CAR T and CRS Adverse Events Considered in Relapsed Multiple Myeloma

Saad Z. Usmani, MD, FACP, MBA

Myeloma Specialist & Cellular Therapist

Memorial Sloan Kettering Cancer Center

New York, NY

This is the first article of a 2-part series.

CASE SUMMARY

• A 60-year-old woman was diagnosed with Revised International Staging System (R-ISS) stage II/R2-ISS stage III IgGκ multiple myeloma​.
• Medical history: acute onset of renal insufficiency and hypercalcemia ​
• Cytogenetics: 1q21+ amplification; t(14:16); high risk​
• ECOG performance status: 0​
• Patient was considered transplant eligible.​
• She received daratumumab (Darzalex), bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone, followed by lenalidomide plus bortezomib maintenance.​
• Achieved ​very good partial response (VGPR) post-induction therapy.
• Patient underwent stem cell mobilization and 2 months later underwent autologous stem cell transplant (ASCT).
• Achieved VGPR post-ASCT

Two Years Later

• The patient continued lenalidomide maintenance therapy​.
• On routine follow-up, she reported having mild fatigue but continued to work full-time​.
  • Bone marrow plasma cells, light chains, and M protein levels rising​
  • Kidney function worsening; estimated glomerular filtration rate: 28.7 mL/min/1.73 m2​
  • Now stage IV chronic kidney disease​
• Following second relapse, the patient was initiated on daratumumab, carfilzomib (Kyprolis), and dexamethasone with a best response of VGPR.

One Year Later

• After 2 prior lines of therapy​, the patient presented to her oncologist with complaints of increased fatigue and persistent bone pain in her lower back exacerbated by minimal movement​.
• She expressed interest in chimeric antigen receptor (CAR) T-cell therapy with her clinical team.​
• She also stated that she wants to travel out of the country for her daughter’s wedding in 3 months.

Targeted Oncology: What are the main CAR T-cell options available for this patient with relapsed multiple myeloma?

Saad Z. Usmani, MD, FACP, MBA: The good news is that the CAR T-cell therapies that were originally approved in 2021 and 2022, ide-cel [idecabtagene vicleucel; Abecma] and cilta-cel [ciltacabtagene autoleucel; Carvykti], were for 4 or more prior lines of treatment with proteasome inhibitor [PI], immunomodulatory drug [IMiD], and anti-CD38 exposure and refractoriness. Now both of these products have moved into earlier lines of treatment.

Cilta-cel was approved for patients who have had 1 or more prior lines of treatment, they had to have IMiD and PI exposure, and they have to be lenalidomide refractory. Ide-cel was approved by the FDA for 2 or more prior lines of treatment with PI, IMiD, and anti-CD38 exposure, and a major proportion of the patients who went on that trial were daratumumab or anti-CD38 refractory. So the populations in both these studies are different. With ide-cel in KarMMa-3 [NCT03651128], it was a bit more heavily pretreated, more late line, more triple-class exposure than with the cilta-cel study. But those are the 2 CAR T cells that are important ones to consider here.

CASE UPDATE

• The patient ultimately proceeded to CAR T-cell infusion.
• Patient demonstrated stringent complete response (CR) at day 30.

How do the KarMMa-3 data fit into treatment for this patient?

This was the clinical trial that led to the FDA approval of ide-cel in earlier lines of treatment.¹ Patients who had 2 to 4 prior lines of treatment were randomly assigned 2:1. For every patient going to standard-of-care treatment, 2 were randomly assigned to receive ide-cel. The primary end point was progression-free survival [PFS], and the population was pretty advanced. The vast majority of patients were refractory to daratumumab. In the ide-cel arm, 95% of the patients were daratumumab refractory. Triple-class refractory patients made up two-thirds of the population. This is essentially the kind of population that was enrolled on the original late relapse study. But we're seeing more of these patients get into that earlier line setting.

The median PFS was 13.8 months compared with 4.4 months in patients who were receiving ide-cel vs the standard regimen, respectively [HR, 0.49; 95% CI, 0.38-0.63].² Overall response rate [was] 71% compared with 42%. I think the minimal residual disease–negative CR rates were quite compelling for the ide-cel arm of the study. CAR T cells are here to stay, and they're very effective. Depending on the change in burden of disease over time—so PFS by independent review committee—there were patients in this cohort who had their disease burden escalate as they were going into ide-cel therapy. Regardless of that part, the PFS curves appear to be similar for those patient populations.

What about patients whose multiple myeloma had increased, decreased, or no change in terms of their depth of response?

The patients who did have sensitivity to the bridging therapy had a pretty high disease response and that speaks to the disease biology, essentially. I think that's important.

The other thing that we are learning [is] soluble B-cell maturation antigen assay can be done on the peripheral blood. It's more of a reflection of disease burden and activity and it correlates with either having a response or lack of response.... That is a myeloma-specific issue; it's not a treatment modality specific issue.

Can you discuss why cytokine release syndrome [CRS] is relevant for patients receiving ide-cel?

You're giving these revved up T cells to patients and asking them to become hyperactive as soon as they're exposed to that specific surface marker or antigen. So of course they're going to become active, release cytokines, and essentially make the patient feel like they have a bad flu. That's what, essentially, CRS is. When we were using CAR T cells 10 to 12 years ago, there was a concern that if you try to stop that process, you may not get the efficacy. But pretty soon we learned that if we let that go too long, patients may even die from it.

The [important thing] is you recognize CRS early and intervene, and don't let it get bad. If you dial down the CRS, it does not have any bearing on the outcome of patients in terms of efficacy. We see CRS in a majority of patients, but if you look at the grading, it's mostly grade 1 and 2.¹ Grade 1 CRS management is Tylenol. Grade 2 CRS management is where you think about giving tocilizumab [Actemra] or steroids. The grade 3 or 4 CRS rate is only about 4% and it's short lived. You manage that adverse event. CRS with ide-cel is very predictable. It happens within 48 hours. So if it happens, it happens early, you manage it, and it gets better. It doesn't continue to occur.

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. Rodriguez-Otero P, Ailawadhi S, Arnulf B, et al. Idecabtagene vicleucel (ide-cel) versus standard (std) regimens in patients (pts) with triple-class–exposed (TCE) relapsed and refractory multiple myeloma (RRMM): updated analysis from KarMMa-3. Blood. 2023;142(suppl 1):1028. doi:10.1182/blood-2023-178933