In this issue of Blood, Wang et al describe that the combination of carfilzomib, lenalidomide, and low-dose dexamethasone (CRd) can be a valuable option in relapsed and refractory multiple myeloma patients.1
In 1958, Blokhin et al reported the first experience with sarcolysin (melphalan) in neoplastic diseases,2 and a few years later Drs D. Bergsagel and R. Alexanian pioneered studies showing the efficacy of melphalan in multiple myeloma. However, in the subsequent 30 to 40 years, progress in myeloma treatment remained stagnant. In fact, the major innovation was the use of high-dose therapy, which was again mainly based on melphalan, followed by autologous stem cell support. The situation has significantly changed in the last decade with the approval of 2 immunomodulatory drugs (IMIDs) (thalidomide and lenalidomide) and 1 proteasome inhibitor (PI) (bortezomib).
Carfilzomib is a second-generation PI that belongs to the epoxiketone family and irreversibly binds the chymotrypsin-like activity of the proteasome. It has shown marked activity, as simple agent, in phase 1 and 2 clinical trials, with 40% to 52% of responses in bortezomib-naïve patients and 17% to 19% in bortezomib-refractory cases and a very low incidence of peripheral neuropathy (PN).3-5 The possibility of combining PI with IMIDs is very attractive, and the positive results of the bortezomib-lenalidomide-dexamethasone (VRD) combination6 were the basis for the study reported in this issue of Blood by Wang et al.1 In a previous phase 1b dose-escalation study,7 the same authors identified the maximum planned dose (MPD) for CRd as 20/27 mg/m2 for carfilzomib, 25 mg for lenalidomide, and 40 mg for dexamethasone. Here, they show the efficacy and safety of CRd at the MPD in a total of 52 patients; the response rate (RR) was 76.9%, with a median progression-free survival (PFS) of 15.4 months. The benefit of adding carfilzomib to lenalidomide-dexamethasone will be determined in the ASPIRE randomized trial that compares CRd vs Lenalidomide plus low-dose dexamethasone, but the present data already suggest that in lenalidomide-naïve patients, the RR (85%) and median PFS (not reached) is superior to that previously reported for lenalidomide-dexamethasone.8,9 Moreover, 68% of patients refractory to lenalidomide responded to CRd with a median PFS of 9.9 months. Whether or not the results with CRd combination are superior to previously reported data with VRD is difficult to determine, because the patient populations were rather heterogeneous and small in size. Perhaps the clearest advantage of CRd is the lower incidence of PN (27% vs 64% for any grade PN); however, in the Richardson trial, the more friendly bortezomib schedule (weekly and subcutaneous) was not used. Accordingly, the answer to this question will only come from a randomized trial.
The second relevant question, in the relapse setting, is whether it is preferable to use a combination of the 2 new drugs (PI plus IMID) or to combine one of them with an alkylator (ie, cyclophosphamide) and to reserve the other one for subsequent relapses. In this comparison, costs should also be taken into consideration. How many countries will pay for this expensive triple combination unless there is a study design showing that the triplet at relapse is superior in terms of overall survival (not in terms of RR or PFS) to a sequential treatment approach? If this proves to be positive, then CRd will be cost-effective and will become a new standard for relapse/refractory patients.
A different scenario at relapse is that of young patients who are candidates to receive a transplant as part of the rescue therapy, particularly if this is an allotransplant, because in this setting we want to obtain the best possible response as soon as possible, and therefore the combination of a PI with IMIDs is clearly justified.
Conflict-of-interest disclosure: The author has participated in some advisory boards for Millennium, Celgene, Novartis, Onyx, and Janssen.
