Approvals Expand Multiple Myeloma Treatment Options

Several therapies for multiple myeloma have hit the market in recent years, including the monoclonal antibody daratumumab (Darzalex; Janssen). The FDA has now granted approval to two more—idecabtagene vicleucel (Abecma; ide-cel; Bristol Myers Squibb) and isatuximab-irfc (Sarclisa; Sanofi)—further expanding the tool kit for clinicians.

“It seems like we are getting drug approvals all the time now, which is great for patients,” says Natalie Callander, MD, of University of Wisconsin Carbone Cancer Center in Madison.

Treatment with idecabtagene vicleucel, a chimeric antigen receptor (CAR) T-cell therapy, involves collecting a patient's T-cells, engineering them to express a receptor protein that targets B-cell maturation antigen, and infusing them back into the patient. In the phase II KarMMa trial, which enrolled 128 patients who had already received at least three therapies, 94 patients (73%) responded to the therapy; 42 patients (33%) had a complete response.

“It's an extremely powerful treatment,” says Nikhil Munshi, MD, of Dana-Farber Cancer Institute in Boston, MA, lead author of the paper reporting the KarMMa trial's findings (N Engl J Med 2021;384:705–16). Of note, 33 patients (26%) were minimal residual disease (MRD)–negative after treatment. “That opens up a whole new area that we can achieve MRD negativity even at late stages of the disease,” he says.

One advantage of idecabtagene vicleucel, Callander says, is that patients can stop taking daily doses of lenalidomide or pomalidomide if it's successful. However, researchers don't yet know if the treatment can be curative, or whether a maintenance therapy could increase the duration of the response.

Idecabtagene vicleucel does have limitations, however. Its use is restricted to centers with expertise in administering CAR T-cell therapies so that side effects—potentially lethal cytokine release syndrome, for example—can be readily identified and treated. Plus, because collecting, modifying, and reinfusing the T cells can take about 4 weeks, the disease can worsen before treatment begins, Munshi says, adding that researchers should work to reduce that time to about 1 week.

Like daratumumab, isatuximab-irfc is a monoclonal antibody that binds selectively to an epitope of CD38, which is highly expressed on multiple myeloma cells. It induces apoptosis of tumor cells and activates immune effector mechanisms, such as antibody-dependent cell-mediated cytotoxicity.

In the phase III IKEMA trial, the 179 patients who received isatuximab-irfc plus carfilzomib (Kyprolis; Amgen) and dexamethasone had a 45% lower risk of disease progression or death at a median follow-up of 20.7 months than the 123 patients who received carfilzomib and dexamethasone.

“It looks like a terrific option,” Callander says, noting that daratumumab and isatuximab-irfc both target CD38 and have relatively few side effects. However, isatuximab-irfc might be preferred in some cases because it is less expensive and requires fewer doses early on. Isatuximab-irfc is taken weekly for the first month and then biweekly for the second month, whereas daratumumab is taken weekly for 2 months. Additional studies need to determine which patients are mostly likely to benefit from each of the approved drugs and to help clinicians choose the ideal sequence of therapies, Callander says.

Munshi says that the greater availability of agents for multiple myeloma has altered the conversation with new patients. “The whole outlook has changed,” he says. “Life expectancies are now 8 to 10 years plus and counting. It's becoming sort of a chronic disease, and patients can go about their life.” –Conor Gearin