Dara-KRd Leads to Encouraging Responses in Newly Diagnosed Multiple Myeloma

The phase 2 MASTER trial of daratumumab, carfilzomib, lenalidomide, and dexamethasone demonstrates the promise of minimal residual disease surveillance in newly diagnosed multiple myeloma with 0 or 1 high-risk cytogenetic abnormalities

The combination of daratumumab (Darzalex), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (Decadron; Dara-KRd), autologous hematopoietic cell transplantation (AHCT), and minimal residual disease (MRD) response-adapted consolidation led to high rates of MRD negativity in patients with newly diagnosed multiple myeloma (NDMM).1

Findings come from the phase 2 MASTER trial (NCT03224507) which were published in the Journal of Clinical Oncology. In the trial, 80% of patients reached MRD negativity, including 78% with 0 high-risk cytogenetic abnormalities (HRCA), 82% with 1 HRCA, and 79% for patients with 2+ HRCA. Another 66% reached MRD < 10–6, and 71% reached 2 consecutive MRD-negative assessments during therapy, entering treatment-free surveillance.

Additionally, the 2-year progression-free survival (PFS) was 87% (91% with 0 HRCA, 97%, with 1 HRCA, and 58% 2+ HRCA. The cumulative incidence of MRD progression 12 months after the end of therapy was 4%, 0%, and 27% for patients with 0, 1, or 2+ HRCA, respectively.

Ultimately, this strategy creates the opportunity of MRD surveillance as an alternative to indefinite maintenance for patients with NDMM with 0 or 1 HRCAs.

“Although MRD has been demonstrated to be a powerful prognostic factor for patients with NDMM, this is among the first studies to use real-time MRD assessment to adjust the intensity of therapy. We demonstrated the feasibility of such an approach in 96% of patients in a multi-institutional setting. Indeed, compliance was > 99% with only a single data point being missed in the entire study,” wrote the study authors, led by Luciano J. Costa, MD, professor at University of Alabama at Birmingham.

MASTER was a single-arm, open-label, multicenter, phase 2 trial assessing the safety and efficacy of Dara-KRd in NDMM.2 Enrollment was open to patients with NDMM with indication for therapy, and ECOG performance status 2 or greater, measurable paraprotein in serum or urine, and adequate hepatic, cardiac, and renal function. Patients who had received up to 1 cycle of therapy containing bortezomib, cyclophosphamide, and dexamethasone were also eligible for enrollment.

There were up to 4 phases of treatments including the induction phase (cycles 1-4), AHCT, and up to 2 phases of consolidation with 4 cycles each (cycles 5-8 and 9-12, respectively). The induction cycles were 28 days long and consisted of intravenous (IV) daratumumab 16 mg/kg on days 1, 8, 15, and 22 (days 1 and 15 for cycles 3 and 4), IV carfilzomib 56 mg/m2 on days 1, 8, and 15 (20 mg/m2 on first dose of cycle 1), oral lenalidomide 25 mg on days 1-21, and IV or oral dexamethasone 40 mg ion days 1, 8, 15, and 22.

Once the induction phase was completed, patients proceeded with collection of autologous hematopoietic cells using granulocyte colony-stimulating factor with or without plerixafor as mobilization. Here, patients received high-dose melphalan ranging from 140-200 mg/m2 followed by AHCT. After subsequent response assessment (60-80 days post-AHCT), patients with indication for additional therapy based on MRD received up to 2 phases of 4 cycles of Dara-KRd consolidation with the doses and schedule for Dara-KRd consolidation identical to what was given in the induction phase. However, daratumumab was administered on days 1 and 15 on cycles 5-6 and on day 1 on cycles 7-12 instead.

For patients who were not willing to proceed with AHCT, they were given 4 additional cycles of Dara-KRd as replacement. MRD was assessed at completion of induction, 60-80 days after AHCT and after the second cycle of Dara-KRd in each phase of consolidation (ie, cycles 6 and 10). Patients reaching two consecutive MRD < 10–5 assessments (eg, postinduction and post-AHCT or post-AHCT and first block of consolidation) transitioned to treatment-free observation and MRD-SURE at the end of the corresponding phase. Patients completing the two phases of consolidation without two consecutive MRD < 10–5 transitioned to lenalidomide maintenance.

Patients were evaluated every 8 weeks for the first 24 weeks and every 16 weeks thereafter during MRD-SURE and patients underwent MRD assessment after 6 and 18 months. While participation in the study was completed after 18 months of MRD-SURE, patients and treating physicians were encouraged to continue yearly surveillance for MRD resurgence. Additionally, MRD was assessed by NGS using the ClonoSEQ platform.

The primary end point of the study was the proportion of patients who reached MRD negativity (MRD < 10–5) at any point during therapy with secondary end points including the rate of MRD < 10–5 upon completion of induction, rate of achievement of complete response (CR), progression-free survival (PFS), and overall survival (OS).

A total of 123 patients were enrolled in 5 locations across the United States between March 2018 and October 2020. Among those enrolled, the median age was 60 years (range, 35-79 years), with 20% 70 years of age and older. Non-Hispanic White patients made up 76% of the population vs those who were non-Hispanic Black (20%) or other (3%). Only 20% of patients had an ECOG performance status of 2, and 20% with Revised International Staging System of 3.

