In a phase II trial reported in JAMA Oncology, Derman et al found that a measurable residual disease (MRD)-adapted strategy with elotuzumab (Elo) plus carfilzomib, lenalidomide, and dexamethasone (KRd) was associated with high rates of stringent complete response and MRD-negative status in patients with newly diagnosed multiple myeloma with no intent for transplantation.
Study Details
In the U.S. multicenter study, 46 patients enrolled between July 2017 and February 2021 received 12 to 24 28-day cycles of Elo-KRd. Patients with MRD-negativity (10−5) on next-generation sequencing after cycles 8 and 12 switched to maintenance with Elo-Rd. Those converting to MRD-negativity between cycles 8 and 12 received 6 additional cycles of Elo-KRd followed by Elo-Rd maintenance, and those with MRD-positivity after cycle 12 received 12 additional cycles on Elo-KRd followed by maintenance. Treatment consisted of: elotuzumab at 10 mg/kg on days 1, 8, 15, and 22 for cycles 1 to 2, days 1 and 15 for cycles 3 and beyond, and day 1 during 28-day maintenance cycles; carfilzomib on days 1, 8, and 15 of each cycle, 20 mg/m2 on cycle 1 day 1, escalated to 70 mg/m2; lenalidomide at 25 mg on days 1 to 21; and oral dexamethasone at 40 mg weekly. The primary endpoint was the rate of stringent complete response and/or MRD-negativity after 8 cycles of Elo-KRd, tested against a null hypothesis of 30% (observed with KRd alone).
Responses
KEY POINTS
- Stringent complete response or MRD-negativity was achieved in 58% of patients after 8 cycles.
- Responses deepened over time.
Stringent complete response and/or MRD negativity after cycle 8 was observed in 26 (58%) of 45 patients evaluable for the endpoint. Responses deepened over time, with subsequent conversion to MRD-negative status resulting in an MRD negativity rate of 70%.
At median follow-up of 28.7 months (range = 1.4–50.1 months), nine disease progression events and eight deaths had occurred, with median progression-free and overall survival not being reached. Estimated 3-year rates were 72% for progression-free survival and 78% for overall survival. Among patients with MRD negativity at cycle 8, estimated 3-year rates were 92% and 100%, respectively.
Adverse Events
The most common grade 3 or 4 nonhematologic adverse events were lung infection (13%) and nonpulmonary infection (11%). The most common grade 3 or 4 hematologic adverse events were neutropenia (11%) and thrombocytopenia (9%). Treatment was discontinued due to adverse events in three patients (7%). Cardiac events occurred in 12 patients (26%), including grade ≥ 3 events in (9%). Hypertension occurred in 11 patients (24%; grade ≥ 3 in 3 [7%]) and thromboembolic events occurred in 5 (11%; grade ≥ 3 in 2 [4%]). Six patients contracted COVID-19, with one having prolonged hospitalization but subsequently resuming study treatment. Adverse events led to death in one patient (myocardial infarction).
The investigators concluded: “An MRD-adapted design using elotuzumab and weekly KRd without [autologous stem cell transplantation] showed a high rate of [stringent complete response] and/or MRD-negativity and durable responses. This approach provides support for further evaluation of MRD-guided deescalation of therapy to decrease treatment exposure while sustaining deep responses.”
Andrzej J. Jakubowiak, MD, PhD, University of Chicago Medical Center, is the corresponding author for the JAMA Oncology article.
Disclosure: The study was supported by Amgen, Bristol Myers Squibb, and the Multiple Myeloma Research Consortium. For full disclosures of the study authors, visit jamanetwork.com.
