Insights From CAR-PRISM: Can CAR T 'Eradicate' Smoldering Myeloma?

For decades, patients with smoldering multiple myeloma have largely been managed with active surveillance, balancing the uncertain risk of progression against the toxicities of early intervention, but advances in immune-based therapies are beginning to challenge this paradigm. Recent studies with agents such as daratumumab (Darzalex) have demonstrated that earlier treatment can delay progression to symptomatic disease. Now, emerging cellular therapies are raising a more provocative question: could some patients be treated aggressively enough to eradicate disease before symptomatic multiple myeloma presents?

“Can you give an effective, potent CAR [chimeric antigen receptor] T-cell therapy to these patients to essentially eradicate the disease?” asks Omar Nadeem, co-lead author of a publication in Nature Medicine on the first prospective study of ciltacabtagene autoleucel (cilta-cel; Carvykti) in smoldering myeloma.¹

In an interview with Targeted Oncology, Nadeem, clinical director of the Myeloma Immune Effector Cell Therapy Program at the Dana-Farber Cancer Institute, discussed findings from the CAR-PRISM study (NCT05767359) evaluating cilta-cel in patients with high-risk smoldering myeloma. The phase 2 trial reported 100% minimal residual disease negativity among 20 treated patients, which is the first time universal MRD negativity has been reported in a plasma cell disorder study. Although therapy was overall well tolerated, cases of neurological toxicities were reported; a known toxicity associated with cilta-cel. Nadeem explained the rationale for moving CAR T-cell therapy earlier in the disease course, the evolving understanding of associated neurotoxicities, and how these data may shape future treatment strategies for asymptomatic but biologically high-risk disease.

Targeted Oncology: Could you explain the background for studying early intervention in smoldering myeloma?

Omar Nadeem, MD: Smoldering myeloma is a precursor to multiple myeloma. It presents when patients have more than 10% abnormal plasma cells in the bone marrow and no end organ damage. These people were historically monitored until they developed disease progression, which is variable in this population. Some of them have what we call low or intermediate risk smoldering myeloma; some have more high-risk smoldering myeloma.

In that high-risk population, over the last 10 to 15 years or so, we have developed several different criteria that we can use to identify some of these patients. Those criteria are still being developed as we get more information about genomics and some of the other markers, but there have been several that have been previously validated, and this population carries approximately a 50% chance of progression to multiple myeloma in the next few years, and that population has been of interest, because of their high risk of progression, about whether we should intervene early or not.

What are the challenges of evaluating risk vs benefit when deciding to treat these high-risk patients?

Historically, they were all observed. They were on active monitoring, typically every 3 to 6 months they'll have [laboratory tests] and then imaging perhaps once or twice a year, depending on their risk profile. Then, as therapies for multiple myeloma started to improve, the question became more relevant. If you find some of these patients, can you give them one of these regimens that are active in myeloma safely and then prevent disease?

There were initial studies of lenalidomide [Revlimid] that were done about a decade [or more] ago that were positive compared to observation,^2,3 and then came daratumumab [Darzalex], a CD38 monoclonal antibody that was compared to active monitoring in the AQUILA trial [NCT03301220], and that showed benefit, so that became our first FDA approval in smoldering myeloma this past November.⁴ We now actually have an agent that we can use in the clinic, so this is an area that's changed quite a bit in the last few years because of these results.

But we're always left with this question: is that sufficient? These are low-intensity therapies, and [although] they're well tolerated as a whole, they do have some toxicities, and ultimately patients want to know, is their disease potentially going to be eradicated by any of these therapies? What we're seeing so far, in terms of their response rates, it's typically around 60% or so. Less than 10% have a complete response, and you still see people develop myeloma, and many times that happens later.⁴ Five-year progression-free survival with daratumumab, for example, is better than active monitoring, but it's not 100%. About 40% of patients still develop myeloma, so it's left a lot of questions about the right intensity of therapy.

Bringing things into the clinic, you use some of these criteria. We use something called the 20-2-20 criteria, where we use certain cutoffs of patients, M-[protein] spikes, light chain ratios, and bone marrow plasma cells. There is also the PANGEA model, which is an evolving criteria where we look at dynamic markers to see if they change over time, and then are able to identify some of these high-risk patients. We look at high-risk cytogenetic abnormalities and other criteria as well.

We put all of this together and then make a determination whether this patient is potentially considered [to have] high-risk smoldering [myeloma], and at which point we discuss…daratumumab or some of our clinical trials [where] we're trying to see [if] a more potent effective therapy leads to even better results.

