Landgren Previews Pivotal ASH 2019 Myeloma Data

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)

Prior results of the 16-patient safety run-in data of GRIFFIN demonstrated no safety concerns with the 4-drug regimen. Additionally, results presented at the 17th International Myeloma Workshop showed that, at a median follow-up of 13.5 months, the sCR rate by end of consolidation therapy was 42.4% with the daratumumab regimen (D-RVd) and 32.0% for lenalidomide, bortezomib, and dexamethasone alone (odds ratio [OR], 1.57; 95% CI, 0.87-2.82; 1-sided P = .068).

Updated findings to be presented at the 2019 ASH Annual Meeting, will show that the addition of daratumumab to lenalidomide, bortezomib, and dexamethasone continued to have a significant improvement in response rates and depth of response, as well as sCR and MRD negativity.

Moreover, the safety profile was consistent with prior results of this regimen. Beyond the updated data to be presented at the meeting, investigators noted in the abstract that the ongoing study has patients continuing on maintenance therapy.

“[This study includes] 4 cycles of VRd-daratumumab followed by autologous stem cell transplant and 4 more cycles of VRd-daratumumab for newly diagnosed multiple myeloma,” Landgren said. “[The regimen] delivers deeper responses and achieves MRD negativity in more patients, when compared to 4 cycles of VRd, ASCT, and 4 more cycles of VRd.”

Phase 2 trial of daratumumab, ixazomib, lenalidomide and modified dose dexamethasone in patients with newly diagnosed multiple myeloma (Abstract 864)

This phase II study is examining the safety and efficacy of this quadruplet regimen in a newly diagnosed population, but with a modified regimen of dexamethasone (≤40 mg intravenously weekly for ≤2 cycles) in an effort to lessen the AEs that can be associated with the steroid.

Data presented in the abstract showed that the overall best confirmed response rate among all 40 patients was 95%, which included a 10% stringent CR rate, a 5% CR rate, and 23% near CR rate—which comprised 13% VGPR excluding near CR. Additionally, the stem cell collection was completed in 17 patients thus far, and all of them required filgrastim and plerixafor. All patients were alive, with 39 (97.5%) patients progression-free at the last follow-up; 4 (10%) patients proceeded to autologous stem cell transplantation off of the study. Dose reductions or dose holds were required in a subset of patients; ixazomib (Ninlaro; 10%), lenalidomide (20%), daratumumab (0%), and dexamethasone (13%).

At the 2019 ASH Annual Meeting, updated results will be presented that will include an additional 6 months of follow-up.

“Oral [ixazomib, lenalidomide, and dexamethasone; (IRd)] plus daratumumab delivers more deeper responses compared to IRd,” Landgren explained. “[This is] another future 4-drug option for newly diagnosed multiple myeloma patients.”

First clinical study of the B-cell maturation antigen (BCMA) 2+1 T cell engager (TCE) CC-93269 in patients (Pts) with relapsed/refractory multiple myeloma (RRMM): interim results of a phase 1 multicenter trial (Abstract 143)

In the relapsed/refractory setting, patients who received ≥3 prior regimens that did not include BCMA-directed therapy were treated with the TCE intravenously in 28-day cycles. Investigators sought to assess the safety and tolerability of the TCE and to determine the maximum-tolerated dose (MTD). The median number of prior therapies was 6 (range, 3-12) and all patients were refractory to their last line of therapy.

In the abstract, results showed that of the 12 patients who were treated with ≥6 mg of CC-93269 in cycle 1, the overall response rate was 83.3% (n = 10), which included 7 (58.3%) patients with a ≥VGPR and 4 (33.3%) with an sCR. Seventy-five percent (n = 9) of patients achieved MRD negativity. The median time to response was 4.2 weeks (range 4.0-13.1), and all of the 10 responses were ongoing. The non-tolerated dose, MTD, and recommended phase II dose have not yet been reached.

“In this phase I study, the investigators show that CC-93269, a 2+1 BCMA T-cell engager has a manageable safety profile and very promising efficacy. Specifically, they show MRD-negativity in 9 (75%) of 12 patients treated with the 6-mg dose,” Landgren concluded. “These results are impressive particularly since the study was based on patients with heavily pretreated relapsed/refractory multiple myeloma.”

Voorhees P, Kaufman JL, Laubach J, et al. Daratumumab + lenalidomide, bortezomib & dexamethasone improves depth of response in transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. Presented at: The 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Abstract 906.

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