Peers Evaluate CAR T Referral and Bridging Process for Early Relapsed Multiple Myeloma

Hira Shaikh, MD

MODERATOR

Clinical Assistant Professor of Internal Medicine-Hematology, Oncology, and Blood and Marrow Transplantation

University of Iowa Carver College of Medicine

Iowa City, IA

EVENT REGION Iowa and Minnesota

PARTICIPANT LIST Nicole Jacobi, MD | Kurt Demel, MD | Birendra Kumar, MD | Sunn Sunn Thaw, MD | Vicki Morrison, MD | Yan Ji, MD | Anastas Provatas, MD

DISCUSSION QUESTIONS

• What are the potential roadblocks and challenges for referral of second-line chimeric antigen receptor (CAR) T-cell therapy for early relapsed/refractory multiple myeloma?
• Are there patients who you would not refer for CAR-T therapy in the second-line setting?

JACOBI: I would not necessarily refer older, frail patients in the second-line setting. We’re lucky because we have tertiary centers very close around us. But even with that situation, many older, frail patients would not be willing to do the multiple trips and so on. A young, fit patient who relapsed early is a completely different situation, especially when they hear that after they respond, they can go about their daily activities of living again.

SHAIKH: I agree. We have to be concerned in cases of very old and frail patients, especially having done many CAR T-cell therapies by now. We’re still doing a lot of ASCT for patients with myeloma, and I think they still have a great role, even after the DETERMINATION study [NCT01208662] in frontline therapy. It makes you see how many adverse events they go through with ASCT, and whenever my patients start hitting 75 [years old], I get concerned. With CAR T-cell therapy, we probably have a slightly higher bandwidth, but even if patients are coming with the best performance status and not having a lot of comorbidities, they will have a prolonged hospital stay, [may] have bad ICANS [immune effector cell–associated neurotoxicity syndrome], and need a nursing home stay. Even if these are fit patients, but are older, something to be thinking about is morbidity, if not mortality. The ICANS and CRS [cytokine release syndrome] are almost always reversible, but still [patients will face] morbidity that comes with…a hospital stay or a nursing home visit, especially if they are living more than an hour away.

JACOBI: Is there any trial collecting stem cells…and upon relapse, doing CAR T-cell therapy and then doing the stem cell transplant later?

SHAIKH: We have been part of multiple trials, and I know there are a lot more. We were part of the CARTITUDE-5 trial [NCT04923893], which recently closed. That was for patients who are transplant ineligible or deferred, and they would collect their stem cells, store them, and go through CAR T-cell therapy so that in the future, they do have an option. It was randomized, so half of the patients would go through CAR T-cell therapy and half of the patients would just go to lenalidomide maintenance after induction. We are part of some other clinical trials as well where we are doing up-front CAR T-cell therapy. They are single-arm [trials], but we do collect stem cells for all patients, unless they never are going to be a candidate [for ASCT], or they never want to go through that.

DISCUSSION QUESTIONS

• In preparation for patients to receive CAR T-cell therapy:
• What is your perspective on bridging therapy for patients prior to CAR T-cell therapy?
• What factors do you prioritize when selecting bridging therapy for your patients?
  

SHAIKH: Even if we are…trying to do it as fast as possible, it can still take a minimum of 6 to 7 weeks from the time you identify a patient to CAR T-cell infusion. We have to think about bridging regimens. How are you all thinking about it, and what are you using until these patients can get an appointment at an academic center?

DEMEL: If you’re saying that it takes 4 weeks for you to coordinate the CAR T-cell therapy and it takes me [up to] 4 weeks to coordinate pomalidomide [Pomalyst], I don’t know if they really have all that much of a bridge. I think if the situation was dire and they had hypercalcemia and new bone lesions and a wildly aggressive myeloma, I don’t think that patient is even a CAR T candidate. We need to get their disease under control with traditional chemotherapy. But for more quiescent, slow-moving myeloma, is bridging therapy even necessary?

