The treatment of multiple myeloma (MM) has been revolutionized over the past three decades, first with the introduction of high-dose melphalan and autologous stem cell transplantation (ASCT) for younger, fitter patients, and then with the development and approval of 20 novel agents and multiple combination regimens within the past 22 years. From a historically poor prognosis, with a median overall survival of only approximately 3-5 years, the outlook for patients with newly diagnosed MM has been transformed by these new targeted treatment options, with median overall survival now more than 10 to 15 years for younger transplant-eligible patients and more than 7 to 10 years for older transplant-ineligible patients. Critical developments in evolving the MM treatment paradigm have included the preclinical evaluation and widespread introduction of novel drug classes such as the proteasome inhibitors (bortezomib, carfilzomib, and ixazomib), the immunomodulatory drugs (thalidomide, lenalidomide, and pomalidomide), and the CD38 and SLAMF7 monoclonal antibodies (daratumumab, isatuximab, elotuzumab), which together now form the backbone of treatment in the newly diagnosed and relapsed/refractory settings in highly active rational combination regimens. Indeed, first highly active triple and then quadruplet regimens based on lenalidomide, bortezomib or carfilzomib, and dexamethasone with the addition of daratumumab or isatuximab, are emerging as the standards of care for transplant-eligible and transplant-ineligible patients with newly diagnosed MM, offering high rates of minimal residual disease (MRD)-negative responses and prolonged clinical outcomes; in this context, the role of high-dose melphalan and ASCT has evolved, with highly effective induction therapy enabling deferred- or non-transplant approaches for selected transplant-eligible patients in the upfront setting, now further enhanced by the use of MRD.
Furthermore, building on our knowledge of MM cell biology, a wide range of additional novel signalling pathways and antigens have been explored and targeted through the development and approval of agents including the histone deacetylase inhibitor panobinostat, the XPO1 inhibitor selinexor, the peptide–drug conjugate melflufen, B-cell maturation antigen (BCMA)-targeting therapies such as the antibody–drug conjugate belantamab mafodotin, the CAR T-cell therapies idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel, and the bispecific antibodies teclistamab, elranatamab, and linvoseltamab, and the G protein–coupled receptor class C group 5 member D (GPRC5D)-targeted bispecific antibody talquetamab. A wealth of additional options are also currently under investigation, including the cereblon E3 ligase modulators iberdomide and mezigdomide, CAR T-cell therapies and bispecific antibodies targeting novel MM-associated antigens, and novel targeted therapies exploiting immune-based mechanisms and specific signalling pathways of importance for MM cell survival. Together, these developments have converted our extensive exploration and translation of MM cellular pathobiology and mechanisms of resistance into an armamentarium of therapeutic options for today’s physicians and providers, and in doing so have transformed outcomes for our patients with this highly complex and previously incurable disease.
