Multi-Refractory MM: After Immunotherapy, What?

NEW YORK — When patients with multiple myeloma (MM) relapse following chimeric antigen receptor (CAR) T-cell therapy, bispecific antibodies (BsABs), or both, likely salvage options remain that are being overlooked, including a second course of immunotherapy.

Two independent experts, addressing this issue at the 2024 Lymphoma, Leukemia & Myeloma Congress, offered several practical recommendations for eliciting a therapeutic response after patients with multi-refractory MM have failed everything. One approach they endorsed was allowing patients to recover from T-cell exhaustion.

“We used to think that as soon as multiple myeloma patients progress on a CAR T-cell therapy, it was sort of game over,” said Joseph Mikhael, MD, professor, Translational Genomics Research Institute, City of Hope Cancer Center Phoenix, Phoenix, Arizona.

“But I think we are seeing many ways to salvage these patients, including going back to a CAR T product,” said Mikhael, who also serves as the chief medical officer of the International Myeloma Foundation.

Now that CAR T cells and BsABs are widely available, Mikhael warned that there will be a growing need for other strategies to offer when these therapies fail.

A similar point was made by Jorge Monge, MD, an assistant professor, Division of Hematology and Medical Oncology, Weill Cornell Medicine, New York City. He largely focused on newer therapies with the potential to provide salvage opportunities in advanced refractory MM, but he pointed out that one application might be to permit T-cell recovery after exhaustion following B-cell maturation antigen (BCMA)–targeted therapies.

The two talks covered some of the same ground. Both, for example, discussed a potential role for the exportin 1 (XPO1) inhibitor selinexor (Xpovio) in the multidrug refractory setting. In combination with bortezomib and dexamethasone, selinexor was approved in 2020 for treatment-experienced patients but is often overlooked in late-stage disease.

As a strategy to elicit a response following BCMA-targeted therapies, both Mikhael and Monge cited data showing selinexor to be active and that side effects are relatively well managed if antiemetics are offered preemptively to control nausea, one of its most common side effects.

Monge also talked about the promise of cereblon E3 ligase modulatory drugs (CELMoDs) that are now in clinical trials. These drugs, such as mezigdomide and iberdomide, both of which are in advanced stages of clinical testing, are similar to the immunomodulatory agents lenalidomide and pomalidomide. However, their greater potency does not appear to substantially increase risk for adverse events, according to Monge.

CELMoDs Active After CAR T-Cell Therapy

Most importantly, from the standpoint of their potential role in multidrug-refractory MM, both mezigdomide and iberdomide have so far shown substantial activity in patients previously exposed to BCMA-targeted therapies, according to Monge. Although the data have been generated in small numbers of patients, he reported that objective response rates have ranged from 37% to 50%.

These rates in treatment-experience patients are lower relative to those achieved in patients with no prior exposure to BCMA-targeted drugs, but Monge said that the durations of response, exceeding 6 months in some studies, might provide enough time for the T-cell recovery needed for a second course of CAR T-cell therapy.

There are other promising therapies on the horizon relevant to controlling multidrug refractory MM, including the likely return of the antibody-drug conjugate belantamab mafodotin (Blenrep). This drug was withdrawn in 2022, when the initial findings from the DREAMM-8 trial failed to show an advantage on the primary endpoint of progression-free survival (PFS) over pomalidomide, bortezomib, and dexamethasone. Now, with longer follow-up, a recently published study has shown a PFS advantage, revising interest in this therapy.

The reintroduction of belantamab mafodotin “might take a year or more” to find its way through the approval process, but Mikhael said that “it is probably coming.”

Many of the newer MM drugs, including bispecifics that engage proteins on the surface of the myeloma cell other than BCMA, such as G protein–coupled receptor family C group, might provide alternatives to BCMA-targeted therapies in late stages of disease, but at least some newer drugs, as well as existing drugs in combinations, might play an important role in refractory MM by restoring BCMA as a target.

“The BCMA target is not easily lost, and I think we can leverage it more than once,” Mikhael said.

This potential, which Mikhael acknowledged is mostly supported with relatively small sets of data, involves “a lot of question marks, a lot of maybes,” so the strategies are hard to compared. However, the “incredible evolution in multiple myeloma therapy” over the past few years is not necessarily linear, according to Mikhael.

Recycling MM Therapies Deserves Consideration

In other words, CAR T cells and BsABs are not the last stop in the available lines of therapy for MM. The next best therapy is dependent on numerous considerations, including prior therapy exposure, but Mikhael pointed out that many patients in advanced stages have not been exposed to therapies known to be active or are not being considered for therapies to which they were exposed but are not necessarily resistant.

Monge made similar comments. He agreed with Mikhael that clinicians faced with a patient with multitherapy-refractory MM might forget about the XPO1 inhibitor selinexor, the alkylating agent bendamustine, or even the B-cell lymphoma 2 inhibitor venetoclax.

Any of these agents alone or in combination could be considered to “give the patient some time to improve” T-cell function, Monge said.

This approach will have even more promise if better assays of T-cell function become available, Mikhael said. Although he explained that T-cell exhaustion is clearly one of the reasons that CAR T-cell therapies stop working, this cannot be measured accurately at this time.

“Better T-cell assays may help,” he said.

Mikhael reported financial relationships with Amgen, Bristol Myers Squibb, Janssen Pharmaceuticals, Karyopharm Therapeutics, Sanofi, and Takeda. Monge disclosed ties with Bristol Myers Squibb and Karyopharm Therapeutics.

Ted Bosworth is a medical journalist based in New York City.