In transplant-eligible patients with newly diagnosed multiple myeloma (NDMM), adding the CD38 monoclonal antibody isatuximab (Isa) to weekly treatment with carfilzomib, lenalidomide, and dexamethasone (KRd) induced deep and durable responses, with or without hematopoietic cell transplantation (HCT) and regardless of cytogenetic risk. The phase II study, published in Lancet Haematology, missed the primary endpoint of complete response (CR). Still, the four-drug combination (Isa-KRd) showed a safety profile comparable to similar regimens in this setting.
“The Skylark study demonstrates the efficacy and safety of this four-drug combination in patients with newly diagnosed myeloma,” said corresponding author Elizabeth K. O’Donnell, MD, of Massachusetts General Hospital Cancer Center, Dana- Farber Cancer Institute, and Harvard Medical School, all in Boston. “The majority of patients elected not to proceed with upfront autologous HCT. Of the patients who deferred transplant, 72% achieved MRD [measurable residual disease] negativity after eight cycles.”
Between July 31, 2020, and January 31, 2022, the single-arm study enrolled 50 patients (median age = 59; 54% male; 88% white) with transplant-eligible NDMM. Of the patients, 46% had disease with high-risk cytogenetics. The primary endpoint was CR after four 28-day treatment cycles of Isa-KRd.
At a median follow-up of 26 months, the primary endpoint was not met, with 32% of the 45 evaluable patients achieving a CR after four treatment cycles. The study showed an overall response rate (ORR) of 90% and a very good partial response (VGPR) or better in 78% of the patients. After completion of consolidation, which involved upfront HCT with two additional treatment cycles (selected by five patients) or deferred HCT with four additional treatment cycles (selected by 40 patients), 58% of patients achieved a CR, and the ORR remained at 90%, with VGPR or better attained by 86% of the patients. The 24-month progression-free survival and overall survival were 91.3% and 95.8%.
“Isa-KRd performed well in young patients, 46% of whom had high-risk cytogentics, suggesting that this is a good combination for high-risk disease,” Dr. O’Donnell said.
The safety results showed that the most common grade 3 or 4 side effects included neutropenia (26%), elevated alanine aminotransferase (12%), fatigue (6%), thrombocytopenia (6%), acute kidney injury (4%), anemia (4%), and febrile neutropenia (4%). Infusion-related reactions occurred in 20% of the patients, all grade 1-2. Grade 1-2 hypertension occurred in 14% of patients, with one report of grade 3 hypertension. Two patients died, with the cause assessed as unrelated to treatment.
The authors noted that the 32% complete response rate (CRR) with Isa-KRd is comparable to that of other four-drug regimens. They highlighted the MASTER trial, in which patients receiving daratumumab with KRd achieved a 36% CRR after four cycles.
Dr. O’Donnell explained that most studies of daratumumab plus bortezomib, lenalidomide, and dexamethasone (Dara-RVd) employ twice weekly bortezomib, but it is often given once weekly in practice. “In our trial, the study dose was once weekly, which is the one that will be used in practice,” she said.
Limitations to the study include its single-arm and non-randomized design, comprising mainly white patients. The authors noted that assessment of response after four treatment cycles occurred in some studies of NDMM, but other studies assessed responses after high-dose melphalan and HCT. They suggested that a later time point may “have allowed for additional treatment to deepen responses further and increase the likelihood of achieving the primary endpoint.”
The authors concluded that the Skylark data support Isa-KRd use translating from clinical trials to real-world practice.
Any conflicts of interest declared by the authors can be found in the original article.
Reference
O’Donnell E, Mo C, Yee AJ, et al. Isatuximab, carfilzomib, lenalidomide, and dexamethasone in patients with newly diagnosed, transplantation-eligible multiple myeloma (SKylaRk): a single-arm, phase 2 trial. Lancet Haematol. 2024;11(6):e415-e424.
