Phase 1/2 Trial of Carfilzomib and Melphalan Conditioning for Autologous Stem Cell Transplantation for Multiple Myeloma (CARAMEL)

Abstract

Background Melphalan (Mel) as a single agent is the most common conditioning regimen prior to autologous stem cell transplantation (ASCT) for multiple myeloma (MM). Incorporation of other drug classes such as proteasome inhibitors (PI) as part of initial therapy or for treatment of relapsed disease has significantly improved outcomes in MM. Based on initial data showing synergy between PI and alkylating agents, we designed this trial to examine if adding carfilzomib (Cfz) to Mel would improve the efficacy of the conditioning therapy. Patients and Methods Patients with MM, undergoing a single, early transplant (≤12 months from diagnosis) were included provided they were eligible for full dose Mel conditioning. Escalating doses of Cfz (27, 36, 45, 56 mg/m2) were administered days -6, -5, -2, -1 with Mel (200 mg/m2) administered in two divided doses on days -4, -3. Stem cells were infused day 0. The phase 1 portion of the trial used a 3+3 dose escalation of Cfz. Responses were assessed using IMWG consensus response criteria. Results 49 patients were enrolled (Table 1). At median follow up of 12.9 months (0.4-48.4), 45 (91.8%) were alive; 41 (83.7%) were without progression. Responses outlined in Table 2. Median PFS from registration was 48.2 mos (95% CI; 21.3-NA). The 1 & 2-year PFS rates were 88.2% (70.5-95.5%) and 71.0% (45.9-86.1%), respectively. Overall, 6 patients had ≥ 1 dose of Cfz omitted (elevated creatinine-3, and 1 patient each with sinus bradycardia, pulmonary edema with atrial fibrillation and rapid ventricular response, and pathologic fracture requiring surgery). A ≥grade 3 hematological or non-hematological toxicity, regardless of attribution, occurred in 94% and 76%, respectively. ≥Grade 3 non-hematological toxicities seen in >1 patient are shown in Figure 1. Conclusion Adding Cfz to Mel as conditioning therapy for ASCT in MM is feasible/safe. Response rates and PFS are comparable to those seen in recent phase 3 trials.