Analyzing Ide-cel’s Trade-offs of Efficacy and Toxicity in Myeloma

Patrick Moore, MD

Assistant Professor

Department of Internal Medicine

Rush University

Chicago, IL

Targeted Oncology: How was idecabtagene vicleucel (ide-cel; Abecma) evaluated in patients with relapsed/refractory multiple myeloma?

Patrick Moore, MD: In the KarMMa-3 trial [NCT03651128], the key inclusions stated patients had to have at least 2 to 4 previous regimens, including an immunomodulatory drug [IMiD], a proteasome inhibitor, and daratumumab [Darzalex], an anti-CD38 [antibody], and be refractory to their last regimen. Most of them were less than 65 years old. Some of them had high-risk cytogenetics and some of them didn't.¹

They were randomly assigned 2:1. We had 254 patient in the ide-cel arm, and then 132 in the standard arm…. These patients were also allowed to cross over if they were confirmed to have progressive disease during that time period as well.

The investigators were looking at progression-free survival [PFS], overall response rates [ORRs], overall survival [OS], complete response [CR] rates, duration of response, minimal residual disease [MRD] negativity, and the safety profile.

Looking at the number of patients on the ide-cel arm vs standard arm, a lot of them had already been exposed to IMiDs, most of them with lenalidomide [Revlimid] and then pomalidomide [Pomalyst], and then very few with thalidomide [Thalomid]. Most people don't use thalidomide nowadays. Then with proteasome inhibitors, a majority of them received bortezomib [Velcade] and then carfilzomib [Kyprolis], and ixazomib [Ninlaro] as well. Pretty much all of them received daratumumab at some point.

There were 24% who had extramedullary disease, 28% with a high tumor burden, 42% with a high-risk cytogenetics, 65% who were triple-class refractory, and 95% were refractory to daratumumab.

Who was included in the KarMMa-3 trial in terms of location and race?

As far as ethnicities and things like that, a lot of patients were here in North America, some European patients, and then there were [a small number of] Japanese patients as well.

I think one thing to look at with these trials is that—especially with showing these data a lot of times to the patients—there weren't a lot of African Americans included in these trials. So that's something [to note], although a significant amount of the population in multiple myeloma are African American. That was one discrepancy I found that I wasn't too pleased about when it comes to that…. A lot of my African American patients do very well and have a high rate of survivability. I haven't seen too many who have had a significant amount of relapsed disease. That’s something I would have love to have seen represented in these data.

What were the efficacy findings for this relapsed/refractory multiple myeloma patient population?

With a median follow-up of 30.9 months, the median PFS for ide-cel was 13.8 months, whereas the standard regimen median PFS was 4.4 months [HR, 0.49; 95% CI, 0.38-0.63]. Then at 18 months, the PFS rate was 41% for those patients receiving ide-cel compared with the standard-of-care arm at 19%. There's a significant difference when it comes to PFS.²

The median OS for patients in the ide-cel arm vs the standard arm was 41.4 vs 37.9 months [HR, 1.01; 95% CI, 0.73-1.40]. There was not a significant difference when it comes to that. The biggest difference would be the PFS, but for the OS, there's not a huge difference.

Of these patients who received ide-cel, 71% of patients had an overall response…compared with the standard arm at 42% ORR.¹ With ide-cel, 41% of those patients were able to achieve a stringent CR, which is beautiful. That allows them to stay disease free and helps maintain disease free [status] during that time period as well, with the PFS. Only 3% given ide-cel had just a CR, and then there were 18% with very good partial response, and 10% with partial response.

This is compared with just 5% with stringent CR with the standard of care, so it's a significant difference. In general, there was a better response with the ide-cel arm compared with the standard of care.

There were 57 patients with MRD-negative CR, 35%, whereas they weren't getting the significant deep remission rates with the standard of care [at 2%].

How did patients on KarMMa-3 do in terms of toxicity with the CAR (chimeric antigen receptor) T-cell therapy?

Ninety-nine percent of the patients had some sort of adverse event [AE] during the [trial] period with ide-cel; grade 3 or 4 AEs were 93% during that time period as well. Patients experienced [high rates of] neutropenia, anemia, and thrombocytopenia.

For lymphopenia and leukopenia…patients can have these prolonged cytopenias up to almost 2 months after they receive CAR T-cell therapy, so it's another reason why you have to monitor them very closely after they receive ide-cel or other CAR T cells. They will experience some nausea and vomiting. A lot of times, I think that's more contributing from the lymphodepleting chemotherapy, possibly more compared with the CAR T itself. But it's hard to decipher because they follow each other very quickly.

Fatigue is something you expect patients to experience and also fever and headache. Headache, many times I'll factor in as possibly a sign of immune effector cell-associated neurotoxicity syndrome [ICANS] when they start to develop a headache, although a lot of times it'll come along with a tremor, and we associate it with some confusion as well. Often, we lump in headache and if it is refractory, we treat it as a version of ICANS.

Also, 88% of patients had experienced cytokine release syndrome, and then 15% of patients experienced neurotoxic events. Grade 3 or 4 cytokine release syndrome [was 4%].

_References:

_{1. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Ide-cel or standard regimens in relapsed and refractory multiple myeloma. N Engl J Med. 2023;388(11):1002-1014. doi:10.1056/NEJMoa2213614}

_{2. Ailawadhi S, Arnulf B, Patel K, et al. Ide-cel vs standard regimens in triple-class-exposed relapsed and refractory multiple myeloma: updated KarMMa-3 analyses. Blood. 2024;144(23):2389-2401. doi:10.1182/blood.2024024582}