Richter Discusses How Quadruplet Therapy Has Changed Treatment Considerations and Outcomes in NDMM

Joshua Richter, MD

Associate Professor of Medicine

Tisch Cancer Institute

Icahn School of Medicine

Director of Multiple Myeloma

Blavatnik Family Chelsea Medical Center at Mount Sinai

New York, NY

Targeted Oncology: What role does minimal residual disease (MRD) play when treating patients with newly diagnosed multiple myeloma (NDMM)?

RICHTER: I talk about it with patients, and I do test their MRD, but it rarely impacts what I do. The question is how aggressive you need to be in therapeutics, which to me matches how aggressive in diagnostics [you are]. For example, I have an 85-year-old patient I’m going to put on daratumumab plus lenalidomide: If [the scores on her blood counts are] even decent, then I’m great.

The younger [the patient is], I get more aggressive therapeutically and diagnostically...because we are starting to learn who we need to push further. And if someone’s going to come back [to treatment] sooner, [we learn who] we need to get onto chimeric antigen receptor [CAR] T-cell therapy.

What data inform your decision-making for maintenance therapy in this patient population?

[The phase 3] SWOG s1803 [DRAMMATIC; NCT04071457] is one of the most important studies that’s being done right now.¹ I love trials [looking ahead] with bispecifics, but at the end of the day, I have a patient in clinic who is getting D-VRd, transplant with lenalidomide maintenance or daratumumab plus lenalidomide, and I want to know who needs more? Who needs less? And who can I stop therapy for? This study is pragmatically one of the most important studies out there.

How do you view the practice of posttransplant consolidation?

Posttransplant consolidation is not popular in the United States. They do it in other parts of the world....² I like the idea; I still do it in some patients…. I tell [patients] after transplant there are 3 types of cells: the ones we killed outright, the ones we were never going to kill because they were so robust, [and a] third group [of myeloma cells] that we kind of knocked off their axis a little bit, and if we hit them a little harder we’ll kill a little more, thus sending the patient into a deeper remission. So there are patients I give induction, I [send to] transplant. But on the other end of transplant, they may have more disease than I feel comfortable with just coasting into maintenance. Therefore, posttransplant consolidation is a nice thing to do at that point.

What were the baseline patient characteristics of the phase 2 GRIFFIN (NCT02874742) trial, and how do they reflect the current population of patients with NDMM?

There were 100 patients in each arm, [so the trial was] pretty well balanced, as well as between patients with high-risk or standard-risk disease, but we’re really starting to parse out these ultra–high-risk patients.³ To put it into context, nobody knows how long a patient diagnosed with multiple myeloma in 2023 will live, but a rough guess for patients with standard-risk disease is [more than] a decade.

We have great drugs, [so if they’re standard risk] they’re living [longer than] a decade. However, [patients with] high risk are probably [going to live an additional] 4 to 6 years right now, whereas those with ultra–high-risk disease have a median survival of 20.8 months, according to data published out of England.⁴ I don’t care what stage [of disease] the patient is at. If they’re an 80-year-old with standard risk, they’re [most likely] dying of something else, [not multiple myeloma].

What in the efficacy data of the GRIFFIN trial stood out to you?

[You have to] remember, this [regimen] is induction, transplant, posttransplant consolidation, and then maintenance therapy, and the rates of stringent complete response [sCR] are through the roof [Table⁵]. For patients who were 65 years or older, they had an sCR rate of 63.0% on D-VRd vs 40.7% on VRd [lenalidomide, bortezomib, dexamethasone].

We’re no longer talking about what’s the response rate up front, as the overall response rates are 100%. Everyone responds, so we’re talking about more than 60% of [patients] in the D-VRd arm had nothing detectable on routine marrow test at the end of this [treatment cycle]. This is next-level stuff. And even [in patients] with high-risk cytogenetics, we’re getting very high rates. It’s definitely muted, but it’s even more muted if we look at VRd, as the number of [patients] to get to sCR is 38.5% compared with 50.0% in D-VRd, and those are the [patients] you worry about even more.⁵ When it comes to MRD negativity [across subgroups of patients], for the most part, they’re all going to favor D-VRd.⁵ Certainly, patients with lower-risk disease will do even better, but even in the high-risk group, everything seems to trend toward improvement with quadruplet therapy over triplet therapy.

