New, Emerging Treatment Options for Patients With Multiple Myeloma

Image credit: freshidea | stock.adobe.com

During a presentation at the National Comprehensive Cancer Network Annual 2024 Conference in Orlando, Florida, speakers Natalie S. Callander, MD, professor of hematology, medical oncology, and palliative care, University of Wisconsin Carbone Cancer Center, and Shaji K. Kumar, MD, professor of medicine, Mayo Clinic Comprehensive Cancer Center, highlighted new treatment options for patients with multiple myeloma, including chimeric antigen receptor (CAR) T-cell therapy and bispecific antibodies.

Callander noted how CAR-T cell therapies and bispecific engagers have revolutionized the treatment for patients with multiple myeloma who have received multiple prior lines of therapy, which are most commonly used in lymphoma. For multiple myeloma, the target for bispecifics is the B cell maturation antigen (BCMA). Notably, teclistamab (Tecvayli; Janssen Biotech, Inc)—which was approved by the FDA about 2 years ago—quickly joined the armamentarium because of its efficiency and its efficacy in patients who received up to 5 prior lines of therapy. Further, teclistamab demonstrated a median survival of 11.3 months, which, according to Callander, is comparable with results presented in trials evaluating CAR T therapies.

Further, elranatamab (Elrexfio; Pfizer) is another BCMA-targeted drug with strong responses for patients. Callander said that patients who were in the groups that achieved complete responses (CRs) or very good partial responses (VGPRs) have yet to meet progression-free survival (PFS). Alternatively, talquetamab (Talvey; Janssen Biotech, Inc) targets GPRC5DxCD3 and was approved by the FDA over 1 year ago. Although the biologic significance of the treatment is relatively unknown, approximately 70% of participants—which includes patients who were on additional BCMA-targeted therapies and those who were not—in a study responded to the drug.

Regarding adverse events (AEs) associated with these therapies, Callander said that reports commonly include cytokine release syndrome, fever, changes in blood pressure, neurological symptoms that are either delayed or immediate (eg, confusion, cranial nerve palsy), among others. She also emphasized that, in CAR T therapies, there are rarer AEs that are of stronger concern compared to others. Hemophagocytic lymphohistiocytosis, or macrophage activation syndrome, was the most concerning AE and needs to be addressed when patients experience exuberant inflammation; however, Callander noted that this AE’s occurrence was rare in patients. Mucocutaneous toxicity AEs were specific to talquetamab, and resulted in dysgeusia-related weight loss in patients that were only able to be managed with dose reductions or dose holds.

Callander noted that currently, researchers are trying to determine what the best sequence is to use T-cell-redirecting therapies. She pointed to a small group of patients who had a BCMA bispecific prior to CAR T-cell therapy and said that these patients did not have strong survival outcomes, noting that most experienced about 5 months of benefit.

“I think we're just trying to figure out what to do. A lot of experts would say [patients should first be treated with] CAR T [therapies], and now that we have this new approval, that's probably going to happen,” explained Callander during the session. “And then maybe the bispecifics come in, maybe not a BCMA bispecific is the next consideration, but this is something that's ongoing and we're learning how to [better treat patients].”

According to Kumar, because of the high need for newer therapies future considerations for multiple myeloma treatment are currently in development and are showing promise in clinical trials. One of these potential treatments is iberdomide (CC-220; Bristol Myers Squibb), and like lenalidomide (Revlimid; Bristol Myers Squibb) and pomalidomide (Pomalyst; Bristol Myers Squibb), it is an oral, potent drug. Iberdomide is a CRBN E3 ligase modulator compound that co-opts CRBN to allow for the enhanced degradation of target proteins, such as Ikaros and Aiolos.

An initial single-arm trial looked at iberdomide with dexamethasone (Decadron; Pfizer)—of which about a third had highly-refractory disease and were refractory to lenalidomide and pomalidomide—demonstrated positive and durable responses to the combination regimen. Particularly, Kumar highlighted the fact that the regimen was oral and that it had mechanisms of action that did not overlap or interfere with each another. Further, they can be used in combination with other standard-of-care multiple myeloma therapies, such as bortezomib, and when response rates were as high as 40% to 60%.

In addition, Kumar discussed venetoclax (Venclexta; AbbVie Inc.), and although it isn’t currently approved by the FDA, it is frequently used as a therapy as well as in clinical trials. In initial studies, venetoclax has demonstrated efficacy in about 30% to 40% of patients with multiple myeloma, and when used in combination with dexamethasone, approximately 60% of patients responded even though many were refractory to other therapies.

“I think there's ongoing effort trying to develop biomarker assays that we can use in the clinic in order to identify the high-risk patients [as well as patients] who are going to benefit the most from venetoclax,” said Kumar during the session. “There are different therapies that are [currently] going through clinical trials, but clearly we have a lot of exciting therapies that are [in development].”

In the initial treatment of patients with multiple myeloma, Kumar emphasized that there are a lot of choices as far as individual drugs and combination regimens, but it is important to choose treatments that are tolerable and preferred by patients. Further, he emphasized the significance of not waiting when it comes the leveraging the newer therapies in patients—particularly the immunotherapies—and decisions should be made earlier on in the patient’s treatment.

“We don't want to wait until they get to that fourth line before we start thinking, ‘Oh, maybe this is a patient for CAR T-[cell therapy],’ and hopefully, that will change, [because] many of these therapies start moving on to the early lines of therapy, as we [know] with idecabtagene vicleucel (Abecma; Bristol Myers Squibb), [for example],” said Kumar during the presentation.

Reference

Callander, NS, Kumar, SK. Updates to the Management of Multiple Myeloma. Presented at: National Comprehensive Cancer Network Annual 2024 Conference; Orlando, Florida; April 5-7, 2024.