P-504: A Phase II Study of Isatuximab, Once Weekly Carfilzomib, Lenalidomide, Dexamethasone, and in Newly Diagnosed, Transplant-Eligible Multiple Myeloma (The SKylaRk Trial)

Introduction: 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). Isatuximab (isa) is approved in combination with carfilzomib 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. Our study evaluates the addition of isa to weekly carfilzomib (K), lenalidomide (len), and dexamethasone (dex) in all-risk, transplant-eligible patients with NDMM and stratifies maintenance based on cytogenetic risk.

Methods: Phase II study of isa-KRd in 50 transplant-eligible NDMM (NCT04430894). All patients received 4 cycles of isa-KRd followed by stem cell collection with option of upfront versus deferred stem cell transplant (SCT). Upfront SCT received 2 additional cycles then maintenance. Deferred SCT received 4 additional cycles then maintenance. Each 28-day cycle consisted of isa 10 mg/kg iv weekly cycles 1-2, Q2 weeks cycles 3-6, then Q4 weeks; K (20 mg/m2 cycle 1, day 1 only) 56 mg/m2 iv days 1, 8, 15; len 25 mg po days 1-21; and dex 20 mg po days 1, 2, 8, 9, 15, and 16 (and days 22, 23 cycles 1-2).

For maintenance, standard-risk received len 10 mg po days 1-21 and high-risk (del 17p, gain 1q, t(4:14), t(14;16), t(14;20)) isa 10 mg/kg iv day 1; K 56 mg/m2 iv days 1, 15; len 10 mg po days 1-21.

The primary end point is complete response (CR + stringent CR) rate after 4 cycles by the IMWG response criteria. Secondary endpoints included safety and tolerability; minimal residual disease (MRD), progression-free survival (PFS), and overall survival (OS) rates.

Results: Fifty patients enrolled between August 2020 and February 2022. Median age was 59 years (range 39-70) and 54% were male. Forty-six percent had high-risk cytogenetics. Median follow-up 26 months. Of 45 patients evaluable for response after 4 cycles, ORR was 100% and 89% (39/45) achieved a very good partial response (VGPR) or better and 36% (16/45) a CR. Of those, 43% (12/28) were MRD negative at 10-5. After the completion of C6/C8, ORR was 100% and 64% (29/45) achieved a CR and 96% (43/45) achieved a VGPR or better. After C6/C8, 41 patients, 66% (27/41) were MRD negative at 10-5. The 24-month PFS was 91.3% (95% CI 83.4% -99.8%) and OS was 95.8% (95% CI 90.2%-100%). 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 in 20%, no grade 3. Grade 1-2 hypertension in 48%, one grade 3. There was one death assessed as unrelated. Two patients withdrew for acute kidney injury. Two patients were not evaluable at C4 and C6/C8 because measurable disease was assessed by PET CT.

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