Could you discuss the design and goals of the CAR-PRISM trial?

CAR T-cell therapy targeting BCMA [B-cell maturation antigen], which is expressed on abnormal plasma cells, has been basically a game-changer for multiple myeloma management over the last 4 or 5 years or so, with our first approval of CAR T cells and relapsed myeloma, and what we've learned in the relapsed setting is that the earlier you give these CAR T cells, the better the outcomes are for these patients. We saw that with cilta-cel, which is our most commonly used CAR T-cell therapy, if patients [who] had it after 3 or more lines of therapy in the CARTITUDE-1 trial [NCT05201781] vs 1 to 3 prior lines of therapy in the CARTITUDE-4 trial [NCT04181827], you started to see outcomes were better.^5,6 This makes sense because the immune system is healthier when patients are earlier in their disease course, and because these are immune therapies, that seems to be better in terms of its efficacy.

The rationale was that you have these [patients with] high-risk smoldering myeloma, they are very early in their disease course, [and] they have not yet developed end organ damage. Can you give an effective, potent CAR-T cell therapy to these patients to essentially eradicate the disease? Since this was the first time this study has been done in smoldering myeloma, we of course wanted to have safety as the primary end point of the study, and we started off by doing a safety run-in of 2 different doses of cilta-cel. Cilta-cel is approved at the 0.5 to 1.0 × 10⁶ CAR-T cells/kg dose. We wanted to start at that lower end of the dosing structure, treat 3 patients with some staggered enrollment to make sure it was safe, and then went on with 3 additional patients at the standard dose, and then opened the expansion cohort. This was a 20-patient study by design to try to see if we can do this safely and then see what long-term outcomes we get.

What were the key outcomes that were reported from this trial?

We enrolled 20 patients into this study when we were in the expansion cohort at the standard dose of cilta-cel.¹ There were a few changes happening in how we use cilta-cel in the relapsed/refractory setting. Namely, when patients develop high absolute lymphocyte counts, we know that could be a marker of potential neurological toxicities with cilta-cel, so we amended the protocol and treated the last 7 patients with a lower dose of cilta-cel at 0.3 × 10⁶CAR-T cells/kg, and also implemented this preemptive dexamethasone strategy for patients [who] have an absolute lymphocyte count of more than 3000/μL just like we do for standard-of-care patients, and ultimately 20 patients were treated.

Two-thirds of these patients met high-risk per the 20-2-20 criteria, although all were high risk by some of the inclusion criteria…. Notably, we excluded patients [who] had more than 40% plasmacytosis because we wanted to avoid high disease burden, since we weren't using any induction or bridging strategies in this particular trial.

After administration of cilta-cel, we didn't see any dose-limiting toxicities at all in the 6 patient safety run, and so we were able to move on to the expansion without any issues. We didn't see any patients with high-grade cytokine release syndrome [CRS]. Everybody had low-grade CRS, and that was very manageable. There was no incidence of late hematologic toxicities or ICANS [immune effector cell–associated neurotoxicity syndrome], which can be a severe complication…along with no cases of enterocolitis or secondary cancers.

What we did see were neurological toxicities that are known to be associated with cilta-cel. We saw cranial nerve palsies in 4 patients, and those ultimately resolved. We had 3 patients with these other NINTs, which are these non-ICANS neurotoxicities, that we have reported in our paper. They're ranging from various symptoms of either neurocognitive changes or some movement disorders that we've seen with cilta-cel in the past. We’ve had some patients [who] have developed a tremor, other patients with some gait instability, and these all improved in the 3 patients [who] had this develop and it all remains grade 1. But at the time the data cutoff, those symptoms were still ongoing in those 3 patients, and we described this at length in our recent publication.

But what was really exciting was that at a median follow-up of a little over 15 months, all of these patients developed MRD [minimal residual disease] negativity. The response rate was 100%, but notably, MRD negativity at 10^-6, which has become the gold standard of how we evaluate effectiveness of any of our myeloma therapies, was universal, and it was seen quite early and remained sustained in all patients at the time of the data cutoff. This is the first time we've seen a single CAR T-cell infusion in a population lead to that degree of depth of response, and it's really exciting to see that it remains sustained in all these patients, raising the possibility that this could have been potentially curative therapy, although we need to now wait for long-term follow-up to see what happens to these patients as they've followed for years and years going forward.

