New phase 3 data are changing how multiple myeloma (MM) is treated, with newer immunotherapy-based combinations helping patients achieve deeper and longer-lasting responses in both frontline and relapsed/refractory settings. As our experts note, first relapse represents an important opportunity to set the best path for patients with MM to achieve a deep durable response and potentially reduce the need for multiple later lines of therapy.

Overall, we are doing so much better with some of these immunotherapeutic strategies in relapsed/refractory MM. We have many therapies that are already US Food and Drug Administration (FDA) approved as single agents and are now starting to be approved as combination strategies.

Recent long-term data from the MajesTEC-3 trial, which investigated the bsAb combination of teclistamab and daratumumab, demonstrated an improved 36-month progression-free survival (PFS) compared with some of the conventional triplets (83.4% vs 29.7%, respectively). Beyond bsAbs, we have data from the DREAMM-7 trial supporting the use of the ADC belantamab mafodotin in combination with bortezomib and dexamethasone (BVd), which has shown an overall survival benefit compared with the anti-CD38 monoclonal antibody (mAb) daratumumab in combination with bortezomib and dexamethasone (DVd; 84% vs 73%, respectively).

Moreover, we have some interesting drug products coming down the pike, specifically the new investigational CELMoDs iberdomide and mezigdomide. From the recent SUCCESSOR-2 phase 3 data, we see that even in a heavily pretreated population, including patients who were refractory to anti-CD38 antibodies and lenalidomide, the investigational combination of mezigdomide plus carfilzomib and dexamethasone significantly improved PFS, extending median PFS from 8.3 to 18 months. These results reinforce the importance of using effective combinations earlier in relapse and is another example of how the treatment landscape for relapsed MM is evolving. Finally, several ongoing studies are also investigating the efficacy and safety of CELMoDs compared with conventional triplets, including the phase 3 SUCCESSOR-1 trial, which is looking at the potential role of the investigational combination of mezigdomide plus bortezomib and dexamethasone in earlier relapse settings.

It is an exciting time for treatment advancements in MM, and current phase 3 trials are really demonstrating the importance of response. In the past, treatment response was considered a complete remission. Now we are seeing measurable residual disease (MRD) negativity sustained for more than 1 year with many of these new drug combinations. I think that immunotherapy, whether it is a CAR T-cell therapy or a bsAb, is producing sustained MRD negativity. It is really a step forward, and it is changing the way we look at MM.

We know that, biologically, patients who achieve MRD negativity tend to have better PFS and overall survival. So, rather than treating it as a chronic disease and then dealing with a second relapse, we need to get it right at the first relapse. The better we do at the first relapse, the better the patient will do in terms of quality and length of life. Take, for example, CAR T-cell therapy. CAR T-cell therapy is not just an option; it represents a window of opportunity. If you do not treat your patient at the right time, you are not serving your patient. They may develop aggressive disease, be unnecessarily exposed to many agents, and/or become refractory and cytopenic.

Overall, all these critical phase 3 trials show the importance of biology- and MRD-driven treatment decisions. I think that it is time to believe in biology, immunotherapy, and MRD.

The advent of immunotherapies and the effectiveness of some of the frontline therapies have really changed how we think about MM. Until a few years ago, treatment decisions had relied partially on the old paradigm used for metastatic breast cancer: one line of therapy after the next, after the next, and so forth. In fact, we still see patients in the clinic with 6 to 10 or more lines of therapy.

Moving away from this paradigm to look at combination therapy, we have updated results from the PERSEUS clinical trial that showed a very long duration of disease control with the CD38-directed mAb daratumumab in combination with bortezomib, lenalidomide, and dexamethasone (D-VRd) as frontline therapy in transplant-eligible patients. By some statistical predictions that are yet to be confirmed, the PFS could be up to 17 years. We see equally excellent results with quadruplet combinations in patients who are transplant ineligible. To me, there is no doubt that these immunotherapies will be part of frontline treatment for MM in the future.

Our mindset that most patients with MM will only need 1 or 2 lines of therapy has to change. However, I think that the world of MM is rapidly changing. We currently have some very exciting investigational compounds in the pipeline (eg, CELMoDs, targeted protein degraders, and P300 inhibitors), and, as things continue to evolve, fewer patients may need third- and fourth-line therapies. The bar for what we consider effective will be very high. For clinicians in the community, early connection and referral to partner academic centers are critical. As Dr Abonour said, particularly in that first relapse, it is a second chance—a second chance to have a very durable response. So, doing it the right way is so important.