Then there’s the incorporation of cyclophosphamide, my least favorite drug. You could do KCd [carfilzomib, cyclophosphamide, dexamethasone]. You could do VCd [bortezomib, cyclophosphamide, dexamethasone]. You could do ICd [ixazomib, cyclophosphamide, dexamethasone]. I tend to save that for when I don’t have other options. The second line wouldn’t be where I’d use it, but those are certainly potentials as well.
Nina Shah, MD: It’s alphabet soup coming in. We’re going to have to be creative with these lines. If we’re going to use 4 letters up front, we’re going to have to save some letters for lines 2, 3, and 4. Josh, do you have anything to add, maybe noncarfilzomib or non-PI–based salvage regimens? Is there anything else in the list there that Sagar didn’t cover?
Joshua Richter, MD: As Sagar pointed out beautifully, when we’re talking about this early on, is it a PI-based backbone, IMiD based, or a CD38? If we’re not going PI based, we may look to monoclonal based, so daratumumab-, isatuximab-, and elotuzumab-based regimens. A lot of this is going to depend on whether you’re lenalidomide refractory. If you’re lenalidomide naїve or sensitive, then elotuzumab-lenalidomide or daratumumab-lenalidomide are completely appropriate. If you’re refractory to lenalidomide, then elotuzumab-pomalidomide, daratumumab-pomalidomide, or isatuximab-pomalidomide are all appropriate regimens.
I hate to bring this up within 30 seconds of Sagar saying he hates cyclophosphamide, but pomalidomide-cyclophosphamide-dexamethasone every now and again in the right situation can get the job done, although I couldn’t agree more with Sagar. With what we’re learning about cyclophosphamide’s effect on patients, it’s going to slowly be going away. It’s a race. What’s going to go away first in myeloma, dexamethasone or cyclophosphamide? I’m happy to see them both go.
Nina Shah, MD: That’s good. There’s a role for everything. Is anyone here using selinexor in the first progression? That’s another option for the non-PI, non-IMiD.
Joshua Richter, MD: Unfortunately, right now, the only approval early on based on BOSTON still has the PI for the XVd [selinexor, bortezomib, dexamethasone] regimen. The 1 scenario where I feel there’s a role for XVd [selinexor, bortezomib, dexamethasone] is the MAIA regimen, daratumumab-lenalidomide-dexamethasone up front, which has had unbelievable responses. The median PFS [progression-free survival] hasn’t been reached but is over 60 months. If you have an early relapse off DRd [daratumumab, lenalidomide, dexamethasone] up front, like you’re on it and you relapse in less than a year, then you’re going to be PI-naїve, not only IMiD-refractory but very poorly responsive to IMiDs. With DRd [daratumumab, lenalidomide, dexamethasone] up front, very poor response could get XVd [selinexor, bortezomib, dexamethasone] as their next-line therapy.
Nina Shah, MD: Good point. Ola, going on about the first relapse to close it out, how do you assess the response to treatment? How long do you continue therapy on that same regimen? Or do you switch after a certain amount of time?
Ola Landgren, MD, PhD: The monitoring is very similar to how we’d treat the patient in the up-front setting. I’d check the laboratory tests on a monthly basis for the myeloma markers. I’d like to see that there’s a response after 1 or 2 cycles for sure, and I’d monitor. After about 6 cycles with all these new combinations, the majority of patients we treat reach a very good response.
Unlike the trials that have all the drugs going continuously, in the real world, patients are asking for feasibility. “Can we start peeling back? It’s too much—too many visits.” I tend to have a bit of a response-adapted approach. After 6 cycles, if you see a really good response, maybe we do it once a week if we started at twice a week. Maybe we take off 1 drug if we have 3 drugs to begin with. But some patients choose to stay on all 3 drugs. I have a conversation with each individual patient about feasibility and efficacy. I address that the trials were designed this way, and if we start taking off drugs, it may last shorter. There’s a conversation with every patient.
Nina Shah, MD: Do you often feel like you take out the dexamethasone first? What do you think is the first thing that goes?
Ola Landgren, MD, PhD: If a patient mentions that they have adverse effects with dexamethasone, I go from 20 mg once a week to 8 mg once a week. If they don’t like it, I do 4 mg. If they still don’t like it, I take it out. If the patients don’t bring it up, I ask them about it.
Nina Shah, MD: Do you switch therapy because of toxicity? Or do you attenuate doses first and try to get that as low as possible?
Ola Landgren, MD, PhD: I cut back the dexamethasone, for sure. And if IMiDs—pomalidomide or Revlimid or whatever you use—cause low counts, I’d cut back on the dose. With daratumumab, there’s no dose reduction. With carfilzomib, sometimes you see shortness of breath. If the dose is 56 mg/m2, if you go down to 45 or 36 mg/m2, many times you can see a difference. I almost never use 70 mg/m2. I don’t like the dose. That’s too toxic.
Nina Shah, MD: That’s good to know. This has been a great discussion about early relapse.
Transcript Edited for Clarity