How has the field’s understanding of the NINTs with CAR T developed over time?

Because we're using so much CAR T-cell [therapy] in patients with relapsed myeloma, this is one of the risks with cilta-cel and in some ways broadly with the BCMA-directed CAR-T cell products. This is one of those toxicities, and in the relapsed setting, the rate of some of these parkinsonism-like features can happen in 3% to 5% of patients, and about 10% of patients get cranial nerve palsies.⁷ We've seen similar findings in this study as well. I think it is related to the product, and we will have to understand it better about who's at risk, how to mitigate it, how to prevent it, and how to manage it.

We are getting there with some of these more effective bridging status strategies in the relapsed patients, [giving] the preemptive dexamethasone…. It is notable that in our trial the disease burden at baseline did not seem to predict who developed some of these NINTs, because soluble BCMA was equivalent in patients [who] developed it vs did not. This is a question that comes up, because if we had given them induction therapy or bridging therapy, could this have been mitigated? At least our data so far suggest maybe not, but future studies will be necessary to answer that question.

What are your conclusions from this study, and what are the next steps?

The conclusions here are that you can give cellular therapy with autologous anti-BCMA CAR T-cells to patients earlier in the disease course and see profound activity at even the lowest doses of CAR T cells that have been given in the past, so I think that is encouraging to see, and it confirms the hypothesis that these therapies are way more active earlier in the disease course and may have the potential to eradicate the disease. I think it is a proof of principle study.

Hopefully over time we're going to see more approaches, either with different products or different T cell therapies. There are already trials of bispecific antibodies in this population that are using the T cell mechanism of action. It will be interesting to see how those perform, and those phase 3 trials are already underway with some of those T-cell engagers. But I think the powerful nature of CAR T-cell therapy being one-and-done, and leading to this degree of MRD negativity is really exciting, and my hope is that it's going to lead to more studies in this space in the future.

How do you foresee the approach to smoldering myeloma changing in the future?

I think we're getting better and better at identifying the higher-risk patients, and it's great that we have an approved agent, so that way we can at least have a discussion about early therapy in these patients. But it's always a bit of a risk-benefit decision. These patients are asymptomatic, and it is still treatment, and they have to understand the risk of disease and what that treatment may prevent, which is development of symptomatic myeloma. But I think it's early. It's just setting the stage for more effective therapies to be given to these patients in the future, and that has to be proven in larger phase 3 clinical trials, and thankfully some of those with these T-cell engagers are already ongoing. But I do think this population that is at risk now has some options, and just like we offer patients with multiple myeloma several different therapies that have various degrees of intensity and toxicity profiles and efficacy data, similar things seem to be happening in patients [who] have high-risk smoldering myeloma.

REFERENCES

1. Nadeem O, Cordas dos Santos DM, Nikiforow S, et al. Ciltacabtagene autoleucel in high-risk smoldering multiple myeloma: the CAR-PRISM phase 2 trial. Nature Medicine. Published April 20, 2026. doi: 10.1038/s41591-026-04365-y

2. Lonial S, Jacobus S, Fonseca R, et al. Randomized trial of lenalidomide versus observation in smoldering multiple myeloma. J Clin Oncol. 2020;38(11):1126-1137. doi:10.1200/JCO.19.01740

3. Mateos MV, Hernández MT, Salvador C, et al. Lenalidomide-dexamethasone versus observation in high-risk smoldering myeloma after 12 years of median follow-up time: A randomized, open-label study. Eur J Cancer. 2022;174:243-250. doi:10.1016/j.ejca.2022.07.030

4. Dimopoulos MA, Voorhees PM, Schjesvold F, et al. Daratumumab or active monitoring for high-risk smoldering multiple myeloma. N Engl J Med. 2025;392(18):1777-1788. doi:10.1056/NEJMoa2409029

5. Lin Y, Martin TG, Usmani SZ, et al. CARTITUDE-1 final results: Phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma. J Clin Oncol. 2023;41(suppl 16):8009. doi:10.1200/JCO.2023.41.16_suppl.8009

6. Einsele H, San-Miguel J, Dhakal B, et al. Cilta-cel in lenalidomide-refractory multiple myeloma (CARTITUDE-4): an updated analysis including overall survival from an open-label, multicentre, randomised, phase 3 trial. Lancet Oncol. 2026;27(2):254-268. doi:10.1016/S1470-2045(25)00653-9

7. 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. Published 2022 Feb 24. doi:10.1038/s41408-022-00629-1