Daratumumab-Based Induction and Response-Adapted Consolidation Induces MRD Negativity in Patients With Newly Diagnosed Myeloma

Induction therapy with daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) followed by autologous transplant and Dara-KRd consolidation guided by measurable residual disease (MRD) leads to high response rates in patients with newly-diagnosed multiple myeloma (MM), according to preliminary results from the MASTER trial presented at the 2019 ASH Annual Meeting.

When combined with a proteasome inhibitor or immunomodulatory agent, the CD38-targeting antibody daratumumab has been shown to increase the duration and depth of response in patients with MM, explained lead author and presenter Luciano J. Costa, MD, PhD, from the University of Alabama at Birmingham. Carfilzomib has shown to be superior to bortezomib in relapsed/refractory MM, and, when combined with Rd, leads to high rates of very good partial response (VGPR) or better in newly diagnosed patients. “While responses are heterogeneous, treatment combinations have traditionally been developed with a fixed number of cycles, not accounting for kinetics or depth of response,” Dr. Costa told ASH Clinical News.

In the MASTER trial, researchers hypothesized that ≥75% of patients with newly diagnosed MM who received quadruplet therapy with Dara-KRd, autologous hematopoietic cell transplantation (AHCT), and MRD-based, response-adapted consolidation therapy with Dara-KRd would reach MRD-negative status. The primary endpoint of the study was MRD-negative remission (<10-5) as defined by International Myeloma Working Group (IMWG) criteria.

MRD testing of bone marrow samples was performed after induction, AHCT, and consolidation. Per study protocol, patients received therapy until they had two consecutive MRD-negative (<10-5) readings, either post-induction and post-transplant, or post-transplant and during consolidation. Patients who reached MRD negativity did not receive further therapy and instead were observed with MRD surveillance at 6 and 18 months after treatment discontinuation. Patients who completed consolidation therapy and remained MRD-positive received lenalidomide maintenance.

Eligible patients had newly diagnosed MM with measurable disease, were previously untreated except for up to 1 cycle of bortezomib, cyclophosphamide, and dexamethasone (VCD), had creatinine levels >40 mL, adequate liver and cardiac function, and an ECOG performance status of ≤2.

The 4 induction cycles consisted of:

  • daratumumab 16 mg/kg IV on days 1, 8, 15, and 22
  • carfilzomib 56 mg/m2 IV on days 1, 8, and 15
  • lenalidomide 25 mg orally on days 1-21
  • dexamethasone 40 mg orally/IV on days 1, 8, 15, 22 (repeated every 28 days)

Induction was followed by AHCT and response-adapted consolidation, consisting of either 0, 4, or 8 cycles of Dara-KRd consolidation therapy, depending on depth of MRD.

Dr. Costa presented results from 81 enrolled patients who received at least 2 cycles of induction therapy. Although there was no age limit, the median age was 61 years (range = 36-78). Nearly one-third of patients (29%; n=20) had high-risk chromosomal abnormalities, including del17p, t(4;14), or t(14;16).

After a median follow-up of 7.4 months (range = 2.1-20), no patients discontinued treatment due to toxicity. However, 2 deaths were reported: 1 from metapneumovirus 9 days after AHCT and 1 sudden death 58 days after AHCT. Serious adverse events included pneumonia (n=5), fever and neutropenia (n=2), pulmonary embolism (n=1), atypical hemolytic uremic syndrome (n=1), infusion-related reactions (n=1), and atrial fibrillation (n=1).

MRD was evaluable in 96% of patients (n=78). Overall, 40% of patients achieved the primary endpoint after the induction period, 73% after transplant, and 82% after consolidation. These rates were similar between patients with standard-risk and high-risk cytogenetic abnormalities, Dr. Costa noted.

At the time of the presentation, 26 patients (19 with standard-risk cytogenetics and 7 with high-risk cytogenetics) had confirmed MRD negativity and entered treatment-free observation. After a median follow-up of 4.9 months (range = 0.2-12.2), there was no relapse or resurgence of MRD among this group.

Dr. Costa reported that all patients had at least a partial response (PR) by the end of the second induction cycle. After induction, 92% of patients obtained a very good PR or better, including 39% who experienced a stringent complete response.

Based on these results, “Intense quadruplet therapy and achievement of confirmed MRD-negative complete response may enable safe transition to observation or MRD surveillance and reduce the physical and financial burden of continuous therapy,” Dr. Costa said. However, these results are limited by the non-randomized design, the small number of enrolled patients, and the short duration of follow-up. The MASTER trial is still accruing patients, and it is expected to reach 123 patients to better inform outcomes.

The authors report relationships with Amgen and Janssen, which supported this trial.

Reference

Costa L, Chhabra S, Godby K, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, autologous transplantation and post-transplant, response-adapted, measurable residual disease (MRD)-based Dara-Krd consolidation in patients with newly diagnosed multiple myeloma (NDMM). Abstract #653. Presented at the 2019 American Society of Hematology Annual Meeting, December 7, 2019; Orlando, FL.