The median duration of follow-up was 23.8 months. For patients with 0 HRCA (n = 53), it was a median follow-up of 24.6, 24.6 for those with 1 HRCA (n = 46), and 16.8 months for patients with HRCA (n = 24). For all patients, the median duration of therapy was 11.6 months and 10.3 months for those who met criteria to enter MRD-SURE. All patients completing induction were considered fit to undergo AHCT, but 3 chose to replace it with 4 cycles of Dara-KRd.

Eighty-four patients (71%) reached 2 consecutive negative-MRD assessments and who transitioned to MRD surveillance (MRD-SURE). Median follow-up for these 84 patients from the time of therapy completion and start of MRD-SURE was 14.2 months. For the other 34 MRD-evaluable patients, 4 remained on therapy, 20 completed their entire therapy without reaching MRD-SURE and transitioned to lenalidomide maintenance, and 10 ended up discontinuing early due to death (n = 3), disease progression (n = 5), or withdrawal of consent (n = 2). Among the 5 non–MRD-evaluable patients, 1 discontinued therapy after AHCT, 3 discontinued after cycle 8, and 1 evolved with disease progression on cycle 8.

Findings also showed that regarding the international myeloma working group response, the response or partial response for the 123 patients was 98%. Additionally, 86% of patients reached complete response. Partial response was 98%, 100%, and 96% and rate of CR was 91%, 89%, and 71% for patients with 0, 1, and 2+ HRCA, respectively. With each phase of therapy, responses improved.

Of the 118 MRD-evaluable patients, 38% reached negative-MRD after induction and a higher number of patients reached negative-MRD with each phase of therapy. Eighty percent of patients reached negative-MRD as best response (78%, 82%, and 79% of patients with 0, 1, and 2+ HRCA, respectively). The rate of CR plus negative-MRD was 73% (76%, 75%, and 63% of patients with 0, 1, and 2+ HRCA, respectively). The proportion of patients reaching MRD < 10–6 was 66%, with 64% having 0 HRCA, 73% with 1 HRCA, and 58% with 2+ HRCA, respectively.

During therapy, there were 6 progressions reported, including 1 during induction, 1 after AHCT and before consolidation, and 4 during consolidation. Among these patients with progression, 5 had del(17p), 5 had 2+ HRCA, 4 died from disease progression or complications of subsequent therapy, and 4 progressed during MRD-SURE.

The 2-year PFS in the entire population was 87% and the 2-year OS rate was 94%. Between patients with 0 and 1 HRCA, the PFS was similar but inferior in patients with 2+ HRCA (2-year PFS 91%, 97%, and 58%, respectively; P < .001). In patients who reached MRD < 10–6, the 2-year PFS was 91% and higher than those with best MRD between 10–5 and 10–6 (2-year PFS = 81%; P = .005 vs MRD < 10–6). This was the same for patients who remain MRD-positive (2-year PFS = 83%; P = .20 vs MRD < 10–6). The OS was also similar between patients with 0 and 1 and inferior in patients with 2+ HRCA (2-year OS 96%, 100%, and 76%, respectively; P = .003).

Each of the 123 patients had at least 1 treatment-emergent adverse event (TEAE). At least 1 grade 3-5 TEAE was observed in 74% of patients with the most common being fatigue (9%), bone pain (6%), neutropenia (35%), and rash (4%).

While toxicity led to the discontinuation of carfilzomib in 2 patients and to discontinuation of lenalidomide in 2 patients, no patients discontinued daratumumab or fully discontinued dexamethasone. Additionally, there were 3 deaths on treatment, including 1 during the second week of induction therapy, 1 patient who died of metapneumovirus pneumonia during the second week after AHCT, and 1 patient who died 2 months after AHCT and prior to the start of consolidation therapy.

Overall, this study showed that the safety profile of Dara-KRd used as induction and as post-AHCT consolidation was comparable with other series of transplant-eligible patients receiving triplet or quadruplet therapy.

“Induction therapy with Dara-KRD, followed by AHCT, MRD-guided post-AHCT consolidation, and treatment cessation is feasible and will lead to the majority of patients with NDMM achieving an MRD-free, treatment-free state. With current follow-up, the majority of patients with 0 or 1 HRCA remain off therapy without progression or resurgence of MRD. For most patients with NDMM, an MRD-directed adaptive treatment plan offers the prospect of sustained deep responses without indefinite maintenance,” wrote the study authors.

References:
  1. Costa LJ, Chhabra S, Medvedova E, et al. Daratumumab, carfilzomib, lenalidomide, and dexamethasone with minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma. J Clin Oncol. 2022;40(25):2901-2912. doi:10.1200/JCO.21.01935
  2. Monoclonal antibody-based sequential therapy for deep remission in multiple myeloma (MASTER). ClinicalTrials.gov. Updated March 29, 2022. Accessed September 7, 2022. https://www.clinicaltrials.gov/ct2/show/NCT03224507