MRD-Based Consolidation Therapy With Dara-KRd Lead to Rapid Responses in Newly Diagnosed Myeloma

Luciano J. Costa, MD, PhD

Results from the phase 2 MASTER trial (NCT03224507) show that minimal residual disease–based consolidation therapy with daratumumab (Darzalex), carfilzomib, lenalidomide (Revlimid), and dexamethasone (dara-KRd) in patients with newly diagnosed multiple myeloma is safe and may elicit rapid responses.

When examining the primary end point of minimal residual disease (MRD) of less than 10-5 as detected by next-generation sequencing (NGS), 38% of patients who were post induction, 65% who were post autologous hematopoietic stem cell transplantation (AHCT), and 80% who received MRD-directed consolidation therapy were MRD negative. Findings were also noted among patients with 0 HRCA (40%, 60%, and 78%, respectively), 1 HRCA (41%, 73%, and 82%, respectively), and 2 or more HRCA (29%, 63%, and 79%, respectively).

The primary objective of the study was to determine the rate of MRD-negative responses utilizing NGS in a population of patients who had been treated with dara-KRd induction, AHCT, and MRD-based response adapted dara-KRd consolidation. Key secondary end points were to determine the toxicity of dara-KRd, conventional responses by International Myeloma Working Group (IMWG) criteria, and outcomes of observation without maintenance following confirmation of MRD-negativity. Additionally, investigators had a n exploratory end point of determining MRD rates by NGS that had a threshold of 10-6.

In order to enroll on the trial, patients were required to have measurable newly diagnosed disease that was untreated, although 1 cycle of bortezomib, cyclophosphamide, and dexamethasone was allowed. There was no age limit for the study, although an ECOG performance status of 0 to 2 and a CrCl of 40 ml per minute were required. Additionally, patients could not have significant cardiopulmonary disease, concomitant, or recent malignancy.

Eligible patients who enrolled on the study received 4 cycles of induction dara-KRd, followed by AHCT, 4 to 8 cycles consolidation dara-KRd, and lenalidomide maintenance. Patients received 16 mg/m2 on days 1, 8, 15, and 22, as well as days 1 and 15 on cycles 3 through 6 and day 1 past cycle 6. Additionally, carfilzomib was administered at a dose of 56 mg/m2 on days 1, 8, and 15; lenalidomide at 25 mg on days 1 through 21, and 40 mg of dexamethasone on days 1, 8, 15, and 22.

A total of 123 patients enrolled on the study, 96% of whom had trackable MRD by NGS. The median follow up was 23.8 months. The median patient age was 60 years, with 20% of patients being 70 years of age or older. Additionally, 21% of patients had lactate dehydrogenase that tested equal to or above the upper limit of normal. Patients were reported to have revised multiple myeloma international staging system scores of 1 (28%), 2 (51%), and 3 (20%).

The most common any grade hematologic adverse effects (AEs) included neutropenia (41%), lymphopenia (28%), and anemia (21%), while non-hematologic AEs consisted of fatigue (55%), bone pain (55%), and maculo-papular rash (41%). Grade 3 hematologic AEs included neutropenia (35%), lymphopenia (22%), and anemia (11%) and non-hematologic AEs consisted of hypertension (10%), fatigue (9%), and bone pain (6%).

The exploratory end point of MRD rates by NGS with a threshold of 10-6 indicated that 24% of patients who were post-induction, 48% who were post-AHCT, and 66% who received MRD-directed consolidation therapy were MRD negative. Investigators also reported findings for patients with 0 HRCA (30%, 44%, 64%, respectively), 1 HRCA (25%, 59%, 73%, respectively), or 2 or more HRCA (8%, 38%, 58%, respectively).

The research also highlighted MRD level by phase of therapy.

“As patients evolve through phase of therapy, there is a trend towards deeper and deeper response,” according to Luciano J. Costa, MD, PhD, an associate director for clinical research at the O’Neal Comprehensive Cancer Center at University of Alabama. “A confirmation of MRD negativity [translates] to treatment cessation and MRD surveillance in 62% of patients with standard risk, 78% of patients with high-risk, and 63% with ultra high-risk.”

With regard to best response by IMWG criteria, after 2 cycles of induction therapy, investigators reported a partial response (PR) rate of 36% and a very good PR (VGPR) rate of 63%. Additionally, after 4 cycles post-induction, 89% of patients had a VGPR, including a complete response (CR) rate of 3% and a stringent CR (sCR) rate of 33%. Post-transplant, a CR rate of 3% and an sCR rate of 67% were reported and following MRD-based consolidation, 86% of patients had a CR or greater.

Several treatment-emergent serious AEs occurred, such as pneumonia (n = 8), pulmonary embolism (n = 3), fever and neutropenia (n = 2), and atypical hemolytic uremic syndrome (n = 1) among others. Three deaths occurred during the study.

_Reference:

_{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). Paper presented at: 18th International Myeloma Workshop; September 8-11, 2021; Vienna, Austria. Accessed September 11, 2021.}