Daratumumab Delays Clinical Progression, Provides Proof-of-Concept for Early Intervention in MRD-Relapsed Multiple Myeloma

Preemptive treatment with single-agent daratumumab significantly delayed clinical progression or significant paraprotein relapse (SPR) vs observation and was well tolerated in patients with multiple myeloma experiencing minimal residual disease (MRD) recurrence, according to Krzysztof Jamroziak, MD, PhD, who added that these findings serve as a proof of concept for early MRD intervention using modern assessment techniques and novel therapies in future clinical trials.

Results from the phase 2 PREDATOR-MRD trial (NCT03697655) presented during the 2025 EHA Congress showed that, at a median follow-up of 17.8 months (range, 2.6-33.3), the median event-free survival (EFS) was not reached for the treatment arm and was 9.5 months with observation (HR, 0.20; 95% CI, 0.05-0.76; P = .0097). Moreover, 12 patients experienced SPR/clinical relapse, 3 of whom received daratumumab vs 9 on observation. MRD negative status was re-achieved by 75% of patients. During cycle 3, patients 1 to 7 were MRD negative, and patients 8 through 12 were MRD positive. In cycle 10, 4 patients were MRD negative, 7 were not assessed, and 1 had progressive disease. In cycle 17, 3 patients were MRD negative, 5 were not assessed, 2 had progressive disease, and 1 had a timepoint that was not reached.

“As this is a small study, the findings should be considered hypothesis-generating.” Jamroziak, a professor at the Institute of Hematology and Transfusion Medicine, the Medical University of Warsaw, in Poland, stated in an interview with OncLive®. “The design may be applicable to future clinical trials incorporating novel MRD monitoring methods, such as peripheral blood mass spectrometry, and evaluating novel therapies.”

In addition to expanding on key findings from this phase 2 study, Jamroziak also discussed the rationale for treating multiple myeloma at the time of MRD recurrence, the design and interim results of the PREDATOR-MRD trial evaluating daratumumab in this setting, and the need for larger studies to validate early intervention strategies such as this one.

OncLive: What was the rationale for conducting this study?

Jamroziak: MRD negativity is associated with best long-term outcomes in multiple myeloma and is recognized as a [viable] end point in clinical studies. Most clinical studies use MRD status after a certain phase of treatment to escalate or de-escalate therapy [appropriately] and importantly, the loss of MRD precedes biochemical and clinical relapse. Therefore, we hypothesized that treating multiple myeloma relapse at early MRD recurrence may be more effective and better tolerated.

What should be known about the study design and baseline characteristics of patients enrolled?

[PREDATOR-MRD] was a multicenter, randomized phase 2 study. The main inclusion criteria were completion or 1 or 2 lines of therapy, achieving complete response with MRD negativity, and maintaining such response and not receiving active anti-myeloma treatment at the time of screening. [One] important exclusion criterion was previous treatment with anti-CD38 antibodies. Eligible patients were included to MRD reappearance observation phase, where we repeated bone marrow aspiration and MRD testing by flow cytometry every 4 months, 6 times. The patients who turned out to be MRD positive and did not meet the criteria of clinical relapse or significant paraprotein relapse were randomly assigned [1:1] to daratumumab or observation. Daratumumab [was administered at a dose of] 16 mg/kg intravenously or 1800 mg subcutaneously [weekly for 8 weeks], then twice weekly for [16 weeks] and monthly for [48 weeks]. Patients in the observation arm were assessed for a response every 4 weeks. The primary end points were EFS, time [from randomization] to SPR, clinical relapse, or death.

What results were presented during the meeting?

We present the interim analysis for the primary end point, which is EFS. Twenty-four patients were included in the treatment phase: 12 were randomized to the daratumumab arm and 12 to the observation arm. Patient characteristics were generally balanced. All patients had received one prior line of treatment consisting of bortezomib-based induction therapy followed by autologous stem cell transplantation.

Patients were followed for a median of 17.8 months. During this time, 12 patients experienced significant paraprotein relapse or clinical relapse: 9 in the observation arm and 3 in the daratumumab treatment arm. The HR for daratumumab-treated patients for significant paraprotein relapse or clinical relapse was 0.2, representing an 80% reduction.

A key exploratory endpoint was the rate of re-achieving MRD negativity in the daratumumab arm. This was assessed on day 1 of cycle 3, at which point 7 of 12 patients had re-achieved complete remission with MRD negativity.

Preemptive treatment with single-agent daratumumab significantly delayed clinical progression or significant paraprotein relapse (SPR) vs observation and was well tolerated in patients with myeloma experiencing minimal residual disease (MRD) recurrence, according to Krzysztof Jamroziak, MD, PhD, who added that these findings serve as a proof of concept for early MRD intervention using modern assessment techniques and novel therapies in future clinical trials.

In summary, this is a small proof-of-concept study demonstrating that daratumumab given at the time of MRD recurrence delays significant paraprotein relapse. The treatment was well tolerated and did not decrease patient quality of life.

What are the next steps needed to validate this approach?

Treating early relapse is very important. It could be biochemical relapse, and even the previous step, which is MRD recurrence, but we need to prove that it is beneficial for patients. Our study is the first of this construction. It needs to be followed by bigger phase 3 studies proving this concept. It is proven in the study that MRD recurrence precedes biochemical relapse, and the time for that in the control arm is 9.5 months. It is probably better to treat earlier, because the extent of disease is lower and treatment tolerance is better. We could potentially see a shortening [of treatment duration] driven by MRD, but it needs yet to be proven for novel therapies.

Are there any important limitations to note when interpreting these data?

This study was designed 10 years ago, in late 2015 and the protocol was written in 2016, so it was a very different myeloma treatment landscape. [As a result], we don't think we can use the exact treatment of daratumumab monotherapy for MRD recurrence. These results need to be treated more as a proof of concept, and the treatment can be with novel therapies, like novel immunotherapies, for instance, bispecific antibodies.

References

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