I’m giving an exaggerated number there, but [pomalidomide approval can take] at least 2 weeks. It’s going to take me 2 to 3 weeks to get authorization for carfilzomib [Kyprolis]. All these things have some type of lag time. If I’m referring this patient to you, and a potential CAR T candidate takes 4 weeks, and then they come back to me, and that’s taking a week—all these things take time. I just don’t know the practicality of bridging therapy in nonemergent myeloma.

SHAIKH: If it is a quiescent myeloma and it’s nonemergent, not everybody needs bridging therapy. [It’s important to] identify these slow relapses sooner, because…we have all seen those patients whose disease just decides to take off at one point. After the CAR T cells are collected, you can store them for 1 year. So, if the patient is going to collect right now, but go through CAR T-cell therapy after 1.5 months, they have something to do. Just getting the ball rolling is important at times.

We typically try to [bridge with] anything that they have not gotten before. If this patient had Dara-VRd, something like carfilzomib, pomalidomide, and dexamethasone would be likely my next go-to, and you are right, pomalidomide takes a minimum of 1 week for me in the fastest case. The average is about 2 weeks or so. So, I would start them on something like carfilzomib, cyclophosphamide, and dexamethasone so that I don’t have to wait for a very long time. I can usually start the same week.

If you see the preauthorization for carfilzomib is taking longer, then I would even think of some kind of variation of VD-PACE [bortezomib, dexamethasone, cisplatin, doxorubicin, cyclophosphamide, and etoposide]. I think VD-PACE itself is a stronger regimen, but maybe [make] some changes to it, where you can drop some drugs and…just do PACE or drop 1 or 2 more drugs, sometimes just VCd [bortezomib, cyclophosphamide, and dexamethasone] alone works because all you have to do is try to stabilize them until they can get another more efficacious therapy.

JACOBI: We learned in these quadruplet-refractory patients that there is a possibility of doing bispecifics just for a short time as a bridging. Have you ever done that, and could you use them later on?

SHAIKH: This would be more for patients who have received 4 [prior] lines. If it is off-trial, then bispecifics are only approved as a fifth-line therapy. I have done talquetamab [Talvey], which is a GPRC5D bispecific antibody, before doing a B-cell maturation antigen [BCMA] CAR T-cell therapy. At this time, for myeloma, we have only BCMA CAR Ts approved. Talquetamab followed by a BCMA CAR T-cell therapy would work very well, rather than doing something like teclistamab [Tecvayli] or elranatamab [Elrexfio], which is the same [target].

You have to be mindful because both these therapies are T-cell–engaging therapies, and you don’t want to exhaust the patient’s T cells too much. If you keep doing bispecifics for months and keep doing it until right after they are going into CAR T-cell therapy, then you run into a risk of the CAR T cells not working as well, because for CAR T-cell therapy, you need some good T cells. For a shorter duration, we have done it. We also presented some data about talquetamab bridging that works very well,¹ but all these therapies are so new, so we are going to have limited data.

How long does it take for you to get patients into an academic institution?

KUMAR: It can be a couple of weeks, and obviously, and many times, we are going through personal email or text message, because if you go through the regular route, sometimes it can take longer. I often start the patient on some kind of treatment while I do the referral, knowing that by the time they get the CAR T from the logistical point and the patient’s preference, it can often be 2 to 3 months down the line from the time I decided on treatment. I go the route of what we did before the CAR T-cell therapy was available, just using the third-line treatment that we always did.

SHAIKH: Is everybody referring patients to the University of Minnesota or the Mayo Clinic?

THAW: I refer to both places, depending on the patient’s preference.

MORRISON: And depending on their insurance coverage.

SHAIKH: That makes sense. Is it taking the same amount of time for everyone, a few weeks or about a month or so to get into an academic center for CAR T-cell therapy referral?

JACOBI: With the Mayo Clinic, we can place an e-consult and those requests are expedited, so at least you can discuss what you are going to do for bridging [with the CAR T provider].