Again, deeper responses tend to correlate with durability. The same trend was seen for progression-free survival. I still love the fact that even with VRd, about 70% of [patients] are in remission at 4 years, which is still pretty good. But we’re really starting to see separation [between VRd and D-VRd] in the curves at this point as almost 90% of [patients] are in remission with D-VRd at 4 years.⁴ It really has become a standard of care for transplant-eligible patients with NDMM.

Are there any factors that make it more difficult for patients to achieve a deep and durable response with treatment?

The [patients who find] it the hardest to overcome the disease [and get deep responses with the therapy] are the ultra– high-risk patients who have 2 or more high-risk cytogenetic abnormalities…. For those who are not tuned into [these subgroups of patients as much,] we all know deletion 17p [del(17p)].

If the patient is del(17p) then it doesn’t matter what tumor you treat, if you mess with p53 [it won’t work out]. Probably the worst thing in the myeloma [space] is a gain of 1q. We have 2 terms for this: gain of 1q and amplification of 1q. A gain of 1q is 3 copies, and amplification is 4 or more, so the more copies you have of 1q, the worse you will do. In many studies, those are the patients who do the absolute worst.⁶ In fact, in the phase 2 FORTE study [NCT02203643], almost everyone did better with high-risk disease if they got carfilzomib [Kyprolis] and lenalidomide maintenance, except those with amplification of 1q.⁷ Nothing overcomes amplification of 1q; that in and of itself is a bad prognostic factor.

What was the toxicity profile of this quadruplet regimen?

Higher rates of neutropenia are clearly what we’ve seen, and I think it caught a lot of us by surprise because we come from the rituximab [Rituxan] world where we add rituximab and it doesn’t really change neutropenia. Does R-CHOP [rituximab, cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate (Oncovin), prednisone] have much more toxicity than CHOP [cyclophosphamide, doxorubicin hydrochloride, vincristine sulfate, prednisone] in terms of hematological toxicities? Probably not, but CD38s are expressed on much more.

So, with daratumumab, lenalidomide, D-VRd, and other daratumumab combinations, you’re going to have more cytopenia. Other than the cytopenia, the patients feel well on it.⁵ It’s not like they feel physically worse, as they don’t have neuropathy or don’t generally have more asthenia. In fact, pain metrics will be better because you can reduce the pain and tumor burden a lot quicker.

What has changed the most about the landscape of multiple myeloma?

Upfront therapy [for patients with multiple myeloma] is different than what it used to be. I almost relate myeloma therapies [to] where treatment for Hodgkin disease has gone. We go to every patient with such enthusiasm saying, “Everyone responds; [you’re] going to do great.” However, the question is, how do you ensure not just that the patient responds, but that they continue to respond? Deeper remissions are the way to go there, and to me, that’s done with quadruplet therapy and transplant for those who are eligible, but obviously, there is still an ongoing discussion about risks and benefits.

_REFERENCES

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_{6. Schmidt TM, Barwick BG, Joseph N, et al. Gain of chromosome 1q is associated with early progression in multiple myeloma patients treated with lenalidomide, bortezomib, and dexamethasone. Blood Cancer J. 2019;9(12):94. doi:10.1038/s41408-019-0254-0}

_{7. Gay F, Musto P, Rota-Scalabrini D, et al. Carfilzomib with cyclophosphamide and dexamethasone or lenalidomide and dexamethasone plus autologous transplantation or carfilzomib plus lenalidomide and dexamethasone, followed by maintenance with carfilzomib plus lenalidomide or lenalidomide alone for patients with newly diagnosed multiple myeloma (FORTE): a randomised, open-label, phase 2 trial. Lancet Oncol. 2021;22(12):1705-1720. doi:10.1016/S1470-2045(21)00535-0}