Induction Therapy Regimens for Transplant-Eligible NDMM


Key opinion leaders on multiple myeloma management review available induction therapy regimens in the transplant-eligible setting.


Joshua Richter, MD: This is a great segue. We’ve all hinted at this to some degree about [how] we’re using regimens [such as] VRd [bortezomib (Velcade)/lenalidomide (Revlimid)/dexamethasone], dara [daratumumab]-VRd, dara-Rev-dex [daratumumab, lenalidomide, dexamethasone] in some patients, and I know there’s been some really great data recently. A lot of [these] data generated from the institutions of the panel members, and I’d love to hear [your] thoughts on some of the more recent studies…. [What are your] thoughts about GRIFFIN [NCT02874742], and how [does it] impact your induction regimen choice?

Alfred L. Garfall, MD: That is the basis for quadruple-based induction and tells us a couple important factors. No. 1, it’s very safe. No safety signal should make us concerned about adding daratumumab or using a quad-based induction. These patients do get onto autologous stem cell collection in transplant. Even though there does seem to be a bit of a decreased stem cell yield, [and] maybe a bit more difficulty collecting, it doesn’t preclude transplant in anybody. You might have to hold the daratumumab a little longer to get the stem cell collected, but it’s not going to preclude that transplant option. [It also has] remarkable efficacy in terms of higher response rates, and now we’re seeing a progression-free survival advantage. Even though I said we’re not using this universally for our patients, we’re comfortable using it when we think we need it and [in] patients [who] we’re worried about. I could easily see this becoming the standard. Just like we moved from RD [lenalidomide/dexamethasone] to VRd with SWOG S0777 [NCT00644228], we may see the same transition eventually, if we see long-term overall survival improved.

Joshua Richter, MD: One of the things you alluded to earlier was the ENDURANCE trial [NCT01863550], which although [it] didn’t focus on this setting, there were some fascinating subgroup analyses, especially for the 1Qs when you start incorporating [carfilzomib]-based induction. I’d love to hear your thoughts on things like the MASTER study and GMMG [HD7; NCT03617731].

Natalie S. Callander, MD: Part of the difficulty of looking at 1Q is that the data out there about what is amplified—meaning 4 vs what is gain vs 3—[are] so complicated. There is an attempt underway to try to look at some of these big data sets to see [whether] we can understand this better. So yes, there was an analysis that suggested maybe [carfilzomib] is a bit better. What we and Dr Bal, who also participated in the MASTER trial, found out is that it’s the double-hit [patients]—1Q plus in most cases—who seem to do the worst, who went into remission, [and] they were MRD [minimal residual disease] negative. But then you start to see them relapse really quickly. By a year, we’re starting to see a fair sizable amount. And then at almost a 2-year follow-up, [approximately] 60% of them are still in remission or have not undergone progression.

Joshua Richter, MD: Have you incorporated [carfilzomib]-based quadruplets into your practice?

Natalie S. Callander, MD: We do for high-risk patients. Certainly, for somebody with plasma cell leukemia; that would be without question. We would go to that rather than DT-PACE[dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide]. I don’t know how many [clinicians] use PACE for those patients routinely. And then what’s coming from the German group is the combination of cetuximab KRd [carfilzomib (Kyprolis)/lenalidomide/dexamethasone] in a very aggressive regimen designed for higher-risk patients; they get induction, [and] they get transplant. If they’re young enough, then they get more KRd, then a triplet maintenance. They’ve got MRD data—it’s 60% when they looked at posttransplant—and we’ll see whether that holds up. But I will say that particular regimen—[due to] the intensity, the induction transplant, [and] more chemotherapy—[has] a high complication rate [and] a pretty high [adverse event] rate.

Elizabeth O’Donnell, MD: It’s interesting. We have a study at Massachusetts General Hospital, which is the same combination—the SKYLARK trial [NCT04442503].