DISCUSSION QUESTIONS

• Based on the CARTITUDE-4 trial (NCT04181827) results:
  • How does the recent efficacy data impact your treatment selection of ciltacabtagene autoleucel (cilta-cel; Carvykti) in patients with multiple myeloma at first relapse?
  • Do the data impact how you approach patients who are functional high-risk vs standard risk?

JI: It’s amazing to see the overall response rate of 86%.2 For those 16% who did not respond to CAR T-cell therapy, are those patients with more soft tissue plasmacytoma? The functional high-risk patients still respond, but who are those patients who did not respond to CAR T, meaning who are those patients we should avoid referring to CAR T?

SHAIKH: Those are going to be probably functionally very high-risk patients, those who have extramedullary disease and also have cytogenetic risk factors. I think extramedullary disease is one group of patients for whom nothing works. They have not shared the data about patients who did not respond yet, but my best bet is it is going to be those patients because we have a lot of other studies showing that nothing works in these patients with extramedullary disease. Even bispecific antibodies don’t [lead to] response with that.

We all know treating myeloma that even if it’s one disease, it’s a heterogeneous disease. No 2 of my patients with 17p deletion are going to [have diseases that] behave the same, and there are patients who have standard risk and still relapse within months after transplant. How were you treating your functionally high-risk patients before CAR T-cell therapy?

JI: We would have enrolled them in a clinical study. We do have a clinical study involved with the bispecific T-cell engagers in the second, third, or fourth line. In that case, we could provide a patient with the benefit of early bispecifics, [especially] if they’re either not willing to get CAR T or their insurance is not covering CAR T, or for some other reason.

SHAIKH: I agree. Clinical trial is always a good option, so you should always go for that. These patients are probably going to go through every line of therapy, so sequencing is a hot debate right now. If they are not going to be a CAR T candidate, or if they can’t get through it, I agree on trying for bispecifics, because we have seen that some of these patients just are touch-and-go through a lot of these triplets, and they don’t do anything for them.

DISCUSSION QUESTION

• How does the safety profile of cilta-cel impact your treatment selection and referral of cilta-cel?

DEMEL: I can’t speak much [about] the early toxicities for CAR T because I typically am not seeing those patients in my institution. But I can extrapolate a little bit from CRS and ICANS concerns in the bispecific population. I think the whole team needs to be aware of some of the algorithms for predose dexamethasone to reduce the potential of CRS and ICANS in the bispecific population. I don’t see the acute toxicities of CAR T-cell therapy.

SHAIKH: Thankfully, the majority of these adverse events such as CRS or ICANS would go away after 1 month,³ and almost all centers that are doing CAR T-cell therapy keep following their patients for at least until day 30, and these patients are required by almost all academic centers to stay within 2 hours driving distance. I can’t even remember seeing CRS [after day 30], and it’s been very rare to see ICANS after day 30. I would feel comfortable as a community oncologist if I were sending my patients to a referral center and they got CAR T there. We know that they’re [past] the window for CRS and ICANS, and now they’re coming back to me, and I’m going to comanage them with the place that did CAR T-cell therapy. I would feel pretty comfortable that they are not going to get CRS or ICANS except in very rare circumstances.

We could still see some of the adverse events such as neuropathy.⁴ Cranial nerve palsies would also happen within the first 6 weeks. Cytopenias and infections need ongoing monitoring, especially IgG [immunoglobulin G] replacement. Whenever we send the patients after day 30 to their local oncologist, we always give them detailed instructions about how to follow [patients], how frequently to follow IgG, and what will be the cutoff and how [IgG] should be replaced. [We do] the same thing for cytopenias. Most of them recover their blood counts, but if they don’t, then we have detailed instructions about that. It’s something to be mindful of, but not anything different from what you would see with your other therapies, and [it] can easily be managed.

DEMEL: What medical comorbidities would make you ineligible for CAR T-cell therapy? I referred a patient who had underlying Parkinson disease, and the referring site said that was a contraindication to CAR T-cell therapy. What are other contraindications to CAR T?

