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Based on the results, consolidation therapy based on minimal residual disease with daratumumab (Darzalex), carfilzomib, lenalidomide (Revlimid) and dexamethasone (dara-KRd) appears to be a safe combination capable of producing rapid responses in patients. patients with newly diagnosed multiple myeloma. of the MASTER Phase 2 trial (NCT03224507) which were presented to the International Myeloma Workshop 2021.
When examining the primary endpoint of minimal residual disease (MRD) of less than 10-5, detected by next-generation sequencing (NGS), 38% of patients who were post-induction, 65% who were post-transplant autologous hematopoietic stem cells (AHCT) and 80% of people who received MRD-directed consolidation therapy were negative for MRD. Results were also noted in 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 using NGS in a population of patients who had been treated with dara-KRd induction, AHCT, and dara-KRd consolidation adapted to the MRD-based response. . The primary secondary endpoints were to determine dara-KRd toxicity, conventional responses according to International Myeloma Working Group (IMWG) criteria, and results of the maintenance-free observation after confirmation of MRD negativity. Additionally, investigators had an exploratory endpoint to determine rates of MRD by NGS which had a cutoff of 10-6.
In order to enroll in the trial, patients had to have a newly diagnosed measurable disease that was untreated, although a cycle of bortezomib, cyclophosphamide and dexamethasone was allowed. There was no age limit for the study, although an ECOG performance index of 0 to 2 and a CrCl of 40 ml per minute were required. In addition, patients could not have significant cardiopulmonary disease, concomitant or recent malignancy.
Eligible patients who entered the study received 4 cycles of induction dara-KRd, followed by AHCT, 4 to 8 cycles of dara-KRd consolidation and lenalidomide maintenance. Patients received 16 mg / m2 on days 1, 8, 15 and 22, as well as on days 1 and 15 of cycles 3 to 6 and on day 1 after cycle 6. In addition, carfilzomib was administered at a dose 56 mg / m2 on days 1, 8 and 15; lenalidomide 25 mg on days 1 to 21, and dexamethasone 40 mg on days 1, 8, 15 and 22.
A total of 123 patients included in the study, 96% of whom had MRM traceable by NGS. The median follow-up was 23.8 months. The median age of the patients was 60 years, 20% of the patients being 70 years or older. In addition, 21% of patients had tested lactate dehydrogenase equal to or greater than the upper limit of normal. Patients were reported to have revised International Multiple Myeloma Staging System scores of 1 (28%), 2 (51%), and 3 (20%).
The most common hematologic adverse reactions (AEs) of any grade included neutropenia (41%), lymphopenia (28%) and anemia (21%), while non-hematologic AEs consisted of fatigue (55%), bone pain (55%), and maculopapular rash (41%). Grade 3 hematologic AEs included neutropenia (35%), lymphopenia (22%), and anemia (11%) and non-hematologic AEs included hypertension (10%), fatigue (9%), and bone pain (6%).
The exploratory endpoint of MRD rates by NGS with a cutoff of 10 to 6 indicated that 24% of patients who were post-induction, 48% who were post-AHCT, and 66% who received directed consolidation therapy by MRD were MRD negative. The investigators also reported results for patients with 0 HRCA (30%, 44%, 64%, respectively), 1 HRCA (25%, 59%, 73%, respectively) or 2 or more HRCA (8%, 38 %, 58%, respectively).
Research has also shown the level of MRD by phase of therapy.
“As patients progress through the treatment phase, there is a tendency for a deeper and deeper response,” according to Luciano J. Costa, MD, PhD, associate director of clinical research at O’Neal Comprehensive Cancer Center at the University of Alabama. “A confirmation of the negativity of the MRD [translates] on discontinuation of treatment and monitoring for MRD in 62% of standard-risk patients, 78% of high-risk patients and 63% at ultra-high risk.
Regarding the best response according to IMWG criteria, after 2 cycles of induction therapy, the investigators reported a partial response rate (PR) of 36% and a very good PR rate (VGPR) of 63%. In addition, after 4 post-induction cycles, 89% of patients had VGPR, including a complete response rate (CR) of 3% and a rate of strict CR (CRs) of 33%. After transplantation, a CR rate of 3% and a CR rate of 67% were reported and after consolidation by MRD, 86% of patients had CR or greater.
Several serious AEs that appeared during treatment have 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 duration and discontinuation of treatment adapted to MRD response in newly diagnosed multiple myeloma (NDMM). Communication presented to: 18th International Myeloma Workshop; from September 8 to 11, 2021; Vienna, Austria. Accessed September 11, 2021.
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