Carfilzomib Weekly 20/56mg/m², Lenalidomide and Dexamethasone for Early Relapsed Refractory Multiple Myeloma

Background. Triplet-based lenalidomide plus dexamethasone combinations have become the new standard of care for early relapse and refractory multiple myeloma (RRMM), including carfilzomib plus lenalidomide/dexamethasone (KRd) based on ASPIRE phase 3 data. In ASPIRE, and as per the marketing authorization, carfilzomib is given twice a week at 20/27mg/m² on days 1, 2, 8, 9, 15, 16 of a 28 days based cycle. In parallel, ENDEAVOR, a second carfilzomib plus dexamethasone phase 3 study validated that carfilzomib 20/56mg/m² twice weekly was safe in early RRMM. We hypothesized that KRd on a weekly basis, with 3 visits per cycle but using a more intense dosing at 56mg/m², rather than 6 visits at 27mg/m² at hospital, was far less inconvenient to patients.The aim of this study was to evaluate the efficacy and toxicity of carfilzomib weekly plus lenalidomide/dexamethasone regimen in patients treated for early RRMM.

Methods. 28 patients were treated with KRd weekly regimen. Patients received carfilzomib plus lenalidomide/dexamethasone in 28-day cycles until disease progression or until occurrence of unacceptable toxic effects. Carfilzomib was administered as a 30-minute infusion on days 1,8,15 (starting dose, 20mg/m² on day 1 of cycle 1; target dose, 56mg/m² thereafter). Lenalidomide (25mg) was given on days 1 through 21. Dexamethasone (40mg) was administered on days 1, 8, 15, 22. All assessments were made according to IMWG.

Results. The median age was 64 years (45 - 80) with 14% older than 70 years, sex ratio M/F 1.3 and ISS disease stage 2 or 3 in 39%. Patients had received a median of 1 (1 - 3) previous lines of therapy including proteasome inhibitors (100%) and immunomodulatory drugs (43%). All but 2 patients had disease that relapsed to the last line of therapy. With a median follow up of 8 months, 3 patients (11%) relapsed, and one patient died. The median number of KRd cycles administered was 6.5 (1 - 12). Overall response rate was 93%, with 89% ≥VGPR and 61% ≥CR. The mean time to a response was 1.6 months. The median TTP and OS at 12 months were 89% and 95%, respectively. 29% of patients have discontinued treatment, with solely 50% due to adverse events. Hematologic adverse events ≥ grade 3 were reported in 57% and non hematologic adverse events ≥ grade 3 in 36%. Adverse events resulted in a reduction of carfilzomib dose in 11% of patients and a reduction of the lenalidomide dose in 7% of patients. No patient died related to adverse events. Overall, adverse events ≥ grade 3 seen in ≥10% of patients were neutropenia, thrombocytopenia, vomiting and pyrexia. No patient experienced any severe cardiovascular adverse event, including cardiac failure or any severe cardiac issues or thromboembolic events. One patient required an increase of antihypertensive treatment, and resumed Carfilzomib.

Conclusion. KRd weekly at 20/56mg/m² is effective and safe to early RRMM patients. Further studies are warranted to confirm this data on a larger MM population. Furthermore, analysis of long-term outcome is needed on our studied population.