SHAIKH: I’ve had one patient as well who was referred to me with Parkinson disease and severe dementia, and I also thought that CAR T-cell therapy was not a great idea for them. The earlier CARTITUDE-1 [NCT03548207] trial showed up to 8% to 10% motor neuron defects, which was scary.⁵ [There were fewer than] 100 patients on the trial, so…not very high numbers.

The other thing I would think about would be severe cardiac dysfunction, [such as] somebody who has a low ejection fraction, because when they are going through CRS, they are going to get a lot of fluids, and if their body can’t handle fluids very well, we are going to run into problems and arrhythmias, and we can, unfortunately, lose patients if it is not managed very well. If patients have severe arrhythmias that are not well managed before CAR T, that would make me worried.

We used to be very worried about renal dysfunction, [such as] GFR [glomerular filtration rate] less than 30 or hemodialysis patients. There was an analysis published and it was presented by the Multiple Myeloma Research Consortium.⁶ A lot of people are more comfortable with doing [CAR T-cell therapy in patients with a] GFR less than 30, not hemodialysis. But I am hearing a few reports that people here and there are doing it [in patients with] hemodialysis, so I think that’s probably going to be more common.

But in patients with severe cardiac dysfunction, frail patients, and patients who don’t have a great support system, I would be worried that if they get ICANS, nobody’s going to know about it. In patients who have severe infections—we had 1 patient who had severe cryptococcal meningitis, and it really made me worried about them going to CAR T. They are not great candidates [for it], but there are some gray zones [such as] patients with hemodialysis or patients with mild heart dysfunction.

PROVATAS: How do you treat those who have CRS related to bispecific vs CAR T-cell therapy? They say to avoid steroids with the bispecifics and use tocilizumab [Actemra]. I had 1 patient who had grade 2 or grade 3 CRS, and I was told not to use steroids. Is there a difference between them?

SHAIKH: There are not much data about it. People used to avoid using steroids with CAR Ts back when they were started. However, we have somewhat more data now both in lymphoma and myeloma CAR Ts that it’s generally safe, and that you don’t reduce the efficacy. Even when patients had ICANS, we used to [be concerned that if] we started doing steroids, we were going to affect the efficacy. But we are now generally more comfortable that steroids don’t reduce the efficacy.

I think the same rule applies to bispecifics as well. Some people are worried that they are going to decrease the efficacy. There are no data for or against this. I do know some places are doing prophylactic tocilizumab or some places are rarely doing prophylactic steroids as well. There is no generalizability to that…but yes, generally we do try to go for tocilizumab first and then steroids, until we have more data.

_REFERENCES

_{1. Shaikh H, Lochner J, Davis J, et al. P-078 Prompt and profound responses with talquetamab in patients with heavily pretreated relapsed-refractory multiple myeloma – another bridging therapy. Clin Lymphoma Myeloma Leuk. 2024;24(suppl 2):S86-S87. doi:10.1016/S2152-2650(24)01981-5}

_{2. Mateos MV, San-Miguel J, Dhakal B, et al. Overall survival (OS) with ciltacabtagene autoleucel (cilta-cel) versus standard of care (SoC) in lenalidomide (len)-refractory multiple myeloma (MM): phase 3 CARTITUDE-4 study update. Presented at: 2024 International Myeloma Society Annual Meeting; September 25-28, 2024; Rio de Janeiro, Brazil. Abstract OA–65.}

_{3. 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}

_{4. San-Miguel J, Dhakal B, Yong K, et al. Cilta-cel or standard care in lenalidomide-refractory multiple myeloma. N Engl J Med. 2023;389(4):335-347. doi:10.1056/NEJMoa2303379}

_{5. Cohen AD, Parekh S, Santomasso BD, et al. Incidence and management of CAR-T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies. Blood Cancer J. 2022;12(2):32. doi:10.1038/s41408-022-00629-1}

_{6. Sidana S, Peres L, Hosoya H, et al. Idecabtagenevicleucel (Ide-cel) chimeric antigen receptor T-cell therapy for relapsed/refractory multiple myeloma (RRMM) with renal impairment: Real world experience. Presented at: 2023 Tandem Meetings, February 15-18, Orlando, Florida. Abstract 42.}