A Phase II Study of Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Isatuximab in Newly Diagnosed, Transplant-Eligible Multiple Myeloma (The SKylaRk Trial)

Background: Clinical data support the combination of a CD38 monoclonal antibody, an immunomodulatory drug, a proteasome inhibitor, and a glucocorticoid for the treatment of newly diagnosed multiple myeloma (NDMM). Recently, the GRIFFIN study evaluated the addition of the CD38 antibody, daratumumab (dara) to lenalidomide (R), bortezomib (V), and dexamethasone (d) (dara-RVd) in transplant-eligible NDMM and demonstrated that daratumumab improved the efficacy of the three-drug combination with an acceptable safety profile. Isatuximab (Isa) is a newer CD38 monoclonal antibody that binds to a unique epitope of the CD38 receptor that eliminates MM cells by antibody-dependent cellular cytotoxicity, antibody-dependent cellular phagocytosis, complement-dependent cytotoxicity and direct apoptosis without the need for crosslinking. Isatuximab is approved in combination with carfilzomib (K) and dexamethasone for relapsed, refractory MM based on the results of the IKEMA study and is now being explored in novel combinations in the newly diagnosed setting including Isa-RVd (GMMG-HD7) and Isa-KRd (GMMG-CONCEPT). Interim analyses of the GMMG-CONCEPT trial demonstrated rapid and deep remissions with Isa-KRd in high-risk NDMM. Our study evaluates the addition of isatuximab to weekly carfilzomib, lenalidomide, and dexamethasone in all-risk, transplant-eligible patients with NDMM and stratifies maintenance based on cytogenetic risk.

Study Design and Methods: This is a phase II trial to evaluate the efficacy of Isa-KRD in 50 transplant-eligible NDMM (NCT04430894). All patients received 4 cycles of induction therapy with Isa-KRd followed by stem cell collection with the option to proceed to upfront versus deferred stem cell transplant (SCT) at investigator's discretion. Patients undergoing upfront SCT received 2 additional cycles of therapy then maintenance. Patients deferring SCT following collection received 4 additional cycles of therapy then maintenance. Each 28-day cycle consisted of isa 10 mg/kg iv weekly cycles 1-2, Q2 weeks cycles 3-6, Q4 weeks thereafter; carfilzomib (20 mg/m² cycle 1, day 1 only) 56 mg/m² iv days 1, 8, 15; lenalidomide 25 mg po days 1-21; and dexamethasone 20 mg po days 1, 2, 8, 9, 15, and 16 (and days 22, 23 cycles 1-2).

For maintenance, patients were stratified based on cytogenetics (high-risk cytogenetics included deletion 17p, gain of 1q, and translocations t(4:14), t(14;16), t(14;20)). Patients with standard-risk cytogenetics received lenalidomide 10 mg po days 1-21. Patients with high-risk cytogenetics received isatuximab 10 mg/kg iv day 1; carfilzomib 56 mg/m² iv days 1, 15; lenalidomide 10 mg po days 1-21.

Main Outcomes and Measures: The primary end point is complete response (CR + stringent CR) rate after 4 cycles of Isa-KRd as assessed by the International Myeloma Working Group response criteria. Secondary endpoints included determining safety and tolerability of Isa-KRd; minimal residual disease (MRD) after 4 cycles, at completion of consolidation (post-transplant) or induction (transplant-deferred) and at 24 months; progression-free survival (PFS), overall survival (OS) rates, and quality of life.

Results: Fifty patients enrolled between August 2020 and February 2022. Median age at study entry was 59 years (range 39-70) and 27 (54%) were male. Twenty-three (46%) of patients had high-risk cytogenetics, 6 (12%) were ISS III, and 2 (4%) were R-ISS III. Median follow up was 10.8 months. Of the 47 patients evaluable for response after 4 cycles, the ORR was 100% and 89% (42/47) achieved a very good partial response (VGPR) or better and 40% (19/47) a CR. Of the 47 patients evaluable for response, MRD results were available after C4 for 28 patients achieving a VGPR or better. Of those, 43% (12/28) were MRD negative at 10^-5 and 32% (9/28) at 10^-6. The 12-month PFS and OS were 97.9% (95% CI 86.1% -99.7%). Most common grade 3 or 4 side effects (≥2 patients) were neutropenia (24%), elevated alanine aminotransferase (10%), acute kidney injury (6%), and thrombocytopenia (6%). Grade 1-2 infusion-related reactions were seen in 20%, no grade 3. Grade 1-2 hypertension was seen in 48% with one grade 3. There was one death assessed as unrelated. Two patients were removed from study for acute kidney injury.

Conclusions: Early data suggest that Isa-KRd induces deep responses in patients with NDMM. The overall safety profile is expected and consistent with previous reports of similar regimen.

O'Donnell:Janssen: Consultancy; BMS: Consultancy, Honoraria. Nadeem:Takeda: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; GPCR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding. Yee:Bristol Myers Squibb: Consultancy, Research Funding; Sanofi: Consultancy; Regeneron: Consultancy; Oncopeptides: Consultancy; Karyopharm: Consultancy; Janssen: Consultancy, Research Funding; Celgene: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding; GlaxoSmithKline: Consultancy; AbbVie: Consultancy; Adaptive Biotechnologies: Consultancy. Branagan:Karyopharm Therapeutics: Consultancy; Janssen/Pharmacyclics: Consultancy; Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; CSL Behring: Consultancy; Genzyme: Consultancy. Rosenblatt:Wolters Kluwer Health Inc: Other: Spouse COI; Karyopharm Therapeutics: Other: DSMB; Dava Oncology: Other: Education; Celgene: Membership on an entity's Board of Directors or advisory committees; Partner Tx: Membership on an entity's Board of Directors or advisory committees; Attivare Therapeutics: Consultancy; Bioclinica: Consultancy; Imaging Endpoint: Consultancy; Parexel: Consultancy; Kite: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Research Funding; BMS: Research Funding; Celgene: Research Funding; Kite: Honoraria. Richardson:Secura Bio: Consultancy; Sanofi: Consultancy; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; AstraZeneca: Consultancy; Regeneron: Consultancy; GlaxoSmithKline: Consultancy; Celgene/BMS: Consultancy, Research Funding; Oncopeptides: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Takeda, Celgene, and GSK: Honoraria; Takeda: Research Funding; Takeda, Abbvie, GSK, and Celgene: Consultancy; Takeda and GSK: Other: Travel expenses from Takeda and GSK. Raje:Medscape: Honoraria; Amgen: Consultancy, Honoraria; Bristol Myers Squibb: Consultancy, Honoraria; Celgene: Honoraria; Research to Practice: Honoraria; Two Seventy Bio: Research Funding; Massachusetts General Hospita: Current Employment; Janssen: Consultancy, Honoraria.