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Spotlight

This roundtable series assesses chimeric antigen receptor T-cell therapy as later-line treatment in patients with relapsed/refractory multiple myeloma, as discussed by key opinion leaders at virtual live events and interviews.

Using CAR T-Cell Therapy in Relapsed/Refractory Multiple Myeloma

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.

Medical history: hypertension controlled with lisinopril

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

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?

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.

 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; 

 = .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.

 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.

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. 

. 2023;142(suppl 1):4866. doi:10.1182/blood-2023-178778

Samer A. Al'Hadidi, MD, MS, reviewed the benefits of cilta-cel in the subgroup analysis of CARTITUDE-4 in patients with relapsed/refractory multiple myeloma and functional high risk, bridging to cilta-cel, and time to treatment in the second article of a 2-part series.

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

A 60-year-old man who was diagnosed 3 years ago with lenalidomide 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.

Dara-VRd (daratumumab [Darzalex], bortezomib [Velcade], lenalidomide [Revlimid], dexamethasone) followed by autologous stem cell transplant (ASCT) with lenalidomide maintenance

After discussion with his oncology team, the patient began evaluations for chimeric antigen receptor (CAR) T-cell referral.

The patient ultimately proceeded to ciltacabtagene autoleucel (cilta-cel; Carvykti) CAR T-cell infusion.

Achieved stringent complete response (CR) at day 30.

Targeted Oncology: Please discuss the trial behind the treatment selection for this patient.

This is a very important study that we should look at in detail. CARTITUDE-4 [NCT04181827] is a phase 3 study, which is a very important because with CAR T-cell therapy, we worry about selecting patients with good biology to give the CAR T cells, so a phase 3 trial was something all of us were waiting to see. This is a study [that enrolled] patients with relapsed disease after 1 to 3 lines of therapy. One requirement was being refractory to lenalidomide, which is almost universal in the United States. Patients were randomly assigned to 1 of 2 triplet regimens vs cilta-cel: either pomalidomide [Pomalyst], bortezomib, dexamethasone or daratumumab, pomalidomide, dexamethasone. These are 2 commonly used regimens for patients who were not anti-CD38 exposed, so something that many of us use.

This study’s primary end point was progression-free survival [PFS].... The randomization was 1:1 [between CAR T-cell therapy and triplet therapy]. The characteristics of the patients who were enrolled in this study showed most patients got between 1 to 3 lines of previous therapy. One hundred percent of patients were on lenalidomide before, and a minority of patients were on daratumumab. So it's a little bit different than our case, where the patient had daratumumab. It's probably the minority here, under 25%. [Around one-third of patients] received bortezomib before, and around one-third got carfilzomib [Kyprolis]. So those patients were not heavily pretreated. All those patients were refractory to lenalidomide [and to] a proteasome inhibitor, [including about 97% with] bortezomib and one-fourth with carfilzomib. But when it comes to anti-CD38, only 1/4 of those patients were refractory.

This is similar to the patient case that we have, where the patient had only 1 line of treatment, and was not heavily pretreated.

What was the efficacy seen on the CARTITUDE-4 study for patients with early relapsed/refractory multiple myeloma?

The Kaplan-Meier curve for PFS showed cilta-cel had better PFS, and the standard of care had worse PFS. There was, early in the study, some crossover where patients went to the cilta-cel group who did have progression events and mortality-related events before getting the CAR T-cell therapy. Looking into the intention-to-treat analysis in this study, the cilta-cel median PFS was not reached, and the standard of care PFS was [a median of] 11.8 months, which is standard on pomalidomide-based regimens. Most pomalidomide-based regimens after 1 to 3 lines of treatments give you around a year of PFS, so that is the usual that we see. But the HR between those was low at 0.26 [95% CI, 0.18-0.38], so those were really good results.

The CR or better and overall response were better, and those responses are really deeper. Almost three-fourths of patients go to CR compared with only around 22% of patients [with triplet]. This was with a median follow-up of around 16 months and in the future, we will get more follow-up on this important study. But even with that, we can see there was improvement on the PFS.

With patients following up for a longer period of time, the responses were becoming deeper.

 The overall responses were better with time at 16-month follow-up, but also [the rate of] VGPR or better is [higher], along with CR or better [86%]. The time to first response after randomization was around 2 months on this cohort, and most patients were progression free at 1 year after getting cilta-cel. That PFS rate was almost 85% and the overall survival rate was high at around 92%. Those responses are really deep, with many of them achieving a minimum residual disease negativity in almost three-fourths. So there were deeper responses, and also that build up with time, which is nice to see.

1. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. 

. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379

During a Case-Based Roundtable® event, Samer A. Al'Hadidi, MD, MS, discussed the CARTITUDE-4 trial of cilta-cel in patients with relapsed/refractory multiple myeloma in the first article of a 2-part series.

Efficacy of Cilta-Cel Is Maintained in Early Relapsed Multiple Myeloma

Binod Dhakal, MD, MS, discusses why patients could benefit from earlier use of chimeric antigen receptor T-cell therapy in relapsed/refractory multiple myeloma. 

Earlier CAR T-Cell Therapy Benefits Functional High-Risk Group in RRMM

Binod Dhakal, MD, MS, associate professor of medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin, discusses why patients could benefit from earlier use of chimeric antigen receptor (CAR) T-cell therapy in relapsed/refractory multiple myeloma (RRMM).

Ciltacabtagene autoleucel (cilta-cel; Carvytki) was approved for patients with RRMM who have been treated with at least 1 prior line of therapy based on the CARTITUDE-4 study (NCT04181827). The initial approval had been for patients who received 5 prior lines.

