Functional High Risk and Bridging in Multiple Myeloma Considered With CAR T Cells

CASE SUMMARY

Samer A. Al'Hadidi, MD, MS

Hematologist/Oncologist

Assistant Professor of Medicine

University of Arkansas for Medical Sciences

Little Rock, AR

• A 60-year-old man who was diagnosed 3 years ago with lenalidomide (Revlimid)- refractory IgG-kappa multiple myeloma presented to his oncologist at first relapse with 1 prior treatment. Patient stated complaints of excessive fatigue and low back pain exacerbated by movement.
• Lived in a rural community.
• Medical history: hypertension controlled with lisinopril
• He received previous treatments with:
• Dara-VRd (daratumumab [Darzalex], bortezomib [Velcade], lenalidomide, dexamethasone) followed by autologous stem cell transplant (ASCT) with lenalidomide maintenance
• Achieved very good partial response (VGPR) post-ASCT
• ECOG performance status: 0
• Weighed 170 lbs (down 15 lbs in last 4 months)
• After discussion with his oncology team, the patient began evaluations for CAR T-cell referral.
• The patient ultimately proceeded to cilta-cel CAR T-cell infusion.
• Achieved stringent complete response at day 30.

Targeted Oncology: What are the expected outcomes for a patient such as this who has only received 1 line of prior therapy if he had relapsed soon after receiving ASCT?

Samer A. Al'Hadidi, MD, MS: If we look at the subgroup analysis of CARTITUDE-4…presented in both 2024 American Society of Clinical Oncology Annual Meeting and 2024 European Hematology Association Congress, it looked into what we call patients with functional high risk.¹ Those are the patients we worry about in the clinic where they have early relapse after transplantation. In this subgroup analysis, they looked at this group specifically, at patients who had 1 line of prior therapy and have functional high risk. These patients with functional high risk who received cilta-cel [vs standard of care]...all in all seemed to be similar to each other [in terms of baseline characteristics]. This subgroup analysis looked at if cilta-cel is better than standard of care for functional high-risk patients.

If you look at all patients who got only 1 line of prior therapy, cilta-cel seems to be better than standard of care for patients with 1 prior line of therapy, because this is the patient we're discussing. Patients didn't get more than 1 line of therapy, and that subgroup of patients still did well with a median progression-free survival [PFS] not reached [and PFS rate of] around 77% at 1 year [with cilta-cel]. But I think more importantly, the functional high-risk patients, those are the patients who had a better result with a median PFS not reached, which is an area of unmet need in myeloma [HR; 0.27; 95% CI, 0.12-0.60; P = .0006]. So those patients who have functional high risk and got early cilta-cel, had high rates of complete response, with almost three-fourths of them responding, and also minimal residual disease negative, which reflects also the depth of response. I think this is extremely important, because with functional high risk, the current treatment modalities will not result in such nice results. Most of us got excited about this subgroup of patients and are offering them early access to CAR T-cell therapy.

The CARTITUDE-4 study did suggest that PFS is better in a randomized fashion compared with a triplet-based regimen. I think this is something we lacked before with a single-agent CAR T-cell therapy because we…didn’t include everybody in the [clinical trials]. But here it's different; this is an intention-to-treat analysis that has shown that PFS is better, and there is a trend for overall survival. One thing I want to highlight is that crossover was not allowed, so patients were not getting cilta-cel at time of progression, which was different in the other trials.

Would you use anti-CD38 therapies before CAR T-cell therapy?

Almost three-fourths of those patients did not receive previous anti-CD38 therapy, but in this specific study, when patients were randomly assigned to cilta-cel, the bridging therapy was using this triplet-based regimen with daratumumab for a majority of patients.² They use this as a bridge to give the CAR T-cell therapy, but they were not using it before randomization. I think it has 2 aspects to it. First, if you use it early on with exposure to anti-CD38 therapy, you have more options to bridge patients so they can wait until they can get the CAR T-cell therapy.

I think that is one aspect to it, but also has to do with the functionally high-risk [patients]. For this specific patient who only had a quadruplet regimen and a transplant and relapsed right after it, we can tell that the biology of this disease is not good. So doing any sort of bridging to get them to something that is different is important. We have more options if we use it early. This is a study where anti-CD38–based regimens were not utilized as much.

Now, the other caveat to this is it also depends on the companion drug that you want to use. If you look at the earlier studies first, 1 to 3 lines of therapy, there are other immunomodulatory-based regimens, or data for carfilzomib [Kyprolis] that when you look at a second proteasome inhibitor, the PFS looks good with roughly 3 years in 2 studies. But in patients who are treated with a pomalidomide [Pomalyst]-based regimen, it's around 1 year now. With around a year and a half of follow up, most patients did not get any progression of their disease. With long follow up, I think that would be important, the durability of response will be good, but if we assume that it will be the same as 4 or more lines of treatment, the PFS was 3 and a half years for patients who got 4 or more lines of therapy. So there is excitement there, but this probably requires more follow up.

Outside of clinical trials, how long would it take to get cilta-cel for this patient from the time you make a decision to use it?

It all depends on the tactics. If I know that somebody is coming to me for CAR T-cell therapy, usually nowadays they could have been seen and the apheresis slot can be reserved for them to get an apheresis done. Doing it quickly could have been facilitated, but we assume that the patient I see I want to get a CAR T-cell approval for with this new FDA approval, this is a standard process. Patients go through a social assessment and all of those things to get them ready.

Once you do the apheresis, nowadays, you're looking about 2 to 3 weeks waiting to get an apheresis slot, which is way better than before. After they do the apheresis, it takes around 6 to 8 weeks for cilta-cel to be manufactured. It's longer than idecabtagene vicleucel [Abecma], which takes around 3 to 4 weeks. This is almost 2 months of waiting, plus or minus another month of preparation, so between 2 to 3 months.

_References:

_{1. Weisel K, Costa LJ, van de Donk N, et al. Ciltacabtagene autoleucel vs standard of care in patients with functional high-risk multiple myeloma: CARTITUDE-4 subgroup analysis. Presented at: EHA Congress; June13-16, 2024; Madrid, Spain. Abstract P959.}

_{2. Sidiqi MH, Corradini P, Purtill D, et al. Efficacy and safety in patients with lenalidomide-refractory multiple myeloma after 1-3 prior lines who received a single infusion of ciltacabtagene autoleucel as study treatment in the phase 3 CARTITUDE-4 trial. Blood. 2023;142(suppl 1):4866. doi:10.1182/blood-2023-178778}