Dara-KRd Quadruplet Makes Waves in Newly Diagnosed Multiple Myeloma

Luciano J. Costa, MD, PhD

Induction therapy with daratumumab (Darzalex), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Dara-KRd) followed by autologous hematopoietic stem cell transplantation (AHSCT) and consolidation with the quadruplet resulted in high progression-free survival (PFS) rates for patients with newly diagnosed multiple myeloma and allowed many to eventually stop therapy, according to Luciano J. Costa, MD, PhD.

Costa presented findings from the final analysis of the phase 2 MASTER trial (NCT03224507) at the 2023 EHA Congress. At a median follow-up of 42.2 months, patients with 0 (n = 53), 1 (n = 46), or 2+ (n = 24) high-risk cytogenetic abnormalities (HRCA) experienced 3-year PFS rates of 88%, 79%, and 50%, respectively (P < .001). Overall survival (OS) rates were 94%, 92%, and 75%, respectively (P = .004).

“Sixty-one percent of patients throughout the trial were able to cease therapy,” Costa said. “At the data cutoff, more than half of those patients remained MRD [minimal residual disease] negative and free of therapy. That’s the highlight of the study.”

Additionally, findings from a post induction landmark analysis showed MRD-adapted therapy reduced the effect of MRD positivity at the end of induction in regard to PFS (P = .94) and OS (P = .13). Similar results were seen in a post AHSCT landmark analysis for PFS (P = .90) and OS (P = .47).

In an interview with OncLive®, Costa, the associate director of clinical research at the O’Neal Comprehensive Cancer Center, of the University of Alabama at Birmingham, discussed extended follow-up data from the trial and explained how the results may affect frontline treatment decisions in multiple myeloma.

OncLive: What was the rationale behind investigating this combination in the MASTER trial?

Costa: The MASTER trial is an investigator-initiated trial performed by the coMMit consortium that I had the opportunity to lead. This trial enrolled 123 patients treated mostly between 2018 and 2020. The rationale was to put our best foot forward. [To do that, we combined] essentially the best available agents in different classes to try to get most patients to a deep remission, [which we] assessed by MRD [and] by next-generation sequencing [NGS], in a way that we could [then] explore a path of treatment cessation.

The study [was] deliberately enriched for high-risk patients, so it has populations that are often not represented or underrepresented in most trials [of newly diagnosed patients with transplant-eligible] myeloma, including 20% of patients over the age of 70 and close to 20% of patients with 2 or more high-risk chromosomal abnormalities. The design consists of 4 cycles of Dara-KRd quadruplet therapy and autologous transplant. Beyond transplant, patients could receive up to 8 cycles, 2 blocks of 4 cycles of Dara-KRd consolidation. What dictated [whether patients received 4 or 8 cycles of consolidation with Dara-KRd] was assessment of MRD by NGS. Patients who had MRD negativity [below] 10-5 in 2 consecutive assessments were able to stop therapy and be monitored by regular laboratories, but also by MRD assessment in the bone marrow.

What were some of the highlights from previously presented findings?

Findings that we reported before with approximately 24 months of follow-up [showed that] the primary end point, achievement of MRD negativity, was possible in 81% of patients. Interestingly, the proportion of patients achieving MRD negativity was very similar for patients with 0, 1, or 2+ high-risk chromosomal abnormalities.

However, when you look at the kinetics of achieving MRD negativity and look at the [exploratory] end point, which is [MRD negativity below] 10-6, you start to see some differences, particularly in the patients with ultra–high-risk disease. They rarely achieve MRD negativity post induction, often it is only after transplant, and there’s a substantially smaller proportion of patients who achieve MRD negativity [below] 10-6. We reported before that the 24-month PFS [curves] already showed some separation, [as] the patients with 0 to 1 high risk chromosomal abnormalities performed very well and very similar, [whereas we saw] a higher rate of progression [and] early resurgence of MRD in patients with 2+ high-risk chromosomal abnormalities.

What were some of the key efficacy findings from the final analysis presented during EHA?

For this final analysis [we had] longer follow-up. We went from 24 months to 42 months of median follow-up, which gives us better insights on how patients [do long term]. The patients with 1 high-risk chromosomal abnormality, which are approximately 15% of our patients, are doing quite well. They look very much like patients with no high-risk chromosomal abnormalities, which is very reassuring. The 3-year PFS rate for [the latter] group is over 80% and OS is near 100%.

For patients with ultra–high-risk disease, PFS at 3 years is closer to 50%, but the OS is still great showing that those progressions are still for the most part [possible] with subsequent therapy. We have seen a few progressions, a few resurgences of MRD, and have some insight into the frequency of how those happen. The 2-year risk of progression is only 9% for patients with 0 or 1 high-risk abnormalities but is 50% for patients with 2 or more.

