Functional cure and long-term survival in multiple myeloma: how to challenge the previously impossible

Multiple myeloma (MM) is a heterogeneous disease with survival ranging from months to decades. The goal of 'cure' remains elusive for most patients, but has been shown to be possible, with durable remission and a transition to a plateau phase (analogous to monoclonal gammopathy of uncertain significance/smoldering myeloma). In this review, two representative cases set the stage to illustrate how this might be possible and what still needs to be determined to achieve functional disease control over a prolonged period. Several developments have emerged, such as improved diagnostics including the definitions and use of SLiM-CRAB criteria and measurable residual disease (MRD) with whole-genome/single-cell sequencing as well as other correlates to better understand disease biology. These advances enable earlier detection, more accurate risk stratification and improved personalized treatment strategies by facilitating analysis of genetic alterations and clonal heterogeneity. Whole-genome sequencing may also identify driver mutations and modes of resistance to immunotherapies as well as other targeted therapies. Today, induction with a CD38 antibody, proteasome inhibitor, immunomodulatory drug, and dexamethasone, potentially followed by autologous stem cell transplantation and lenalidomide maintenance, can be considered standard of care for transplant-eligible (TE) patients with newly diagnosed MM (NDMM). That prolonged disease control and functional cure can be achieved in non-transplant-eligible (NTE) patients is currently emerging as a distinct possibility: data from phase III trials that incorporate a CD38 antibody into the treatment of NTE NDMM patients demonstrate impressive MRD negativity rates that appear sustained over several years. While the long-term durability of chimeric antigen receptor T cells, bi-specific antibodies and other immunotherapies are being evaluated, several clinical trials are now investigating their role in frontline treatment for TE and NTE patients. These trials will address whether chimeric antigen receptor T-cell therapy will replace autologous stem cell transplantation and whether such immunotherapies will represent a truly curative option. We conclude that while cure remains elusive, the concept of operational or functional cure provides a new benchmark to strive for and is an emerging area of active and potentially achievable clinical research for MM.