Phase 1 Trial Of Carfilzomib + High Dose Melphalan Conditioning Regimen Prior To Autologous Hematopoietic Stem Cell Transplantation (AHSCT) For Relapsed Multiple Myeloma

The alkylating agent melphalan, given at the myeloablative dose of 200mg/m² preceding autologous hematopoietic stem cell transplantation (AHSCT), is part of the upfront management of patients with multiple myeloma (MM) and has been used in the salvage setting, often as second transplant. Proteasome inhibitors (PI) have been shown in vitro to impair the fanconi/BRCA pathway of DNA repair and increase DNA fragmentation and apoptosis induced by alkylating agents in MM cells. We hypothesized that combining carfilzomib, a second generation PI, with melphalan would result in more effective anti myeloma activity. We herein performed a phase 1 study to identify the maximal tolerated dose (MTD) of carfilzomib when used in combination with myeloablative doses of melphalan as conditioning regimen for patients with relapsed MM and describe toxicity and preliminary activity profile for the combination.

Phase 1, multicentric, dose escalation trial with traditional 3+3 design. Eligible subjects had symptomatic MM, relapsed after at least one line of therapy, with evaluable disease and having obtained at least a minimal response (MR) after the most recent salvage regimen. Subjects were also required to have at least 2 x 10⁶ CD34+ cells/kg in storage for transplant and additional 2 x 10⁶ CD34+ cells/kg as “back up”. Treatment consisted of two doses of carfilzomib administered IV over 30 minutes on days -3 and -2. The day -2 dose was administered one hour prior to administration of melphalan200mg/m². Carfilzomib dose consisted of 20(day-3)/27 (day -2) mg/m2 (cohort 0), 27/27 (cohort 1), 27/36 (cohort 2), 27/45 (cohort 3) and 27/56 mg/m2 (cohort 4). All subjects received pegfilgrastim 6 mg subcutaneously on day +1. Dose limiting toxicities (DLT, non-hematologic grade 4 and selected grade 3 toxicities) were evaluated during the first 30 days after transplantation. Disease response was assessed 100 days after transplantation.

Enrolment of cohort 4 (last) is ongoing. Twelve subjects were accrued in cohorts 0-3 with no DLT being identified. Median age was 56 (range 45-68). Median number of prior lines of therapy was 3 (range 2-6) and 5 subjects had previously received AHSCT. There was no acute toxicity associated with carfilzomib infusion. Median CD34+ dose infused was 4.15 x 10⁶/kg (range 2.21-9.34). Neutrophil engraftment occurred after a median of 11 days (range 8-15) and platelet engraftment after a median of 17.5 days (range 11-24). There were no non-hematologic grade 4 toxicities. The most frequent grade 3 toxicity was infection in 7/12 subjects consisting of 1 episode of pneumonia, 1 episode of bacteremia, 1 episode of urinary tract infection and 4 episodes of febrile neutropenia. Other grade 3 toxicities were rash (n=2), hypertension (n=1), hypophosphatemia (n=1) and hypocalcemia (n=1). Nine subjects, from cohorts 0, 1 and 2, have reached day +100 response assessment. Prior to transplant the responses to salvage regimen were MR in 1/9, partial response (PR) in 6/9, very good partial response (VGPR) in 1/9 and complete response (CR) in 1/9 subjects. At day +100 cumulative responses were PR in 3/9, VGPR in 3/9 and CR in 3/9 subjects. Pharmacodynamic studies in peripheral blood mononuclear cells revealed that carfilzomib precluded melphalan-induced increase in FANCD2 and FANCI mRNA.

Conditioning with carfilzomib and melphalan prior to AHSCT is well tolerated in patients with relapsed MM. Final results of this phase 1 study will be presented at the meeting. The MTD cohort (or cohort 4 if no MTD is found) will be subsequently expanded for better determination of this regimen’s activity.

Costa:Onyx: Research Funding. Off Label Use: Carfilzomib in conditioning regimen for stem cell transplantation.