As patients with multiple myeloma (MM) receive more effective therapies earlier in their treatment journey, selecting subsequent therapy has become increasingly complex. Our experts discuss why treatment decisions should focus on drug class refractoriness rather than line of therapy and how emerging immunotherapies and biomarker testing may shape future clinical practice.

In MM, quadruplet therapy consisting of an anti-CD38 monoclonal antibody, a proteasome inhibitor, an IMiD, and dexamethasone is being used more up front, so a large majority of patients with MM are truly TCR by the time they have their first—and almost definitely by the time they have their second—relapse. The good news is that newer therapies have completely revolutionized this space (ie, primarily CAR T-cell therapy, bsAbs, and ADCs, specifically belantamab mafodotin). I really see a place for all 3 of these therapy options.

We have consistently seen strong data when comparing these strategies with triplet therapy. Whether you look at the relative difference between the immunotherapy and the triplet or the absolute outcomes achieved with CAR T-cell therapy, the bsAb teclistamab, or belantamab mafodotin in combination with pomalidomide and dexamethasone, we are seeing remarkable outcomes. In some studies of these approaches, progression-free survival has exceeded 3 years, something that has not historically been seen in the early relapse setting. Once someone with MM becomes TCR, we are not going to get a lot out of those triplets, so I think that it is wise to introduce these other therapies earlier rather than later. In other words, do not save the best for last.

We have also gotten better at managing side effects. As our experience has evolved, we have gained a better understanding of some of the toxicities associated with CAR T-cell therapy, including how to reduce the risk of cytokine release syndrome (CRS) and even the late neurological toxicities that are often very concerning. Similarly, for bsAbs, we have learned to use them in ways that not only reduce dosing frequency (resulting in fewer clinic visits) but also lower the risk of infection. There may even be an opportunity for fixed-duration therapy, allowing patients to stop treatment at a certain point instead of continuing indefinitely. Additionally, for ADCs, we have seen a dramatic reduction in eye-related adverse events by administering the drug less frequently.

There is still an ongoing evolution, and I am not going to pretend that we have figured it all out. However, we have come a long way, and these advances have made what may seem like an intimidating treatment approach in the community considerably more manageable.

We need to move away from lines of therapy to classes of drugs. Many of the pivotal immunotherapy studies enrolled patients with 5 or 6 prior lines of therapy. However, as we move more of these therapies into the frontline setting, it raises an important question: What happens when those patients eventually relapse? Many will now be exposed to quadruplet therapy and become not only lenalidomide refractory but also double refractory to lenalidomide and an anti-CD38 monoclonal antibody.

We already know from multiple randomized phase 3 studies that these patients with MM have a dismal prognosis. Across studies such as KarMMa-3, CARTITUDE-4, MajesTEC-9, and SUCCESSOR-2, many patients were double refractory to lenalidomide and daratumumab, and outcomes with standard-of-care regimens remained limited. However, the same studies have consistently demonstrated better response rates, longer progression-free survival, and improved overall survival for immunotherapy compared with standard-of-care regimens.

The KarMMa-3, CARTITUDE-4, MajesTEC-9, and SUCCESSOR-2 studies also highlight the deep learning curve that is involved. For example, we now know that it is important to refer patients early for CAR T-cell therapy and that early supportive care is essential for those receiving any type of BCMA-directed therapy. On the one hand, we have these amazingly potent therapies, but how do we manage treatment-related toxicities such as CRS and immune effector cell–associated neurotoxicity syndrome? Overall, I do not think that Risk Evaluation and Mitigation Strategy (REMS) requirements should be viewed as a barrier to the early administration of these therapies. In fact, with bsAbs and CAR T-cell therapy, higher disease burden is associated with worse outcomes, including more high-grade CRS and less efficacy.

We often think that we know which therapies to save for later lines, but the reality is that the data do not support this approach. We should not delay our most effective therapies in the hope of saving them for later lines. In the end, close collaboration with academic centers and proactive treatment planning can help ensure that patients with MM receive immunotherapy before their disease becomes clinically “explosive.”

For patients with MM who are TCR, I think that you should absolutely go with BCMA-targeted therapy next. That could be an ADC (eg, belantamab mafodotin plus bortezomib or pomalidomide and dexamethasone), CAR T-cell therapy (eg, ciltacabtagene autoleucel or idecabtagene vicleucel), or teclistamab, which is a TCE, with other BCMA TCEs likely to be approved by the US Food and Drug Administration (FDA) soon. As Dr Mikhael noted, patients with MM can now become TCR as early as the second line, and many are by the third line. I also think that talquetamab will continue moving into earlier lines of therapy.

We also have additional therapies on the horizon. For example, anitocabtagene autoleucel, a different BCMA-directed CAR T-cell therapy, will hopefully be FDA approved by the end of 2026. It may not initially be available in the second- or third-line setting, but we certainly hope to move it there. The trispecifics also look promising. It may be that the trispecific approaches, whether they are CAR T-cell or TCE therapies targeting both BCMA and GPRC5D, will become the standard of care because some patients have MM that expresses more of 1 protein than another. Targeting both initially could make it more difficult for the MM cell to escape through mutation or target loss—at least that is what we all hope.

I think that we need to encourage clinicians to use predictive genomic tests, which are becoming more clinically available. For patients with MM who relapse after prior BCMA- or GPRC5D-directed therapy, it is worth doing these tests, some of which can now be performed using peripheral blood rather than a bone marrow biopsy. If the patient has a GPRC5D mutation or a BCMA mutation or deletion, that can help guide treatment decisions in 2 ways. First, you get to a more effective therapy more quickly, and, second, you save yourself the toxicity of a drug or combination that the patient’s MM is not going to respond to. Up until now, we have largely selected therapy empirically based on what else the patient has not yet had and what we think is going to be best. I think that we need to move away from that approach and let biomarkers and the biology of the MM guide our treatment decisions.