Isatuximab Quadruplet Active in High-Risk, Newly Diagnosed Myeloma

Katja Weisel, MD

A quadruplet regimen combining the anti-CD38 monoclonal antibody isatuximab with carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (I-KRd) was safe and had a 100% response rate among 10 patients enrolled in the safety run-in cohort of the phase II, multicenter GMMG-CONCEPT trial.

The 10-patient safety run-in phase was designed to evaluate dose-limiting toxicities during the initial 2 cycles of I-KRd treatment. Following cycle 2, there were 6 patients with a very good partial response (VGPR) and 4 patients with a complete response (CR). Efficacy was also assessed after cycle 6, at which point there were 7 patients with a CR, 2 patients with a VGPR, and 1 patient with progressive disease.

"The GMMG-CONCEPT trial is the first trial introducing quadruplet treatment solely for high-risk multiple myeloma including both transplant-eligible and transplant ineligible patients," said Katja Weisel, MD, Department of Hematology, Oncology and Stem Cell Transplantation, University Hospital Eppendorf, Hamburg, Germany, who presented the results at the 17th International Myeloma Workshop.

All 10 patients experienced treatment-emergent adverse events (TEAEs). Most grade ≥3 toxicities were hematologic, including neutropenia (n = 6), leukopenia (n = 5 ), lymphopenia (n = 2), anemia (n = 2), and thrombocytopenia (n = 1). Nonhematologic grade ≥3 TEAEs included cerebral vascular disorders in 2 patients (n = 2), self-limiting ventricular tachycardia (n = 1), and diarrhea (n = 1). Three patients experienced grade 2 infusion reaction during the first infusion of isatuximab.

There were 5 serious adverse events (SAEs), including 2 infections (1 febrile neutropenia) and the incidents of cerebral ischemia and self-limiting ventricular tachycardia. The 2 cerebral events were classified as non—treatment related due to a preexisting comorbidity. Grade 1/2 infusion reactions occurred in 3 patients during the first isatuximab infusion. There were no deaths due to SAEs or discontinuations due to an adverse event.

"The overall safety profile of I-KRd was favorable and manageable, with no unexpected toxicities and the combination is effective in this setting," added Weisel.

GMMG-CONCEPT is enrolling patients with newly diagnosed multiple myeloma and high-risk disease defined as deletion 17p or t(4;14) or t(14;16) or >3 copies of +1q21; all patients had to be International Staging System stage 2 or 3. Patients could have received 1 cycle (4 weeks) of any treatment for multiple myeloma. Patients are being stratified by transplant eligibility (Arm A, eligible and age ≤70 years) or non-eligibility (Arm B ineligible or age >70 years).

At the meeting, Weisel presented results for the safety run-in cohort of the first 10 patients in Arm A of GMMG-CONCEPT. Nine of the 10 patients had completed 6 cycles of induction therapy. The median age was 56 years (range, 42-67), 4 were male, 6 had del 17p, 2 had t(4;14), and 5 had >3 copies of +1q21.

The primary objective is minimal residual disease (MRD) negativity by flow cytometry to a sensitivity of 10-5. The secondary objectives is progression-free survival. Additional objectives include overall response rate, survival, duration of MRD-negativity, time to next treatment, time to response, and quality of life. Experimental objectives include the best method for defining MRD-negativity (flow, next-generation sequencing, PCR, or imaging) and evaluation of immunologic reconstitution during maintenance.

In the original study design, Arm A was to receive 6 cycles of I-KRd followed by cyclophosphamide-based stem cell mobilization, HD melphalan and ASCT, a second HD melphalan and SCT if the response to the first was not a CR or near CR, consolidation with 4 cycles of I-KRd, and maintenance with I-KR. Arm B was to receive I-KRd for up to 12 cycles, followed by I-KR maintenance. As of September 10, 2019, 112 of the 153 planned patients (117 for Arm A and 36 for Arm B) have been enrolled.

All 10 patients in the safety run-in received cyclophosphamide-based stem cell mobilization with a median stem cell yield of 5 (4-9) × 10⁶ CD34+ cells/kg. Of these, 3 patients required plerixafor for collection; sufficient stem cells could not be collected from 3 patients. Therefore, the study was amended so that stem cell mobilization would take place after the 3rd rather than the 6th induction cycle.

With regard to the difficulties in stem cell collection after 6 cycles of I-KRd induction, Weisel said, “We were surprised we couldn’t collect stem cells. I think this is a real finding and we have to look at this in other quadruplets.”

In her concluding remarks, Weisel said that the results overall are encouraging and data on additional patients will be reported soon.

Weisel K, Asemissen AM, Schieferdecker A, et al. Isatuximab, carfilzomib, lenalidomide and dexamethasone (I-KRd) in front-line treatment of high-risk multiple myeloma: results of the safety run-in cohort in the phase II, multicenter GMMG-CONCEPT trial. Presented at: The 17th International Myeloma Workshop; Sept. 12-15, 2019; Boston. Abstract 362.

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