Multiple myeloma (MM) is a hematologic neoplasm characterized by a bone marrow (BM)-predominant proliferation of malignant plasma cells (MPCs) and overproduction of a monoclonal protein (M-protein), either as serum free light chains (sFLCs) or intact immunoglobulin. To date, despite its incurable nature, there have been increasingly successful treatment options to control the disease process (Kumar et al., 2017). Initial chemotherapy regimens combining alkylating agents (e.g., melphalan, cyclophosphamide, and carmustine) with prednisone or dexamethasone (Dex) were introduced in the latter half of the 20th century. Later on, traditional cytotoxic drugs gave way to the so-called “novel agents” such as immunomodulatory drugs (IMiDs; thalidomide, lenalidomide, pomalidomide) and proteasome inhibitors (PIs; bortezomib, carfilzomib, ixazomib) (Kyle and Rajkumar, 2014). Compared to historical reports of 8.5 months without treatment, first-line triplet (PI-IMiD-Dex) induction was associated with a median progression-free survival (PFS) of > 40 months, leading to its establishment as the standard-of-care for most patients with newly-diagnosed MM (NDMM) (Cowan et al., 2022).

During the late 2010 s, the advent of anti-CD38 monoclonal antibodies (mAbs; daratumumab [Dara] and isatuximab) allowed for further improvement in outcomes, with an overall response rate (ORR) > 90% being achieved in randomized controlled trials (RCTs) of Dara-based quadruplet therapy (Wudhikarn et al., 2020, Menon et al., 2021). Meanwhile, other drug classes were approved by the US Food and Drug Administration (FDA) and European Medicines Agency (EMA) for use in salvage settings, such as anti-SLAMF7 mAbs (elotuzumab) and selective inhibitors of nuclear export (selinexor) (Cowan et al., 2022, Costa et al., 2022). More recently, immunotherapy has really taken root with the approval of two B-cell maturation antigen (BCMA)-directed chimeric antigen receptor T-cell (CAR-T) therapies for relapsed/refractory MM (RRMM), idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), as well as the anti-BCMA/CD3 bispecific antibody (BsAb) teclistamab (Munshi et al., 2021, Berdeja et al., 2021, Moreau et al., 2022).

Response rates continue to rise and, in turn, patient outcomes continue to improve. While the 5-year survival of MM patients was 26.3% in 1975, this rate increased to 57.9% for patients diagnosed between 2012 and 2018 (National Cancer Institute, 2020). Overall survival (OS) is expected to continue rising as more anti-myeloma drugs continue making their way into the clinic. Along with the improvement in responses, there has been a general trend towards improvement in the toxicity profile. Akin to using a fine scalpel, immunotherapies directed to specific tumor-associated antigens can more precisely hijack the disease, ultimately leading to more on-target activity and less off-target activity (Cho et al., 2021).

Despite the appeal of such therapeutic finesse, there are clinical scenarios that may benefit from a blunter approach, either to achieve urgent debulking or to synergistically deepen responses to novel agents. Furthermore, low-income and lower middle-income countries still lag behind in the access to the full spectrum of treatment options currently available and depend heavily on alkylating agents for MM management. For instance, melphalan/prednisone (MP) remains the therapeutic backbone in Sub-Saharan Africa (Nwabuko, 2018). Even in upper middle-income countries, a considerable proportion of prescribed regimens are alkylator-based, as novel agents are often not covered by public health care systems (Vargas-Serafin et al., 2021). In a retrospective cohort of MM patients seen between 2008 and 2015 at one of 30 centers in Argentina, Brazil, Chile, Colombia, Mexico, Panama, and Guatemala, traditional cytotoxic chemotherapy (with or without steroids) was the treatment of choice in 10.2% of NDMM patients and 23.4% of individuals at first relapse (Hungria et al., 2020).

In light of the increasing utilization of antigen-targeted modalities (e.g., mAbs, BsAbs, and CAR-T) worldwide, the role of classical alkylator-based chemotherapy in MM has become a topic of debate. This review aims to explore the historical, current, and future uses of alkylators in anti-myeloma therapy, providing a broad insight into the various applications of these agents in clinical practice (whether in resource-rich or resource-constrained settings) and ultimately answering the following question: given the recent advances in anti-myeloma therapy, is there still a place for alkylating agents in modern-day MM management?