Fellow's Perspective: Impact of Quadruplet and MRD in Newly Diagnosed Multiple Myeloma

[Continued from part 1]

TRANSPLANT AND MINIMAL RESIDUAL DISEASE IN MYELOMA

BRAUNSTEIN: Dr Main, with the introduction of novel induction therapies, is there a continued role for transplant in patients with newly diagnosed myeloma?

MAIN: This is a topic of continued discussion, especially as you mentioned with the introduction of these novel therapies. At this time, stem cell transplant is still the recommendation. Of course, there are some caveats to that. If you have an older, frailer patient who you’re on the fence about putting through transplant to begin with, then perhaps the novel therapy would be preferred. But it is still shown to offer these patients a greater depth of response and a more durable response, and you can save some therapies for later lines. Given this, I think it’s a part of the conversation, but I would still say that transplant would be favorable.

BRAUNSTEIN: I agree. We don’t have any randomized data in the setting of quadruplet induction where patients were randomized after their 4-drug induction to transplant or no transplant. But we know that transplant at least improves progression-free survival [PFS] when used immediately following induction, as well as overall survival in some studies. So, I think there still is a role and a benefit for transplanting newly diagnosed, fit patients.

Marc J. Braunstein, MD, PhD, FACP

Associate Professor of Medicine

Fellowship Program Director

NYU Grossman Long Island School of Medicine

NYU Perlmutter Cancer Center

New York, NY

Olivia Main, MD

PGY5 Fellow, Hematology/Oncology

NYU Grossman Long Island School of Medicine

NYU Perlmutter Cancer Center

New York, NY

MAIN: Dr Braunstein, how does the patient’s minimal residual disease [MRD] status impact your approach to the duration of maintenance therapy?

BRAUNSTEIN: I get to ask you a complicated question, and you get to ask me one, too. There’s no clear answer to this question, but it is very attractive to be able to use MRD status as a marker for withdrawing therapy or stopping maintenance therapy. Likewise, hypothetically, if someone is remaining MRD positive, you might use that as an indicator to intensify therapy to get them into an MRD-negative state, but that’s not established as standard of care.

I think MRD is readily measurable; you don’t need to wait for an event to measure it. The FDA has decided that it is a suitable regulatory end point for clinical trials, so I think in the future, we’ll likely use MRD status to decide whether to stop maintenance therapy. In the next parts of this discussion, we’re going to review… some early data that suggest that perhaps MRD is a tool to decide whether you can discontinue maintenance therapy.

There is a relatively recent iteration of the NCCN guidelines for transplant-eligible patients and which maintenance to decide on.¹ There are multiple studies that have shown the benefit of lenalidomide [Revlimid] single-agent maintenance improving both PFS and overall survival when used post transplant as maintenance. Other recommendations include bortezomib [Velcade] or the combination of bortezomib and lenalidomide.

Historically, that was particularly favored in high-risk patients. Then there are some category 2B recommendations for using oral ixazomib [Ninlaro].

DARATUMUMAB TRIALS UTILIZING MRD

BRAUNSTEIN: SWOG S1803 [DRAMMATIC; NCT04071457] is a phase 3 study with 2 randomizations. One randomization is to maintenance therapy, whether patients get single-agent lenalidomide vs lenalidomide plus daratumumab [Darzalex]. Then there’s an MRD assessment during the maintenance. If patients are MRD positive, they continue on their assigned maintenance. [If they’re MRD negative], they’re randomized…to stopping maintenance.

This study will answer 2 questions; one is whether single- or doublet-agent maintenance strategy using a monoclonal antibody is preferred, and the second is whether we can use MRD to help guide discontinued maintenance, as patients on a doublet maintenance strategy may be more likely to have MRD negativity, theoretically, and those patients may be able to stop maintenance therapy. This study remains ongoing.

Marc J. Braunstein, MD, PhD, FACP; and Olivia Main, MD, discuss the patient case with Peers & Perspectives in Oncology.

The MANHATTAN study [NCT03500445] was a nonrandomized phase 2 study of approximately 40 patients who received a quadruplet regimen, this time with carfilzomib [Kyprolis] as the proteasome inhibitor, as opposed to bortezomib and GRIFFIN [NCT02874742] and PERSEUS [NCT03710603]. The study of D-KRd [daratumumab, carfilzomib, lenalidomide, dexamethasone] looked at the rates of MRD, and what was presented in a swimmer plot is the proportion of patients who achieved MRD negativity; 71% of those patients achieved MRD negativity within the first year of treatment. This is a pretty impressive result that warrants further investigation; it not only confirms that quadruplet induction is very effective, but it also suggests that the combination of D-KRd can lead to high rates of response and improved depth of response.²

The phase 2 MASTER study [NCT03224507] was not a randomized study but did also use D-KRd induction. This was a study that was looking at whether you could use MRD status that was assessed at various time points— before transplant, after transplant, during consolidation, and maintenance—and if patients had 2 consecutive MRD-negative results, they stopped their treatment. The study was enriched for approximately 35% of high-risk patients. The primary end point was investigating MRD negativity and whether there are any differences in the rates of PFS in patients with high-risk abnormalities compared with those who are standard risk.³

What the investigators demonstrated is there weren’t major differences in patients with standard risk vs those with 1 high-risk cytogenetic abnormality when they applied this approach of using D-KRd with an MRD-guided strategy to withdraw maintenance therapy. The patients who had more than 1 high-risk cytogenetic abnormality did not fare as well, but the ones who had 1 did just about as well as those who had 0. Again, it’s not a randomized study. Those are subgroups that were investigated, but the data suggest that it may be a suitable strategy—even for patients with 1 high-risk cytogenetic abnormality—to use MRD status to guide whether to stop maintenance therapy. These kinds of studies remain ongoing.

