How to Manage Patients with Lenalidomide-Refractory Multiple Myeloma

Abstract

Although lenalidomide-based combinations, such as lenalidomide plus a proteasome inhibitor or an anti-CD38 monoclonal antibody, improve the overall response rate, progression-free survival, and overall survival of patients with relapsed/refractory multiple myeloma (RRMM), there is a tendency to use these regimens as a frontline treatment. This strategy has led to the development of refractoriness early in the disease course, usually after the patient’s first treatment. Since lenalidomide-free regimens have so far shown limited efficacy in lenalidomide-refractory patients, there is an unmet need for other treatment options. In this review, we discuss the therapeutic options available to treat the general population of lenalidomide-refractory patients (mono, double and triple refractory) and the subpopulation of patients with other high-risk features such as renal failure, extramedullary disease, and high-risk cytogenetics. Moreover, new promising individual therapies and the possible impact of immunotherapy in RRMM patients are debated.

A real‐world retrospective–prospective analysis of efficacy and safety of combined ixazomib, lenalidomide, and dexamethasone in relapsed/refractory multiple myeloma: The northern Italy experience

“…[24][25][26] As a result, the vast majority are Len-exposed and, more often, Len-refractory as early as at first relapse, raising the issue of the optimal placing of this Len-based triplet. 16,17 We therefore conducted a retrospective/prospective analysis to assess the efficacy and safety of IRd in a realworld population of 106 patients treated in 21 centers in the North of Italy between January 2017 and May 2021.…”

“…However, an increasing proportion of MM pts, both transplant eligible and non‐transplant eligible, receive Len‐based first line regimens until progression 24–26 . As a result, the vast majority are Len‐exposed and, more often, Len‐refractory as early as at first relapse, raising the issue of the optimal placing of this Len‐based triplet 16,17 …”

“…This raises the issue of the feasibility of this Len-based treatment in previously Len-exposed or refractory pts and the optimal placing within the current therapeutic scenario. 16,17 In this perspective, we conducted an observational analysis of 106 RRMM pts treated with IRd between January 2017 and May 2021 in 21 centers in Northern Italy, with the aim to evaluate efficacy and safety of IRd in a real-world population including a significant proportion of Len-refractory pts (20.7%) in addition to Len-exposed, non-refractory pts (36.8%). The issue of rechallenge with this all-oral, Len-based, triplet regimen, might be especially relevant for the elderly population, where frailty and comorbidities limit the therapeutic options in the relapsed/refractory setting.…”

“…However, over the last few years, an increasing proportion of MM pts, both transplant eligible and non‐transplant eligible, receive Len‐based first line regimens until progression, with the result that the vast majority are Len‐exposed and, more often, Len‐refractory as early as at first relapse. This raises the issue of the feasibility of this Len‐based treatment in previously Len‐exposed or refractory pts and the optimal placing within the current therapeutic scenario 16,17 …”

Design, synthesis, and activity evaluation of 2-iminobenzimidazoles as c-Myc inhibitors for treating multiple myeloma

“…Multiple myeloma (MM), the second most common blood cancer, is a plasma cell malignancy frequently accompanied by hypercalcemia, immune dysfunction, and renal failure [ [1] , [2] , [3] ]. Despite the employment of various therapeutic methods, such as immunomodulatory agents, proteasome inhibitors, and autologous stem cell transplantation (ASCT), MM remains an incurable disease with nearly 160,000 new cases and 106,000 deaths annually [ 4 , 5 ].…”