Phase 2 master trial: treatment with Dara-krd plus AHCT with NGS-MRD response-adapted therapy in NDMM patients

25 Feb 2022

Combination therapy with proteasome inhibitors (PIs), monoclonal antibodies, immunomodulatory agents (IMiDs), dexamethasone plus autologous hematopoietic cell transplant (AHCT) may be an important course of treatment for newly diagnosed multiple myeloma (NDMM).1,2 However, predicting long-term outcomes remains challenging, while discovering more sensitive approaches for detecting minimal residual disease (MRD) is necessitous.3 Recent findings published in the Journal of Clinical Oncology incorporated daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd), followed by AHCT and MRD-response-adapted post-AHCT consolidation.4 Assessment of MRD by the next generation sequencing (NGS) was used to adjust the intensity and duration of therapy and proved salient in achieving MRD-negativity and the discontinuation of treatment.4

The MASTER trial (NCT03224507) was a single-arm, open-label, multicenter phase 2 study.4 Some 123 NDMM patients were recruited between March 2018 to October 2020 in 5 sites of the United States.4 The age range of patients was 35-79 years (median age was 60 years).4 The profiles of patients having high-risk cytogenic abnormalities (HRCAs) were: 43% with 0 (standard risk); 37% with 1 (high-risk); 20% with 2+ (ultra-high risk).4 About 96% of the participants had trackable MRD.4 The median duration for follow-up was 25.1 months.4

Patients were treated in 4 phases: Induction with Dara-KRd, AHCT, followed by 2 phases of 4 cycles of Dara-KRd consolidation.4 The induction cycles lasted for 28 days.4 Patients were treated with 16mg/kg of daratumumab on days 1, 8, 15 and 22; 56mg/m2 of carfilzomib on days 1, 8 and 15; 25mg of lenalidomide on days 1-21; 40mg of dexamethasone on days 1, 8, 15 and 22.4

MRD assessment by NGS using the ClonoSEQ platform was used to evaluate at the end of induction, the 60-80 day post-AHCT and after the second cycle of Dara-KRd in each phase of consolidation.4 Patients who achieved 2 consecutive MRD-negative responses (<10-5) progressed to treatment-free observation and MRD surveillance (MRD-SURE).4 During MRD-SURE, patients were evaluated every 8 weeks for 24 weeks, and every 16 weeks thereafter.4 MRD assessments occurred after 6 and 18 months.4

The primary endpoint of the clinical study was patients achieving MRD negativity (<10-5) at any time during the investigation.4 The secondary endpoints were the rates of MRD-negativity after induction, the rate of reaching complete response (CR), progression-free survival (PFS) and overall survival (OS).4

The overall results showed that 80% of the participants attained MRD <10-5 (78%, 82% and 79% with 0, 1 and 2+ HRCAs, respectively).The proportion of CR + MRD <10-5 was 73% (76%, 75% and 63% of patients with 0, 1 and 2+ HRCAs, respectively).4 The ratio of patients who attained MRD <10-6 was 66% (64%, 73% and 58% with 0, 1 and 2+ HRCAs, respectively).4

Overall, 84 patients (71%) reached 2 consecutive MRD-negative assessments and transitioned to MRD-SURE.4 Of the 84 patients, half of them achieved MRD-SURE post ACHT, while 33 (39%) and 9 (11%) of them followed 4 and 8 cycles of Dara-KRd consolidation, respectively.4 Also, among the 84 patients, 33, 36 and 15 of them had 0, 1 and 2+ HRCAs, respectively.4 The median follow-up post-treatment cessation was 14.2 months.4

The cumulative occurrence of progression or MRD resurgence at 1 year after the termination of therapy was 6.4% (4%, 0% and 27% for patients with 0, 1 and 2+ HRCAs, respectively).4 The 2-year PFS was achieved for 87% of the total population (91%, 97% and 58% for patients with 0, 1 and 2+ HRCAs, respectively; p=0.001).4 The OS was achieved for 94% (96%, 100% and 76%, respectively; p=0.003).4

With regard to safety, all 123 patients experienced a minimum of 1 treatment-emergent adverse event (TEAE) and 74% experienced a minimum of 1 grade 3-5 TEAE.4 The most common TEAEs were fatigue, bone pain, neutropenia, rash and nausea.4 Experience of serious TEAEs occurred in 18%, and the most common TEAE was pneumonia and thromboembolic events.4

This trial illustrated that Dara-KRd induction therapy, followed by AHCT and MRD-response-adapted post-AHCT consolidation, can result in a high rate of MRD negativity in NDMM patients.4 This study was among the first to use real-time, NGS MRD-guided adapted therapy to evaluate either the cessation of therapy to those patients who demonstrated an early and deep response, or the development of continuous and new therapies for ultra-high-risk patients.4

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