We showed patterns of patients who have progression without any warning, but as you move to 2- or 3-years of follow-up, you see more patients with MRD resurgence without biochemical or clinical progression. Those patients for the most part are amenable to clone control with reinstitution of anti-myeloma therapy.

Were any new safety signals observed in the long-term analysis?

[The safety data] are also very reassuring because [they came from] a long-term analysis with more time for patients off therapy. By definition, [there shouldn’t] be any more treatment-emergent adverse effects, [and we saw there were] no long-term signals such as excessive second malignancies or pervasive high risk of infection.

What impact do these data have on the treatment landscape of multiple myeloma?

This is an excellent regimen, probably the best combination you could come up with nowadays with available [agents]. It is a very [suitable] therapy for high-risk and standard-risk patients with myeloma.

This helps set a path for treatment cessation, particularly [for] patients without ultra­–high-risk disease. It’s not only this trial [that we’ve seen the potential for treatment cessation]. Data from the [phase 3] CASSIOPEIA trial [NCT02541383] with daratumumab, bortezomib [Velcade], thalidomide [Thalomid], and dexamethasone induction/consolidation and no maintenance [showed that] patients who achieve MRD negativity do extremely well without any subsequent or ongoing therapy. There’s this sentiment that therapy alone might be sufficient to buy people a very long remission and it’s becoming stronger and stronger.

Perhaps the most humbling message is regarding the ultra­–high-risk patients. There were more than we would expect in this trial because of the deliberate enrichment, but in general they represent approximately 10% to 15% of our patients, and that is a challenge. We saw in this trial that they don’t do as well as the other groups in part because of some of them progressing, even on quadruplet therapy. Though this trial had an approach of treatment cessation, that does not explain the whole behavior because this subset of patients had the same trajectory on the [phase 2] GRIFFIN trial [NCT02874742] with continuation of daratumumab and lenalidomide. [Data presented at the 2023] ASCO Meeting with carfilzomib/pomalidomide [Pomalyst], 2 outstanding drugs––a proteasome inhibitor and third-generation immunomodulatory [agent]––combined post-transplant as maintenance [showed a similar pattern] with patients having high rates of progression in the first couple of years.

That tells us the solution for those patients is not going to be any combination or continuation of existing regimens. Our best shot is trying to bring as quickly as possible [practices] that have revolutionized the care of patients with myeloma in later phases, particularly CAR T-cell and bispecific [antibody therapies], and trying to overwrite that high-risk prognostic projector theory.

Reflecting on the 2023 EHA Congress as a whole, what other presentations caught your eye?

In the myeloma field there are a lot of interesting data. We’ve seen the [phase 3] CARTITUDE-4 [NCT04181827] data, which I believe is revolutionary, bringing high-level evidence for BCMA-directed CAR T-cell therapy for patients into earlier lines of therapy, as early as second line, that are not even triple-class exposed. We’re going to be digesting those data and seeing how that’s going to affect our practices.

I’m very excited with the update that my colleague presented on the GPRC5D-[targeted] CAR T-cell therapy in patients [who received] 3 or more prior lines of therapy. Those data look incredible, and we are in an ocean of many different BCMA-directed CAR T-cell therapies. Seeing a CAR T-cell therapy developing so well with a different target is very exciting.

We also saw for the first time the combination of 2 bispecific agents, teclistamab-cqyv [Tecvayli] and talquetamab-tgvs [Talvey], with different targets showing a surprisingly high rate of response, including [for] patients with extramedullary disease—that is certainly intriguing. We saw updates on a series of other BCMA-directed T-cell engagers. It’s a bit of stiff competition there to see which one of those [agents] will prevail and make it to the market.

We’re also seeing more data with elranatamab-bcmm [Elrexfio]* in a cohort of patients who had received prior BCMA-directed therapy, showing a surprisingly good performance even in patients who had prior BCMA-directed CAR T-cell or prior BCMA-directed antibody-drug conjugate [treatment], which starts to give us some hint into how those therapies can be sequenced.

Editor’s Note: This interview took place prior to the approval of elranatamab for the treatment of patients with relapsed/refractory multiple myeloma who have received at least four prior lines of therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 monoclonal antibody.

Reference

Costa LJ, Chhabra S, Medvedova E, et al. Quadruplet induction therapy, ASCT and MRD-modulated consolidation and treatment cessation in newly diagnosed multiple myeloma: final analysis of the MASTER trial. HemaSphere. 2023;7(suppl 203):e1332195. doi:10.1097/01.HS9.0000967724.13321.95