In oncology, historically and across different malignancies, there have been varying strategies regarding sequencing, combination therapy, and the aggressiveness of first-line treatment. One model or approach has been to reserve highly effective therapies for use in later lines (eg, planning ahead for the high likelihood or inevitability of recurrence). In fact, some 15 years ago, the desire to keep a treatment in reserve, I believe, fueled arguments against using lenalidomide, bortezomib, and dexamethasone (the RVd regimen) in patients with newly diagnosed multiple myeloma. At that time, clinicians were concerned about not having effective treatment options when their patients relapsed. 

We have been fortunate in multiple myeloma in that, at least over the last decade, we have always had a pipeline of drugs in the approval process geared toward the treatment of relapse. Therefore, I do not like the idea of saving therapies for later. That is, I think that every patient with multiple myeloma should, at some point in the course of their disease, have access to immunomodulatory drugs, proteasome inhibitors, and CD38- and BCMA-directed therapies. My approach is to use the most efficacious treatment early, when possible. 

That said, we know that therapeutic attrition is a big problem. For example, in the large study by Fonseca et al, among patients who did not receive autologous stem cell transplantation, 57% received only 1 line of therapy. When a patient has not been availed of all of these treatments, it may be that they are not getting to an agent because they are too frail or that the sequence was not optimized to allow them to have access. I believe that we should put our best feet forward early and at every point possible to attain the longest remissions possible. That is one of the reasons why I advocate for transplantation early, in the first remission, because of the 2-year improvement in remission duration. 

Regarding sequencing therapies that employ the same target, questions such as the following arise: How do we use a second BCMA-targeted therapy after progressing on a first BCMA-directed agent? At this time, data suggest that giving a BCMA-directed chimeric antigen receptor (CAR) T-cell agent first does not appear to induce significant resistance to a T-cell engager down the road. In contrast, when a T-cell engager is used first and is then switched to a BCMA-directed CAR T-cell agent, we are more likely to have a lower response rate and a shorter duration of remission, and we may actually lose the target. 

As previously noted, we are fortunate with our pipeline of agents that are in development for relapsed multiple myeloma. As we look to the future, new targets are in development, such as GPRC5D. This is the target of the bispecific antibody talquetamab, which has demonstrated activity in patients who had heavily pretreated relapsed or refractory multiple myeloma that had progressed with established therapies (a median of 6 previous lines of therapy). This target is also being pursued using a CAR T-cell construct.