Phase 1 Trial of Carfilzomib + Melphalan (CarMel) Conditioning and Autologous Hematopoietic Stem Cell Transplantation (AHSCT) for Relapsed Multiple Myeloma (MM)

Background: Proteasome inhibitors (PI) impair the fanconi/BRCA pathway of DNA repair and increase DNA fragmentation and apoptosis induced by alkylating agents in in vitro 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 used in combination with melphalan (200mg/m²) as conditioning regimen prior to  AHSCT for patients with advanced MM.

Methods: Phase 1, multicentric, dose escalation trial with traditional 3+3 design. Inclusion criteria required symptomatic MM, relapse after at least one line of therapy (prior AHSCT allowed), evaluable disease and at least minimal response (MR) after the most recent salvage regimen. Subjects were required to have at least 2 x 10⁶ CD34+ cells/kg in storage + 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 latter dose was administered one hour prior to melphalan (Figure 1).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). Dose limiting toxicities (DLT, non-hematologic grade 4 and selected grade 3 toxicities) were evaluated during the first 30 days after AHSCT. Disease response was assessed 100 days after AHSCT.

Results: Fifteen subjects were accrued in cohorts 0-4. At the time of this report 14/15 subjects have completed the DLT period with no DLT being identified and the third subject in cohort 4 (last cohort) is being treated. Median age was 54 (range 45-68). Median number of prior lines of therapy was 3 (range 2-6) and 7 subjects had previously received AHSCT. Median CD34+ dose was 4.6 x 10⁶/kg (range 2.21-9.34). Median time for neutrophil engraftment was 11 days (range 8-15) and for platelet engraftment 18 days (range 11-24). There were no non-hematologic grade 4 toxicities. The most frequent grade 3 toxicity was infection in 8/14 subjects consisting of 1 episode of pneumonia, 1 episode of bacteremia, 1 episode of urinary tract infection and 5 episodes of febrile neutropenia. Other grade 3 toxicities were rash (n=2), hypertension (n=1),  hypophosphatemia (n=1) and  hypocalcemia (n=1). Twelve subjects, from cohorts 0, 1, 2 and 3 have reached day +100 response assessment. Distribution of subjects by category of response before and after AHSCT is displayed in Figure 2.

Conclusion: 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 to 28 subjects for better determination of this regimen's activity and toxicity.