The MASTER study looked at PFS by MRD status. Not surprisingly, those patients who had sustained MRD negativity had better PFS than those who did not have sustained MRD negativity, although those patients were very much the minority in this study. Most patients did have sustained MRD negativity.

ISATUXIMAB TRIALS UTILIZING MRD

BRAUNSTEIN: The phase 2 GMMG-CONCEPT German group study [NCT03104842] was looking at whether induction using the anti-CD38 antibody isatuximab [Sarclisa] with KRd as the backbone [Isa-KRd] is effective before and after transplant in patients who are younger or older than 70 years. Investigators enrolled patients who specifically have high-risk myeloma. The patients received either Isa-KRd with transplant or Isa-KRd without transplant if they’re older than 70 years, and then went on to several cycles of consolidation and finally maintenance Isa-KRd until progression or toxicity, with the primary end point of MRD negativity.⁴

What they showed is the patients who were either transplant eligible or transplant ineligible had sustained rates of improved depth of response throughout induction, transplant, and end of consolidation when treated with this quadruplet regimen. Although the rates of MRD negativity were higher in the transplant-eligible patients—likely because they were consolidated with transplant—both groups had more than 50% MRD negativity rates at the time of the follow-up of the study: 67% in transplant eligible and 54% in the transplant noneligible patients. This was sustained in the transplant-eligible group in 62% of those with at least 12 months follow-up. What these data suggest is that high-risk patients have high rates of MRD negativity when treated with quadruplet induction, including transplant.

MAIN: The phase 3 IsKia trial [NCT04483739] design was looking at a quadruplet vs a triplet regimen using Isa-KRd vs KRd. These patients went on to transplant in this case and were then offered posttransplant consolidation with either the triplet or the quadruplet regimen, and then a light consolidation at the end. This was in transplant-eligible patients who were younger than 70 years. The investigators were looking at postconsolidation MRD negativity and demonstrated statistical significance in the quadruplet compared with the triplet regimen, both for 10^-5 and 10^-6 in both populations.⁵ Looking at the subgroup analysis for MRD negativity, as Dr Braunstein had mentioned previously, we know that the quadruplet regimen, specifically with KRd, is favorable for those patients who have higher-risk cytogenetics. This could be an important regimen for patients who have higher-risk cytogenetics at the time of diagnosis.

WHAT’S NEXT FOR QUADRUPLETS

BRAUNSTEIN: For our discussion, the question is where the field is headed in terms of quadruplet therapy. I would say that there are plenty of options, whether we use quadruplet induction with daratumumab or isatuximab or…bortezomib or carfilzomib; they all lead to very high response rates. I think we need to further investigate the subgroups, like the high-risk patients, to see what the ideal induction regimen is, but I think it’s dealer’s choice at this point. What do you think, Dr Main?

MAIN: I would agree. Right now, the quadruplet regimen shows superiority in either the daratumumab or the isatuximab trials. It’s just nailing down which patient population may benefit from one vs the other.

It’s hard to do a lot of cross-trial comparisons, but perhaps these patients with less favorable cytogenetics may benefit from the Isa-KRd up front.

_REFERENCES

1. _{NCCN. Clinical Practice Guidelines in Oncology. Multiple myeloma; version 1.2025. Accessed November 8, 2024. https://www.nccn.org/professionals/ physician_gls/pdf/myeloma.pdf}
2. _{Landgren O, Hultcrantz M, Diamond B, et al. Safety and effectiveness of weekly carfilzomib, lenalidomide, dexamethasone, and daratumumab combination therapy for patients with newly diagnosed multiple myeloma: the MANHATTAN nonrandomized clinical trial. JAMA Oncol. 2021;7(6):862-868. doi:10.1001/jamaoncol.2021.0611}
3. _{Costa LJ, Chhabra S, Medvedova E, et al. Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): final report of the multicentre, single-arm, phase 2 trial. Lancet Haematol. 2023;10(11):e890-e901. doi:10.1016/S2352-3026(23)00236-3}
4. _{Leypoldt LB, Tichy D, Besemer B, et al. Isatuximab, carfilzomib, lenalidomide, and dexamethasone for the treatment of high-risk newly diagnosed multiple myeloma. J Clin Oncol. 2024;42(1):26-37. doi:10.1200/JCO.23.01696}
5. _{Gay F, Roeloffzen W, Dimopoulos M, et al. Results of the phase III randomized Iskia trial: isatuximab-carfilzomib-lenalidomide-dexamethasone vs carfilzomib-lenalidomide-dexamethasone as pre-transplant induction and post-transplant consolidation in newly diagnosed multiple myeloma patients. Blood. 2023;142(suppl 1):4. doi:10.1182/blood-2023-177546}