Clinical Challenges: Staying Up to Date on Immunotherapy in Multiple Myeloma

When it comes to the clinical application of immunotherapy for the treatment of patients with newly diagnosed or relapsed/refractory multiple myeloma, questions remain.

“Last year I think one of the main questions that clinicians had was whether patients should be getting an anti-CD38 antibody,” said Faith E. Davies, MD, of NYU Grossman School of Medicine in New York City. “We can say now that yes, they should, but which one is better? We don’t yet have the answer.”

There are currently two anti-CD38 monoclonal antibodies approved by the FDA for the treatment of multiple myeloma. Daratumumab (Darzalex) is approved in combination with other therapies in both newly diagnosed and relapsed/refractory disease. Isatuximab (Sarclisa) is currently only approved in relapsed/refractory disease.

“At ASH [the American Society of Hematology annual meeting] there were a lot of data demonstrating how isatuximab could be used in the newly diagnosed setting,” Davies told MedPage Today. “The assumption is that at some point soon Sanofi will file [for approval] in this setting.”

The German GMMG-HD7 trial looked at isatuximab in combination with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (RVd), finding extremely good responses, she noted, including more minimal residual disease-negative responses compared with RVd alone.

An Australian phase II study tested a response-adapted approach in which isatuximab was added for transplant-ineligible patients with newly diagnosed disease with inadequate response to lenalidomide and dexamethasone. This approach was safe and effective, inducing very good responses, Davies said. However, the study did not have a control arm for comparison.

If isatuximab gains approval for newly diagnosed patients, clinicians may have to choose which agent to use first. Theoretically, they each have a different mechanism of action, Davies pointed out. In addition, daratumumab can be given subcutaneously or intravenously and isatuximab is intravenous only. Side effect profiles are also very similar.

“It is difficult to compare these drugs head-to-head as they have not been compared in the same patient population,” Davies explained. “One can’t really say which is better. All we can tell our patients is that they should be given a CD38 antibody at some point and whichever is available or the physician is more comfortable giving should be the one used.”

The IgG1 monoclonal antibody elotuzumab (Empliciti) is another immunotherapy option for patients with relapsed/refractory multiple myeloma, used in combination with lenalidomide and dexamethasone.

“Elotuzumab is a bit of a forgotten drug because these other two anti-CD38 [agents] have come through and seem to be more effective,” Davies noted. “This isn’t helped by the fact that there have been a couple of negative trials suggesting that it does not improve survival outcomes in patients with high-risk disease.”

Another German trial presented at this year’s ASH meeting, GMMG-HD6, tested elotuzumab with RVd and autologous transplant in newly diagnosed disease, but the addition did not result in improved progression-free or overall survival. These data combined with findings from ELOQUENT-1 and SWOG-1211 suggested that elotuzumab may be effective only in the relapsed setting.

“This does not mean the drug is not effective, though,” Davies said. “It is definitely something that should be in our toolbox, but is often not the first drug physicians are reaching for.”

There has also been concern that use of a prior anti-CD38 antibody could affect the subsequent use of T cell-directed therapies. In theory, CD38 can be expressed on immune cells, as well as myeloma cells, she added.

“There is a theory that if we treat patients with CD38 antibodies that when we use a bispecific antibody later, that the patient may have depleted some of their immune repertoire and will not get the full beneficial effect,” Davies explained. “If you look at patients on the clinical studies for bispecific antibodies, they have all received a CD38 antibody and have still had response rates of 70% or greater.”

In fact, early studies are looking at combining an anti-CD38 antibody with a bispecific antibody. A phase I study of teclistamab combined with daratumumab (Darzalex) in relapsed or refractory multiple myeloma showed “preliminary efficacy,” with a manageable safety profile.

Bispecific Antibodies and CAR-T

Another question on clinicians’ minds has been if one bispecific antibody seems to be performing better than others. It is still too early to know, Davies said. Bispecific antibodies bind to two different antigens, one commonly being on T cells. There are several currently being studied in clinical trials.

“Preference of bispecific antibody, assuming multiple are eventually approved, may also come down to patient factors,” she explained. “Some are subcutaneous, some are intravenous, some are weekly, some are twice weekly. These things may be important factors.”

Clinicians are also interested in how bispecific antibodies will fit into the treatment schedule. Will these agents be used before CAR T-cell therapy or after?

“There was interesting data coming out of ASH confirming continued good response rates in people undergoing CAR T-cell therapy,” Davies noted.

Updated results from the CARTITUDE-1 study of ciltacabtagene autoleucel (cilta-cel) — which is currently under review by the FDA — showed that it produced “early, deep, and durable responses” at a median follow-up of 18 months in heavily pretreated patients with multiple myeloma.

Davies said there were also updated data on idecabtagene vicleucel (ide-cel), which showed improved progression-free survival.

“The main potential issue with CAR T-cell therapy will be availability of these treatments in the real world,” she added. “This is something that all CAR T-cell manufacturers, be it commercial or in the research world, are trying to address: matching supply with demand.”

She said it will be interesting to see how bispecific antibodies — a more off-the-shelf regimen — will affect treatment choice, especially as early data seem to indicate that they could be safe to employ prior to CAR T-cell therapy.

“There are still a lot of questions being asked about the best ways to use immunotherapy in multiple myeloma,” Davies concluded. “So far, we don’t have all the answers. For now, clinicians must continue to take a patient-specific approach.”