Isatuximab Displays Promise in Early-Relapsed Multiple Myeloma, as Researchers Eye CAR T-Cell Therapy

Beyond the progress seen across the multiple myeloma armamentarium, unmet needs remain for patients with high-risk disease, poor prognostic factors, and relapsed disease, according to Faith E. Davies, MD.

“Things are changing in multiple myeloma, and it is definitely becoming more of a chronic disease. However, there are certain patient groups that we need to pay particular attention to, and those would be the high-risk patients that still have a poor survival,” said Davies, a professor in the Department of Medicine and director of the Clinical Myeloma Program at NYU Langone Health’s Perlmutter Cancer Center. “Also, we need to learn how to embrace many of the new therapies that are being developed, and particularly, learn how to manage their adverse effects [AEs] so that we can better utilize them with our patients.”

Combination strategies featuring isatuximab-irfc (Sarclisa) may hold the key in improving outcomes in this patient population. In March 2020, the FDA approved isatuximab for use in combination with pomalidomide (Pomalyst) and dexamethasone for patients with multiple myeloma who have received at least 2 prior therapies, including lenalidomide (Revlimid) and a proteasome inhibitor. A second indication for isatuximab was granted in March 2021 for use in combination with carfilzomib (Kyprolis) and dexamethasone in the relapsed/refractory setting for patients who have received 1 to 3 prior treatments.

The 2021 Institutional Perspectives in Cancer webinar on multiple myeloma focused on up-front and relapsed/refractory updates in the disease, as well as how to approach patients with high-risk myeloma. In an interview with OncLive^®, Davies discussed the latter, as well as how isatuximab and CAR T-cell therapies fit best for that patient population.

OncLive^®: There are several therapeutic options for patients with relapsed/refractory myeloma. How do you choose what is best for someone with early relapsed disease?

Davies: When we are thinking about treating patients with early relapsed multiple myeloma, we need to [consider] a whole host of factors. The first one would be how well [the patient] did with their initial therapy and exactly what that treatment was, so that we can decide whether we need to stay with the same class of drugs or change it. We also need to think about the adverse effects [AEs] that the patient may have [experienced] with their initial therapy so that we can ideally try to avoid those AEs moving forward.

Finally, we need to think about comorbidities, because many patients may have aged a little since we started their initial therapy, and therefore, we need to think [more] about cardiac and neuropathy issues, diabetes, etc., so we can get a handle on which drug classes we should be including in our combinations.

The phase 3 IKEMA trial (NCT03275285) led to the FDA approval of isatuximab plus carfilzomib and dexamethasone in the relapsed/refractory setting. What do you find most intriguing about the data that led to this approval?

It has been exciting over the last few months because we now have 2 approvals for isatuximab, which is a CD38 monoclonal antibody. The first [approval] is in combination with pomalidomide and dexamethasone, based on the phase 3 ICARIA-MM trial [NCT02990338], and the second one is in combination with carfilzomib and dexamethasone. [This] really gives us [more] options, to include either an immunomodulatory drug or a proteasome inhibitor, when we are treating [patients with relapsed/refractory disease].

Importantly, thus far, the data show us that there were no unexpected toxicities. Isatuximab was well tolerated with [just] a few infusion reactions, which were very well managed; these reactions tended to occur on the first dose.

[This] gives us 2 really good options. We have the opportunity to look at our patient and say, “Our backbone is going to be isatuximab, so will this patient be better off having pomalidomide in the combination, or would they be better having carfilzomib [with isatuximab]?”

What are the next steps for isatuximab, and how does the agent fit in with others in the space?

One of the nice things about the [IKEMA and ICARIA-MM] studies that we have seen data on with isatuximab was that it really seems to be a great drug that you can combine others with. That means, moving forward, we have the opportunity to use it with any of the multiple myeloma drugs that we currently have in practice.

We are all really looking forward to seeing the data in the newly diagnosed setting, because that is certainly an area that we would like to be able to use [isatuximab]. There has [also] been some early data that has been presented from German [researchers] using the combination of isatuximab in newly diagnosed, high-risk patients, and certainly that seems to have shown a high response rate, which is encouraging. [Additionally,] there are other clinical data coming through which is going to be important for us moving forward.

One of the talks during the program focused on CAR T-cell therapy in patients with multiple myeloma. What promise has this modality demonstrated in the early relapse setting?

For CAR T cells, most of the studies have been performed in patients with relapsed/refractory disease. The data in that patient group—where in the past we have always been surprised if patients have a response or if they have a long remission—have shown that there is a high response rate, that there is a high number of patients achieving minimal residual disease negativity, and that many of those patients can have a prolonged disease-free period.

[There are] certainly a number of AEs associated with [CAR T-cell] therapy, which need some management, but it shows a lot of promise. The promise may actually be earlier in the disease course, because if you think that the kinds of results we are seeing in patients who have previously had 10 lines of therapy, imagine what kind of results we might get in patients who are at their first relapse, for instance. Many of the clinical studies that are being undertaken now are looking at [CAR T-cell therapy in] earlier lines of therapy, or indeed, looking at those high-risk patients who may be in their first line of therapy. We are looking to see whether CAR T-cell therapy may be appropriate for them.