Triple-class refractory sounds like it would be referring to very late-line treatment; however, in the current paradigm, a patient who receives daratumumab plus bortezomib, lenalidomide, and dexamethasone (D-VRd) in the front line and progresses would be considered triple-class refractory.

Currently, we have several options for patients in this category. Clearly, BCMA-directed approaches represent a strong option here. I would also note that many of these patients may not have received alkylators, perhaps aside from a transplant, and I have found that the combination of carfilzomib, cyclophosphamide, and dexamethasone (KCd), in particular, is a good option, especially when there is refractoriness to bortezomib but not carfilzomib. The KCd regimen can be combined with daratumumab (D-KCd) as well.

Ultimately, we will find ourselves in a penta-refractory state. That is, unfortunately, patients will experience refractoriness to therapies targeting BCMA and CD38, as well as to immunomodulatory drugs (IMiDs), proteasome inhibitors, and alkylators. If patients have never had a transplant and if they are eligible, then that may be an option. I am not very optimistic about the selinexor-based combinations that are under study in this population, but, certainly, one could try those. In an attempt to better control this type of refractory multiple myeloma, sometimes we give a cycle of the VDT-PACE regimen, which is bortezomib, dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide, to try to reset the disease.

New and emerging treatments in this space include bispecific antibodies that target something other than BCMA, such as talquetamab (which targets GPRC5D) or cevostamab (which targets FCRH5). We might also consider the new cereblon E3 ligase modulators (eg, iberdomide and mezigdomide) and hope that they can overcome resistance to IMiDs.

Overall, we have an idea of how to proceed in the pathway, and we are happy that there are so many new options on the horizon. But there is clearly more work that needs to be done, so clinical trials at every stage are critical.

Today, triple-class refractory multiple myeloma refers to resistance to IMiDs, proteasome inhibitors, and anti-CD38 monoclonal antibodies. In the previous treatment era, patients would have had 5 or 6 prior lines of therapy before becoming triple-class refractory, but today, it is common to see patients who have had 1 or 2 prior lines of therapy and are already functionally triple-class refractory. This group of patients is rapidly growing and is very relevant to clinical practice.

BCMA-directed therapy is typically what we consider first right now for triple-class refractory multiple myeloma. This includes the BCMA-directed chimeric antigen receptor (CAR) T-cell agents idecabtagene vicleucel (ide-cel) and ciltacabtagene autoleucel (cilta-cel), as well as the BCMA-directed bispecific antibody teclistamab. The choice between a CAR T-cell therapy and a bispecific antibody depends on patient characteristics, the time frame of treatment, and the patient's ability to wait for additional treatment.

Beyond that, selinexor is typically used in combination with a proteasome inhibitor such as bortezomib or carfilzomib or in combination with an IMiD such as pomalidomide. There are phase 2 data showing that the combination of selinexor with these agents is effective even when patients are resistant to those partner drugs.

Venetoclax for the subset of patients with t(11;14) multiple myeloma is something that should be considered earlier in the disease course; however, for a patient in this subset who becomes triple-class refractory and has not already been exposed to venetoclax, that may be an option. 

There are also the new cereblon E3 ligase modulators, such as iberdomide and mezigdomide, which are available in the context of clinical trials. Monoclonal antibodies against other targets, such as GPRC5D or FCRH5, are also emerging. Cevostamab, which targets FCRH5, is available in clinical trials, and talquetamab, which targets GPRC5D, was recently granted accelerated approval by the US Food and Drug Administration for patients who have received at least 4 prior lines of therapy, including a proteasome inhibitor, an IMiD, and an anti-CD38 monoclonal antibody. 

Patients can become triple-class resistant or even penta-class resistant relatively quickly. It is notable that, when patients relapse after BCMA-directed CAR T-cell therapy, the use of a BCMA-directed bispecific T-cell engager can produce a durable response. GPRC5D CAR T or a GPRC5D bispecific T-cell engager can also produce durable responses after BCMA-directed CAR T-cell therapy. Additionally, there is some evidence that something may change with BCMA-directed CAR T-cell therapy, allowing for a renewed responsiveness to drugs that were ineffective prior to the CAR T-cell treatment.

The main message for me, though, is that additional research is still urgently needed. All 3 of us still quite frequently see patients whose multiple myeloma is, unfortunately, growing despite all of these new treatments. This highlights the need for improvements to the current treatments, including CAR T-cell therapies and bispecific T-cell engagers, and, hopefully, entirely new classes of agents that could attack alternative growth and survival mechanisms that multiple myeloma cells use. 

It is very exciting and most promising that we can effectively treat triple-class refractory multiple myeloma; however, the disease still recurs after these treatments, and there is an urgent need for the development of novel targeted and immune treatments.