As treatment options continue to expand for relapsed/refractory multiple myeloma (RRMM), selecting later-line therapy has become increasingly complex. Treatment sequencing, target selection, and patient- and disease-related factors can help guide the use of CAR T-cell therapies, bsAbs, and ADCs.

In early RRMM, we have an ever-increasing number of options: CAR T-cell therapies to bsAbs to ADCs. The problem is that we have very limited data on the optimal sequence.

Among the 3 options, CAR T-cell therapy has the single best progression-free survival (PFS) based on results from the CARTITUDE-1 clinical trial of approximately 3 years in heavily treated patients, with one-third of patients not having relapsed for 5 years. We have not attained a median PFS or possible cure fraction yet from CARTITUDE-4, but I think that those outcomes are going to be even better, as multiple studies are demonstrating better outcomes when these therapies are used earlier in the disease course, with better T-cell health and less genomically complex MM. However, CAR T-cell therapy is associated with high-grade cytokine release syndrome (CRS), which is not well tolerated in patients with frailty who have comorbidities. You also want to consider whether the patient has rapidly progressive/bulky disease, since such individuals often experience worse safety and efficacy profiles. Lastly, CAR T-cell therapies are narrowly available compared with other therapies; patients must have access to an academic center to receive these treatments. Currently US Food and Drug Administration (FDA)–approved CAR T-cell therapies for RRMM include BCMA-directed idecabtagene vicleucel and ciltacabtagene autoleucel. Other types are being investigated to improve efficacy, safety, and access.

My next consideration would be bsAbs. These agents are off the shelf and do not have the access constraints of CAR T-cell therapies. Four bsAbs are currently approved by the FDA for RRMM based on single-arm accelerated approval studies, including 3 BCMA-targeted bsAbs (ie, teclistamab, elranatamab, and linvoseltamab) and 1 GPRC5D-targeted bsAb (ie, talquetamab). In the phase 3 MajesTEC-3 trial, teclistamab plus daratumumab showed a significant 36-month PFS benefit over standard-of-care regimens (daratumumab, pomalidomide, and dexamethasone [DPd regimen] or daratumumab, bortezomib, and dexamethasone [DVd regimen]). We also recently saw positive phase 3 PFS and overall survival data for teclistamab monotherapy vs standard-of-care pomalidomide, bortezomib, and dexamethasone or carfilzomib and dexamethasone (PVd/Kd) in the MajesTEC-9 trial. Additionally, we recently saw positive PFS and overall survival trends in the phase 3 MonumenTAL-3 trial of talquetamab plus daratumumab (with or without pomalidomide) vs standard-of-care options. As of March 2026, teclistamab plus daratumumab received FDA approval based on MajesTEC-3, while MajesTEC-9 and MonumenTAL-3 remain investigational for their respective earlier-line treatment strategies.

Notably, there are not any absolute contraindications for bsAbs, but I do think that patients with bulky disease can experience higher-grade CRS with these agents, and, more importantly, I worry about infection, which is among the most common adverse events that are observed with BCMA-targeted bsAbs, particularly respiratory infections. Immunoglobulin replacement is critical to prevent these infections while on BCMA-targeted bsAbs and likely for at least 6 months after stopping the bsAb. The GPRC5D-targeted bsAb does not carry the same degree of infection risk/need for immunoglobulin replacement, but bsAbs are associated with other adverse events, including oral toxicities (eg, dry mouth, loss of taste, and difficulty swallowing).

ADCs are another great off-the-shelf option for RRMM. Belantamab mafodotin is the only ADC that is FDA approved in combination with bortezomib and dexamethasone (BVd regimen) for RRMM in patients who have received 2 or more prior lines of therapy. ADCs are associated with ocular toxicity, but they do not carry the CRS and immune effector cell–associated neurotoxicity syndrome issues that bsAbs have. Overall, I think that ADCs are particularly useful for older patients with more frailty and comorbidities who are not willing or able to go to an academic center for treatment, patients who have infection risks and are not ideal for BCMA-targeted bsAbs, and/or patients who want less frequent long-term dosing of belantamab and intravenous immunoglobulin supportive care.

The question is: How do we sequence these therapies? Every data set has shown that any targeting of BCMA adversely affects the PFS of the next BCMA-targeted agent, although the caveats are that there are few patients in these data sets and that patients were receiving bsAbs and ADCs until progression. That said, given the costs and logistics of CAR T-cell therapy, I think that we should treat with CAR T-cell therapy first to provide patients with the longest treatment-free interval and quality-of-life benefits. And if we target BCMA by 1 modality, we should probably move to another target second line. Even when we treat with a BCMA-targeted CAR T-cell therapy first, we still see a drop-off in PFS when patients are treated second line with teclistamab. This has not been observed to the same extent with the GPRC5D-targeted therapy talquetamab. However, even when we switch the target (eg, teclistamab to talquetamab), there are still consequences. I overcome this by combining talquetamab with other agents such as daratumumab and/or pomalidomide. This is based on results from our TRIMM-2 study, in which talquetamab plus daratumumab resulted in encouraging PFS, even in bsAb-refractory patients.

As clinicians, I know that we are worried about treatment down the road for RRMM, but not all patients get to that end line of therapy. So, it is important to ensure that, at each juncture requiring a treatment change, we pick the best possible option at that moment.