Four-Drug Regimen Leads to Unprecedented MRD Negativity Rates in Multiple Myeloma

April 2020 Vol 11, No 4


Multiple Myeloma

In patients with newly diagnosed multiple myeloma, treatment with weekly daratumumab plus carfilzomib, lenalidomide, and dexamethasone (KRd) resulted in an “unprecedented” minimal residual disease (MRD) negativity rate of 77% without stem cell transplantation. An MRD-negative result means no evidence of disease was found after treatment. These data come from a 2-arm, phase 2 clinical trial presented by Ola Landgren, MD, PhD, at the 2019 ASH Annual Meeting.

Standard-of-care treatment for newly diagnosed multiple myeloma, as recommended by the National Comprehensive Cancer Network, is a 3-drug combination of either bortezomib/lenalidomide/dexamethasone (VRd) or KRd. In the current literature, the best published MRD rates with either of these regimens are in the range of 30% to 40%.

Emerging data suggest that the addition of daratumumab can safely increase the efficacy of existing myeloma combination therapies, and as evidenced in the study presented by Dr Landgren, adding daratumumab to KRd led to MRD rates far surpassing those currently published in the literature.

“In newly diagnosed multiple myeloma patients, 8 cycles of weekly KRd-daratumumab, without autologous stem cell transplant, resulted in about 80% MRD negativity, opening the door for delayed transplant for many patients,” reported Dr Landgren, Chief of Myeloma Service at Memorial Sloan Kettering Cancer Center.

Patients in the study were enrolled on 1 of 2 cohorts that included weekly carfilzomib at 52 mg/m2 or biweekly carfilzomib at 36 mg/m2; the lenalidomide, dexamethasone, and daratumumab doses remained the same in each cohort. For “medically fit” patients, stem cell collection was recommended after 4 to 6 cycles, and therapy was resumed after collection to a total of 8 cycles.

The primary end point of the study was to rule out MRD of 60% and to target up to an 80% MRD negativity rate. MRD status was assessed with parallel bone marrow–based assays: 10-color single-tube flow cytometry and immunoglobulin heavy chain variable next-generation sequencing.

The biweekly and weekly arms had comparable efficacy and safety, but due to the substantial reduction in the number of infusion days in the weekly arm (51 vs 27), the investigators decided to close the biweekly arm after fully enrolling the first stage of the study. Dr Landgren presented results only from the patients who received weekly dosing.

When these data were presented at ASH, the weekly KRd-daratumumab arm was fully enrolled at 41 patients (61% female; median age 57 years); about half of these patients were classified as having high-risk disease. A total of 30 patients were evaluable for the primary end point of MRD negativity as a best response after up to 8 cycles of treatment, and all patients were evaluated for safety. After a median follow-up of 8.6 months, 24 patients had completed all 8 cycles.

MRD negativity has been observed in 77% of all evaluable patients. The median time to MRD negativity was 6 cycles and ranged from 1 to 8 cycles. Complete response (CR) and very good partial response (VGPR) or better was observed in 97% of evaluable patients, with an overall response rate of 100%.

In the subanalysis focusing on the patients who completed all 8 cycles, the MRD negativity rate was 75% and the rate of CR/VGPR or better was 92%, with an overall response rate of 100%.

“None of the MRD-negative patients have progressed,” he reported.

Although the study protocol permitted peripheral stem cell collection after 4 to 6 cycles of weekly KRddaratumumab, Dr Landgren noted that the clinical experience of the researchers suggests better yield if collection is conducted after 4 (rather than 5 or 6) cycles. Of note, MRD status was determined prior to autologous stem cell transplant in those patients who did go on to transplant after 8 cycles of treatment.

Overall, the investigators observed no additional grade ≥3 toxicities with weekly KRd-daratumumab compared with standard-of-care biweekly KRd. There was no grade ≥3 peripheral neuropathy, and there were no deaths on the study. A total of 30 dose reductions were required in 21 patients; the majority of these were lenalidomide in 15 patients and dexamethasone in 12 patients.

With a comparable efficacy and safety profile coupled with a substantial reduction in the number of infusions with weekly carfilzomib, the investigators conclude that daratumumab plus KRd offers an attractive treatment modality for newly diagnosed patients with multiple myeloma.

“Weekly KRd-daratumumab is a convenient regimen with a rapid and deep response, as evidenced by median time to MRD negativity of 6 cycles.” said Dr Landgren. “These exciting results have prompted the launching of a large, randomized multicenter study, ADVANCE, with a similar design, which is evaluating weekly KRd-daratumumab in relation to established standard of care.”

The investigators anticipate that the results of the ADVANCE study could be practice changing.

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Last modified: August 10, 2023

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