C. Ola Landgren, MD, PhD
Ahead of the 2019 ASH Annual Meeting, C. Ola Landgren, MD, PhD, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center, shared insight on the potentially practice-changing data in the multiple myeloma paradigm that will be discussed at the conference in Orlando, Florida.
From novel 4-drug combinations for patients with newly diagnosed multiple myeloma to encouraging BCMA T-cell engagers (TCEs), several therapeutic approaches are slated to make an impact on the field.Daratumumab, carfilzomib, lenalidomide and dexamethasone (Dara-KRd) induction, autologous transplantation and post-transplant, response-adapted, measurable residual disease (MRD)-based Dara-Krd consolidation in patients with newly diagnosed multiple myeloma (NDMM; Abstract 860)
This study highlights a monoclonal antibody-based quadruplet regimen with daratumumab (Darzalex), carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone with measurable residual disease (MRD)–based response-adapted therapy in patients with newly diagnosed disease. In the abstract, results showed that all patients responded to treatment by the end of induction cycle 2, 92% of patients obtained at least a very good partial response (VGPR) after induction, and 91% of patients who went on to transplant achieved a complete response (CR) or stringent CR (sCR) as their best response to therapy.
Additionally, the MRD-negative remission rate was 34%, 70%, and 80% after induction therapy, transplant, and at best response, respectively. All of the 11 patients who achieved confirmed MRD-negative remission and discontinued treatment also achieved imaging plus MRD-negative CR. At the time of follow-up, there were no relapses or reappearance of MRD.
No patients discontinued treatment due to adverse events (AEs); 1 patient died from metapneumovirus pneumonia posttransplant, but it was not considered to be related to the investigational regimen. The most common grade 3/4 AEs were neutropenia (n = 7), infection (n = 6), insomnia (n = 4), hyperglycemia (n = 2), and rash (n = 2). Fifteen serious AEs included pneumonia (n = 5), fever (n = 2), neutropenia (n = 2), pulmonary embolism (n = 1), and atypical hemolytic uremic syndrome (n = 1).
“[This study comprises] 4 cycles of KRd-daratumumab followed by autologous stem cell transplant, MRD testing, and MRD response-adapted consolidation with additional KRd-daratumumab,” said Landgren. “This is a study designed to form the basis for MRD-driven stopping of therapy.”Weekly carfilzomib, lenalidomide, dexamethasone and daratumumab (wKRd-D) combination therapy provides unprecedented MRD negativity rates in newly diagnosed multiple myeloma: a clinical and correlative phase 2 study (Abstract 862)
In this 2-arm, phase II trial, patients with newly diagnosed myeloma are enrolled on 2 cohorts that include weekly carfilzomib at 52 mg/m2
or biweekly carfilzomib at 36 mg/m2
; the lenalidomide, dexamethasone, and daratumumab doses remain the same in each cohort. Treatment response has been assessed with 10-color single tube flow cytometry and invivoscribe IGHV sequencing, and the baseline bone marrow samples were evaluated with targeted DNA sequencing for sequential–fluorescence in situ hybridization and somatic mutational characteristics via myTYPE.
Results thus far, which were released in the abstract, showed an 83% MRD-negativity rate for the weekly carfilzomib dose schedule. Due to these data, the multicenter, randomized ADVANCE trial will evaluate the weekly quadruplet regimen and is slated to start enrollment by the end of 2019.
“In newly diagnosed multiple myeloma patients, 8 cycles of weekly KRd-daratumumab, without autologous stem cell transplant, resulted in about 80% MRD-negativity—opening the door for delayed transplant for many patients,” said Landgren, who is the lead author of the study. “These exciting results have prompted the launching of a large multicenter study, ADVANCE, which is evaluating weekly KRd-daratumumab in relation to standard of care.”Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): Griffin study update (Abstract 691)