Minimum residual disease can inform approaches to treatment of newly diagnosed multiple myeloma for patients receiving daratumumab plus carfilzomib, lenalidomide, and dexamethasone following autologous transplant.
Therapy for newly diagnosed multiple myeloma can be determined by minimal residual disease (MRD) assessment through next-generation sequencing (NGS). The selection and duration of treatment with daratumumab (Darzalex) plus carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Dara-KRd) following autologous transplant (AHCT) can be guided by the patient's MRD status, according to data from the phase 2 MASTER Trial (NCT03224507) that were presented during the 2021 ASH Annual Meeting & Exposition.
NGS-MRD response-adaptive therapy is feasible in approximately 96% of the patients in a multicenter setting, with 71% of the patients reaching MRD-SURE [treatment-free observation and MRD surveillance],” explained Luciano J. Costa, MD, PhD, associate director for clinical research at the O’Neal Comprehensive Cancer Center at University of Alabama at Birmingham, during a presentation of the results at the 63rd American Society of Hematology Annual Meeting and Exposition.1
“Patients with standard and high-risk newly diagnosed myeloma have similar depth of response, and low-risk MRD resurgence or progression when treated with this regimen including MRD-adapted treatments.”
In the MASTER trial, Costa and colleagues aimed to determine the rate of MRD-negative responses using NGS in patients treated with Dara-KRd, AHCT, and MRD response-adapted Dara-KRd consolidation therapy. Secondary end points were toxicity of the combination regimen, conventional International Myeloma Working Group response, and outcomes of observation without maintenance therapy following MRD-negative responses. The investigators also aimed to determine MRD-negative rates by NGS with a threshold of 10-6 as an exploratory end point.
“Importantly, MRD was tested on ‘first pull’ fundamental aspects and reported that utilizing intent-to-treat principle, according to international harmonization,” Costa added.
Patients were treated with 16 mg/kg intravenous (IV) daratumumab on days 1, 8, 15, and 22; 56 mg/m2 IV carfilzomib on days 1, 8, and 15; 25 mg lenalidomide on days 1 through 21; and 40 mg dexamethasone on days 1, 8, 15, and 22, which was repeated every 28 days. According to MRD status, patients received 4 cycles of Dara-KRd as induction, followed by AHCT, and then received 0, 4, or 8 cycles of Dara-KRd consolidation therapy.
Dara-KRd was administered until achievement of 2 consecutive MRD-negative responses, defined as 10-5. Those with confirmed MRD-negativity then underwent treatment-free observation and MRD surveillance, or MRD-SURE. Surveillance was done 6 months after treatment ended, and yearly thereafter. For those who received consolidation therapy without confirmed MRD-negativity, maintenance therapy with lenalidomide was given.
In total, 123 patients were enrolled across 5 sites, of whom 118 (96%) had trackable MRD. Median follow-up was 23.8 months.
The majority of patients were male (57%), White (76%), and had an ECOG performance status of 0 or 1 (80%). Median age was 60 years (range, 35-79).
In the study, 53 patients (43%) had no high-risk chromosome abnormality (HRCA [gain/amp 1q, t(4;14), t(14;16), t(14;20) or del(17p)]; standard-risk), 46 (37%) had 1 HRCA (high-risk), and 24 (20%) had 2 or more HCRA (ultra-high risk).2
Among all patients, 80% achieved MRD negativity after MRD-directed consolidation therapy, including 78% of those with standard-risk, 82% of those with high-risk, and 79% of those with ultra–high risk disease. Per the exploratory end point of the trial, 66% of patients achieved MRD negativity 10-6 following MRD-directed consolidation therapy, including 64%, 73%, and 58% of the standard-, high-, and ultra-high–risk groups, respectively.
In addition, MRD negativity was reached in 38% of patients after induction therapy and 65% of patients after AHCT. “The proportion of patients reaching MRD-negativity increases with each phase of therapy with a substantial gain,” Costa said.
Following cycle 4 of post-induction therapy, 88% of patients experienced a very good partial response (VGPR), which improved to 98% after MRD-adapted consolidation therapy.
The 2-year progression-free survival rates in the standard-, high-, and ultra-high–risk groups were 91%, 97%, and 58%, respectively (P < .001). Similarly, the overall survival rates in those groups were 96%, 100%, and 76%, respectively (P = .003).
In total, 84 patients achieved MRD-SURE, including 62% in the standard risk group, 78% in the high-risk group, and 63% in the ultra–high risk group. Median follow-up with MRD-SURE was 14.2 months.
The risk for MRD resurgence or progression at 12 months following the end of treatment was 4% in the standard risk group, 0% in the high-risk group, and 27% in the ultra-high–risk group.
Of note, no patients who entered MRD-SURE died from myeloma progression.
Grade 3 or higher adverse events (AEs) occurred in 91 patients (74%). Twenty-five treatment-emergent serious AEs were reported, including pneumonia (n = 8), pulmonary embolism (n = 3), fever and neutropenia (n = 2), atypical hemolytic uremic syndrome (n = 1), infusion-related reaction (n = 1), atrial fibrillation (n = 1), and other (n = 9). Three deaths occurred.
1. Costa LJ, Chhabra S, Callander NS, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd), autologous transplantation and MRD response-adapted consolidation and treatment cessation. final primary endpoint analysis of the MASTER trial. Presented at: 2021 ASH Annual Meeting and Exposition; December 11-14, 2021; Atlanta, Georgia. Abstract 481. https://bit.ly/3EQZSLo
2. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd), autologous transplantation and MRD response-adapted treatment duration and cessation in newly diagnosed Multiple Myeloma (NDMM). Clinical Lymphoma Myeloma and Leukemia. 2021;21(2):S33. doi:10.1016/S2152-2650(21)02125-X