Natalie S. Callander, MD: That’s your trial?

Elizabeth O’Donnell, MD: Yes. It was well tolerated [and] highly efficacious. We presented it at [American Society of Hematology]. We’ll be publishing it shortly. But one of the things that’s nice about that vs the twice-weekly [bortezomib] is the fact that you give the carfilzomib once weekly. And in general practice, we [often] give [bortezomib] once weekly, but I don’t know that that’s appropriate in a high-risk patient. So one of the nice aspects of the carfilzomib design is the once-weekly administration…it’s much more feasible, strongly effective, and [is] pretty well tolerated. But again, it’s a younger population and the [patients] who are going on this study—there’s a bias toward putting the healthier, more fit patients. So it’s not surprising that we’re seeing it’s better tolerated in that group.

Susan Bal, MD: Also from MASTER, we learned that we traditionally think of the younger vs older populations, but there was a subgroup analysis published by our colleague, Dr Geary, looking at patients who are older vs younger. What we saw was there was no difference in their tolerability overall. As long as they were eligible for this study and met other criteria, they did quite well with the quadruplet.

Alfred L. Garfall, MD: Another way to incorporate early carfilzomib into these high-risk patients’ treatment is in the maintenance setting. The data from the FORTE study [NCT02203643] on the KR [carfilzomib (kyprolis)/lenalidomide (revlimid)] maintenance and using it every 2 weeks [intravenously] is a nice, sustainable maintenance regimen. A lot of these super high-risk patients will still respond very well to [bortezomib]-based induction. It’s just the early relapse that you’re worried about. Maybe you could incorporate the carfilzomib in the maintenance setting combined amid proteasome inhibitor [PI], more potent PI, and that’s been safe in the FORTE trial. That’s another strategy to include early carfilzomib.

Natalie S. Callander, MD: I will mention that I was very impressed yesterday looking at Dr Ajay K. Nuka’s [MD, MPH, FACP] presentation about carfilzomib, pomalidomide, [and] dexamethasone maintenance, and they still had the same results that we did in MASTER and in GRIFFIN, that those high-risk patients are still falling out. We would probably all agree—and we’ll be talking more about this later—that this is the area where we’re going to probably incorporate different agents with different mechanisms.

Elizabeth O’Donnell, MD: That’s part of the challenge now in all these patients: What is appropriate maintenance? That’s a hard question to answer because it takes many years to arrive at that conclusion. But for your high-risk patients, is it a triplet? SKYLARK employs a triplet for high-risk patients vs standard risk, which [administers] lenalidomide alone. But what is the right combination? The Perseus study [NCT03710603], which is very much like GRIFFIN, has a randomized maintenance. These are important factors that we need to build into our trial design to ultimately [figure out] what our patients—particularly even standard risk, too, to your point earlier—what is the ideal combination for the maintenance setting for the duration? Can we take [patients] off? Is there [a certain] amount of time? We don’t have good answers for that yet.

Joshua Richter, MD: You 2 brought up phenomenal points about the difference between what the trial says and did in their protocols and what’s actually done. You mentioned FORTE. I think KR maintenance is tremendous. In the FORTE study, carfilzomib is given [on] days 1, 2, 15, [and] 16; every 28 days, 4 times a month, to me, is not maintenance. And I don’t think [most] of us in the United States use carfilzomib in that fashion. To your point—GRIFFIN and the up front—we’re mostly using bortezomib once a week. So, I love the concepts that you’re all talking about. Yes, great regimens for maintenance high levels, but we need to make them applicable and more tolerable long term.

Elizabeth O’Donnell, MD: That’s right, and that is a hard thing. We want to talk about things as they’re studied and unlabeled, but the practical considerations—especially when you’re talking about years of therapy—we do often administer these very differently. Again, once weekly [bortezomib] is simple, easy, and probably the most done thing, but that’s not how our trials are designed.

Transcript edited for clarity.

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