The multiple myeloma treatment paradigm is evolving in a number of different ways, and this has become particularly apparent over the last few years. The first major paradigm change is that we are entering an era in which we are willing to start therapy early to prolong progression-free survival (PFS) and overall survival (OS). With developments such as the revised diagnostic criteria, the earlier identification of higher-risk smoldering multiple myeloma, and randomized clinical trials on the treatment of smoldering multiple myeloma, we are going to see more and more patients starting therapy earlier at the high-risk smoldering multiple myeloma stage in order to prolong PFS and OS.

The second change relates to the advent of immunotherapy, first with monoclonal antibodies and then, more recently, with chimeric antigen receptor (CAR) T-cell and bispecific antibody therapies. Monoclonal antibodies such as daratumumab, isatuximab, and elotuzumab have really helped patients with multiple myeloma, and daratumumab is now used in both the newly diagnosed and the relapsed/refractory settings. But now we are also using CAR T-cell therapy and bispecific antibodies. Currently, there are 2 US Food and Drug Administration–approved CAR T-cell therapies for adult patients with relapsed/refractory disease after at least 4 lines of therapy: idecabtagene vicleucel and ciltacabtagene autoleucel, both of which have shown PFS and OS benefits in heavily pretreated populations. All of these therapies have changed how we approach relapsed/refractory multiple myeloma, and they will affect how we treat patients with earlier-stage multiple myeloma in the near future. 

Third, the approach to autologous stem cell transplantation has been shifting. Although transplantation is still an important tool for many patients, it appears that there are subsets of patients who can delay transplant and still attain the same OS benefits. Now, if you have a choice between doing a transplant or not doing a transplant at all, it is important to understand that transplantation will provide improved OS. This is shown in the data from the early randomized trials conducted by the Intergroupe Francophone du Myélome (IFM) and the Medical Research Council groups and from more recent trials, including the EMN02/HO95 and the FORTE trials. However, with regard to the timing of transplant, data from the DETERMINATION and the IFM 2009 trials suggest similar OS rates among patients in whom transplantation is delayed and those who undergo early transplantation, but the median PFS is shorter with a delayed transplant approach.

Although OS is similar in the IFM 2009 and the DETERMINATION trials, we tell our patients that there are many reasons why we generally prefer early transplantation. First, individuals with high-risk disease clearly benefit from earlier transplantation. Second, for those who are willing to undergo a transplant but may wish to wait for relapse to do so, it is important to note that sometimes things happen in the interim and that a patient who might have been fit enough for transplantation in previous years may not be a candidate at the time of relapse. 

Standard-risk patients who have other important life concerns and/or quality-of-life, caregiver, or family life issues might prefer to undergo transplantation at first relapse. What is often not talked about, beyond OS benefit, is that a transplant changes a patient’s life. It may not be an option for someone who is in a caregiving role, for instance, to take time off to become a transplant patient and leave the caregiving to someone else.

Finally, with the availability of multiple newer therapies, there are now more options for tailoring the treatment approach to the individual patient’s wishes and priorities. We must be cognizant of our patients’ values regarding the trade-offs between treatment efficacy and toxicities. We are now using minimal residual disease assessments not only to escalate therapy for those who need it but also to identify patients who may be able to deescalate or stop therapy to pursue a better quality of life.