According to Dhakal, there are not good treatment options for patients who have received between 2 and 5 prior lines of therapy. Patients have already received at least 1 prior immunomodulatory drug (IMiD), proteasome inhibitor (PI), and anti-CD38 antibody, and they are more frequently receiving all 3 in the first line based on recent trial data in both transplant-eligible and -ineligible patients. Only CAR T cells and bispecific antibodies would offer a different mechanism of action that has shown strong efficacy, and so cilta-cel could fill a gap in this treatment space.

In particular, patients who have functional high-risk disease stand to benefit from the approval. These patients relapse rapidly and will not respond well to additional IMiD, PI, and anti-CD38 therapy. However, these patients had favorable responses to cilta-cel in CARTITUDE-4, highlighting that subpopulation could be high-priority candidates for CAR T-cell therapy in the first=relapse setting, even if other patients delay CAR T-cell therapy due to logistics or tolerability concern.

Before this approval, cilta-cel was approved as a fifth line. Now we have the second-line approval. If you look at the types of treatment that we offer for [patients with RRMM], to be frank…after second line, there is not much good treatment out there.

 Once you have exposure to 3 different classes of drugs: the…PI, IMiD, and CD38, the next option is whatever available options, [which] are not that great, besides the CAR T and the bispecific antibodies. Before this approval, patients who are after second line, especially the majority of the patients in the [United States], even before were already exposed to these 3 classes of drugs. Now with the newer evidence of using CD38 in the frontline in both transplant eligible patient [and] the transplant ineligible, I think the majority of them will be exposed to 3 classes as early as first line. I think after that, there is not much effective treatment beyond what I said about the CAR T and bispecifics. I think having that approval is really going to fill the gap of that important treatment in that space. I think that's definitely going to change the landscape of what we're going to offer, especially after the second line, and definitely after the third line.

 What happens is that there are a lot of patients who get initial treatment, they relapse very early on. We call these functional high-risk patients. [For] these patients, regardless of what you do, there are not a lot of good therapies out there. But the emerging data, including the CARTITUDE-4 patient population, when we look at the patients who are relapsing early, they derive significant benefit using the cilta-cel. So I think those are the patients [who] really can benefit right away, having the cilta-cel in early line. That will help change the landscape—both the treatment landscape as well as the outcomes of these patients.

video on Binod Dhakal on approval of cilta-cel after CARTITUDE-4 

Patient Selection Factors for Earlier Use of CAR T-Cell Therapy

Binod Dhakal, MD, MS, assistant professor of medicine in the Division of Hematology and Oncology at the Medical College of Wisconsin, discusses selecting patients for chimeric antigen receptor (CAR) T-cell therapy by considering each patient’s condition and logistics.

Ciltacabtagene autoleucel (cilta-cel; Carvytki), a CAR T-cell therapy, was approved for patients with relapsed/refractory multiple myeloma who have been treated with at least 1 prior line of therapy based on the CARTITUDE-4 study (NCT04181827), whereas it was previously approved for patients after 5 lines. Before CAR T-cell therapy can be initiated, T cell collection and lymphodepletion, potentially causing delays. After treatment, patients still need to be monitored for CAR T-cell–related toxicities including cytokine release syndrome (CRS) and immune effector cell–associated neurotoxicity syndrome (ICANS) afterward.

Dhakal says that in the late relapse setting, CAR T-cell therapy is the only highly effective treatment available to patients, and delays can harm patients. However, in the earlier setting opened by this approval, patients still have other options and can afford to wait before initiating cilta-cel.

He added that in CARTITUDE-4, CAR T-cell–related adverse events (AEs) were lower in occurrence and severity than when it was investigated in more heavily pretreated patients in CARTITUDE-1 (NCT03548207). With this in mind, he suggested considering the patient’s performance status, the time of relapse and number of prior therapies, and caregiver support to ensure patients can be monitored after treatment easily. Although Dhakal believes most patients could benefit, not all meet these criteria. Nevertheless, making cilta-cel available earlier in the course of treatment can benefit patients who are eligible for CAR T-cell therapy.

Once you get the CAR [T-cell therapy], there are definitely some short-term and long-term, what we call CAR [T-cell therapy]–related toxicities that we have to monitor. So I think there is a requirement to monitor afterwards as well. It's not that when you get the CAR T-cell therapy you're done. So I think when you choose a patient...you have to think about...all these aspects. For example, when the patients are in late relapses, I think what happens is they don't have a lot of options. And so when you think of the CAR [T-cell therapy]...that is the one treatment that is only effective treatment that is available now. In the second line and beyond, I think the good thing is that they are still early on, they could still try other options. And so there is an opportunity for the patient to wait for about a couple of months easily while getting the CAR [T-cell therapy] afterwards. So I mean to say that the urgency to get the CAR [T-cell therapy] is not that immediate. In the majority of the patients, they can wait.

What we also saw in CARTITUDE-4 is that if you give it, CAR [T-cell therapy]–related AEs, when you compare to CARTITUDE-1, were lower, like CRS, ICANS, the other related neurotoxicities, etc. Both rates and severity were lower. So that means if you're giving the CAR T at an earlier line, which...is dictated by the disease burden in that setting, I think the CAR [T-cell therapy]–related AEs can go down. So I think when you offer this treatment, you have to make sure how the patient's disease is, how they are relapsing, what is the patient's overall condition, the performance status, and then at the same time…it's important to have that monitoring from the caregiver as well after they receive the CAR [T-cell therapy]. All these things will help in deciding the right patients to get this therapy. Ideally, I would like to give it to all patients, but not all patients will fit the criteria. But moving this earlier than later, I think the majority the patients will be able to get this [rather] than when they are at the later stages.

Transcription created with AI and edited for clarity.

Binod Dhakal, MD, MS, discusses selecting patients for chimeric antigen receptor T-cell therapy by considering each patient’s condition and logistics. 