Daratumumab-Based Quadruplet Therapy Demonstrates MRD Negativity Benefit in Newly Diagnosed Myeloma

Douglas W. Sborov, MD, MS

Quadruplet therapy with daratumumab (Darzalex), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone, followed by autologous stem cell transplant (ASCT) and consolidation with the quadruplet, generated high rates of minimal residual disease (MRD) in patients with newly diagnosed multiple myeloma, according to data from the phase 2 MASTER trial (NCT03224507).¹ These findings could help shape how future treatment decisions are approached for fit, transplant-eligible patients, according to faculty from an OncLive® State of the Science Summit™ on multiple myeloma.

The event was chaired by Douglas W. Sborov, MD, MS, associate professor, Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, director, the Multiple Myeloma Program and Division of Hematology Biorepository, the Huntsman Cancer Institute, University of Utah School of Medicine, member, Experimental Therapeutics Program, physician leader of the Multiple Myeloma/Bone Marrow Transplant arm of the HCI Clinical Trials Office (CTO), active member of the HCI Protocol Review and Monitoring Committee, Huntsman Translational Scholar. Sborov discussed findings from the MASTER trial, which showed that 80% of patients achieved MRD negativity and 71% reached two consecutive MRD-negative assessments during therapy.

Sborov was joined by colleagues:

• Amandeep Godara, MBBS, medical oncologist, Huntsman Cancer Institute at the University of Utah
• Brian L. McClune, DO, associate professor, the Division of Hematology and Hematologic Malignancies, Department of Internal Medicine, interim research division chief of Hematology/BMT, associate chief of Clinical Affairs, director of Hematology Clinical Operations, Huntsman Cancer Institute at the University of Utah
• Manni Mohyuddin, MD, assistant professor, Internal Medicine, Huntsman Cancer Institute at the University of Utah

Sborov, Godara, and McClune summarize the main messages from their presentations below.

MASTER Regimen Elicits Promising MRD-Negativity Rates in Newly Diagnosed Multiple Myeloma

Sborov: The [phase 2] MASTER trial was a brilliant study [of daratumumab, carfilzomib, lenalidomide, and dexamethasone] that has helped shape what we think the future may hold for our fit, transplant-eligible patients.

The MASTER trial was a phase [2] trial [of] 123 patients that investigated daratumumab, carfilzomib, [lenalidomide], and dexamethasone induction, followed by [ASCT], followed by up to 2, 4-cycle rounds of consolidation with daratumumab, carfilzomib, lenalidomide, and dexamethasone, followed by lenalidomide maintenance.

In this trial, MRD was assessed after ASCT and then after each round of consolidation. In those patients that had MRD negativity confirmed, they entered a treatment-free phase. On the trial, 71% of patients had confirmation of MRD negativity. Additionally, in all-comers, 80% of patients achieved MRD negativity at 10-5, and 66% achieved MRD negativity at 10-6. What's interesting is that these rates of MRD negativity improved over the course of the trial, and these rates were consistent for patients without high-risk cytogenetic features and those with 1 or 2 high-risk cytogenetic features.

When we look at progression-free survival [PFS] in patients treated on MASTER and on the [phase 2] GRIFFIN trial [NCT02874742], the PFS in patients with 2 or more high-risk [cytogenetic] features was [approximately] 65% at 2 years—a high rate in patients that previously lived only 1 to 2 years. Ultimately, we see that the quadruplet [regimens] are performing nicely, and these should be considered for all our fit patients.

Currently, we are enrolling most, if not all, of our patients on the [phase 2] ADVANCE trial [NCT04268498] that is investigating carfilzomib, [lenalidomide], and dexamethasone vs daratumumab, carfilzomib, [lenalidomide], and dexamethasone. If [patients] are unable to go on trial, we are using quadruplet [therapy] and picking our favorite proteasome inhibitor, based on comorbidities or physician discretion.

Following quadruplet induction, we’re recommending early transplant and then using a risk-adapted approach to decide on single-agent lenalidomide or lenalidomide-based doublet maintenance.

The Promise of Bispecific Antibodies in Relapsed/Refractory Multiple Myeloma

Godara: We know bispecific antibodies are effective, but we need to find better ways to use these drugs in a way that patients do not suffer from morbidities and infections. The toxicities so far [with bispecific antibodies], beyond infection, are manageable and reversible. These are off-the-shelf therapies, so some of the issues that we face with autologous CAR T-cell therapies are not going to be seen here.

One way of overcoming some of the toxicities may be a fixed duration of therapy or a response-guided duration of therapy that might help keep patients away from getting complications related to these therapies. There are already several trials that are looking at combining bispecific antibodies in an earlier course of disease to see if they would be more effective in that place and improve PFS.

Novel Anti-BCMA CAR T-Cell Therapies Under Exploration in Relapsed/Refractory Multiple Myeloma

McClune: There are other BCMA-targeted agents that are [currently] in trials, [such as] CT103A. [Some] preliminary data [were presented] at the 2022 ASH Annual Meeting, [with some] agents showing impressive overall response rates, high rates of MRD negativity, and decent PFS in a very early look at some of these agents.

We have seen the New England Journal of Medicine publication on MCARH109, [which targets] GPRC5D [and generated] a [58%] overall response rate [at lower doses between 25 x 106 CAR T cells and 150 x 106 CAR T cells], which may be more important when we're looking at immune effector cell–associated neurotoxicity syndrome and cytokine release syndrome incidents.

Also recently published [were data] on ALLO-715, the [allogeneic, anti-BCMA CAR T-cell therapy], which is one of the first off-the-shelf products for use in trials in multiple myeloma. The [ORR] was an impressive [55.8% in all patients and [70.8% in patients who received 320 × 106 CAR T cells and a fludarabine-, cyclophosphamide- and ALLO-647–based lymphodepletion regimen].

All these agents are highly effective in patients with refractory disease. We still have a lot of work to do in the optimal sequencing and bridging strategies, as well as the support that comes after the CAR T-cell therapy is over. It is important for academic and community practice partnerships to help us manage these patients.

Reference

Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol. 2022;40(25):2901-2912. doi:10.1200/JCO.21.01935