Treatment of Lenalidomide Exposed or Refractory Multiple Myeloma: Network Meta-Analysis of Lenalidomide-Sparing Regimens

Over the past 10 years, the treatment of multiple myeloma (MM) dramatically changed due to the introduction of a number of new agents and combination regimens both in the frontline and in the relapsed/refractory setting. Currently, at least 11 classes of therapeutic agents, including steroids, alkylators (melphalan and cyclophosphamide), proteasome inhibitors (PI: bortezomib, carfilzomib, ixazomib), immunomodulatory agents (thalidomide, lenalidomide, pomalidomide), monoclonal antibodies (mAbs: elotuzumab, daratumumab), HDAC-inhibitors (panobinostat), BCL2 inhibitors (venetoclax), selective inhibitors of nuclear export (selinexor), drug-conjugated mAbs (belantamab mafodotin), bispecific agents and CAR-T, are approved (or are going to be approved) alone or in different combinations for the treatment of this disease, while few or no data are available to guide the therapeutic strategy to adopt at diagnosis or relapse (1). The choice of the treatment at relapse (2), in particular, poses particular challenges, and is currently dependent on patients (age, comorbidities, fitness, renal impairment, frailty) and disease characteristics (aggressive vs biochemical relapse, cytogenetics, presence of extra-medullary disease), previous treatments (classes of agents, duration of response, progression while on therapy), regional drug access (approval of combinations, reimbursement, costs) and, finally, patient’s choice. Unfortunately, there is a lack of trials specifically designed to help in this choice, and often, pre-planned subgroup analyses, do not include a sufficient number of patients to reach statistical evidence. Recently, since lenalidomide is progressively becoming the preferred one-line option to treat MM patients (and often, it is administered until progression), the choice of the treatment to be offered at relapse should be carefully evaluated. Interestingly, it has been reported that the longest prior lenalidomide treatment duration (>12 months) and IMiD-free interval (>18 months) could positively impact patients’ outcome (3), making the choice of a lenalidomide-sparing regimen of particular interest in this setting. On the bases of these premises, we performed a systematic review and a frequentist network meta-analysis in R [by using the netmeta package (4)] comparing direct and indirect evidence on the efficacy of seven different lenalidomide-sparing regimens (bortezomib-dexamethasone, VD; daratumumab-VD, DVD; carfilzomib-D, KD; daratumumab-KD, KdD; pomalidomide-VD, PVD; isatuximab-KD, IKD; selinexor-VD, SVD) in lenalidomide-exposed and lenalidomide-refractory patients, to provide statistical evidence to support clinical decision making