Management of multiple myeloma (MM) changed dramatically following introduction into the therapeutic armamentarium of immunomodulatory drugs (e.g., thalidomide and lenalidomide) and proteasome inhibitors (e.g., bortezomib). Use of these drugs in various combinations with corticosteroids (primarily decadron) produced rapid, deep, and durable responses that translated into significant improvement in long-term outcomes. Carfilzomib is a second-generation, targeted drug that binds irreversibly to the 20S proteasome, blocking its chymotrypsin-like activity and thereby providing sustained inhibition of proteasome protease activity. Early-phase clinical studies showed that carfilzomib, in combination with lenalidomide (Revlimid) and low-dose dexamethasone (CRd), was active in patients with relapsed and/or refractory MM. Based on the favorable results of those studies, a phase 1/2 trial designed to test the tolerability, safety, and efficacy of CRd in patients with previously untreated MM was launched at four institutions in the United States. Both transplant-eligible and transplant-ineligible patients were allowed to enroll.
The study population consisted of 53 patients. Thirty-five patients were included in the phase 1 arm designed to determine the maximum tolerated dose (MTD) of carfilzomib within the CRd regimen. The maximum planned dose (MPD) of carfilzomib was 36 mg/m2. Because the MPD was well tolerated, the investigators elected to use that dose in the subsequent phase 2 efficacy component of the study rather than amending the protocol to allow for further dose escalation to identify the true MTD. The primary endpoint of the phase 2 arm was near complete response (nCR) or better after four treatment cycles. At the end of four cycles, 38 percent of patients achieved nCR or better with 6 percent in stringent complete response (sCR). Prolonged treatment with CRd increased the proportion of patients in at least nCR to 78 percent for those who received eight or more cycles, with 61 percent of those receiving eight or more cycles achieving sCR status. After a median follow-up period of 13 months, disease progression was observed in two patients, while disease progression was absent among all patients in the sCR group after a median follow-up period of nine months. The CRd regimen was well tolerated, as only one patient discontinued treatment because of toxicity, and dose reduction to manage myelosuppression was required in only a small portion of patients. Peripheral neuropathy was documented in 23 percent of patients with no grade 3-4 events. By comparison, the authors cited a phase 1-2 study of bortezomib in combination with lenalidomide and decadron for frontline treatment of MM in which sensory neuropathy of all grades was noted in 80 percent of patients (2% with grade 3 neuropathy).
The investigators acknowledged the limitations on interpretation imposed by the relatively small sample size, the single-arm non-randomized study design, the lack of independent central review of response results, and a study population that included both transplant-eligible and transplant-ineligible patients. Is newer better? While the results of the current study are promising, especially given the favorable toxicity profile of the regimen that allowed prolonged treatment (the median number of CRd cycles was 12), carefully designed, randomized controlled trials will be required to establish the role of carfilzomib in the management of MM.
Conflict of Interests
Dr. Leleu receives lecture fees, board honorarium, and research funding from Celgene, Janssen, and Onyx.
back to top