Deep Responses Support Push for CAR T-Cell Therapy in AL Amyloidosis

Amyloid light-chain (AL) amyloidosis is a disease with a more challenging prognosis than other plasma cell disorders like multiple myeloma due to cardiac and other organ involvement and lack of survival benefit from many established myeloma therapies. However, using B-cell maturation antigen (BCMA) as a target has shown promise for chimeric antigen receptor (CAR) T-cell therapy, opening up a new single-infusion treatment approach in this rare disease setting.

In the phase 1/2 NEXICART-2 trial (NCT06097832), the investigational CAR T-cell therapy NXC-201 demonstrated deep responses in patients with relapsed/refractory AL amyloidosis with a favorable tolerability profile.¹ As of latest follow-up, there was a complete response (CR) in 19 of 20 evaluated patients with no relapses for these patients, who had a median of 4 prior lines of therapy.² There was a high rate of minimal residual disease (MRD) negativity with MRD at 1 month translating into later achievement of CR within 1 year.

“There is no comparison to this kind of response in the relapsed setting, and that’s truly an area of unmet medical need, where we don’t have any products that are nearly as effective or safe for this patient population,” said Heather J. Landau, MD, in an interview with Targeted Oncology.

Immix Biopharma stated its intention to report further 1-year follow-up data by the end of March 2027, in support of a biologics license application for FDA approval of NXC-201.¹

In the interview, Landau, director of the amyloidosis program and a member of the bone marrow transplant and cellular therapy services at Memorial Sloan Kettering Cancer Center, discussed the key findings from the study while also emphasizing the challenge of developing trials for this disease setting. The disease’s rarity and heterogeneity, as well as regulatory obstacles, have stood in the way of getting new treatments to the AL amyloidosis patient population, but progress is being made toward advancing this therapy to the upfront setting as well as achieving FDA approval.

Targeted Oncology: Could you discuss the background for developing targeted treatments for AL amyloidosis?

Heather Landau, MD: Light chain amyloidosis is a plasma cell disorder where the plasma cells make toxic light chains that misfold and cause organ damage, and in that setting, patients get very sick from not just the underlying hematologic disease but also the organ dysfunction that occurs as a result of this toxic deposition. Amyloidosis is unique because it’s both a hematologic and an organ disease, and it’s a rare disease which has made drug development in this area particularly challenging—not only because it’s not a straightforward hematologic disease, [but] because patients with the most advanced disease have a risk of sudden death. In the early years, we couldn’t even get pharmaceutical companies to partner with us to study their drugs in this patient population that had a risk of sudden cardiac death.

Fortunately, Janssen did the pivotal ANDROMEDA study [NCT03201965], which showed that daratumumab (Darzalex), the anti-CD38 antibody, in combination with standard chemotherapy, was far superior [to] standard chemotherapy alone, and led to the first and only drug regimen approved for this condition.³

[Although] that…has been beneficial for our patients, patients who…have insufficient responses to that therapy or relapse thereafter have a true unmet medical need. They don’t have any available treatment options that are FDA approved, and most of the treatments that we use for a related disease, multiple myeloma…that have been tried in amyloidosis either don’t work or are too toxic. Our patient population is [very] fragile, and therefore the drugs that are available that we borrow from multiple myeloma are often not tolerated well in our patient population.

In the second-line setting and beyond, there’s an unmet medical need for this patient population. The patient population even gets more heterogeneous with the breadth of organ disease [and] the relapse potential, [so] these studies in the second line and beyond have been difficult to meet regulatory approval benchmarks because of the nature of the disease. Fortunately, I was able to work with this company who’s developing this BCMA-directed CAR T-cell [therapy], which had preliminary efficacy in the AL [amyloidosis] population in an initial trial [NCT04720313] out of Israel, which was at the time the only CAR T-cell study that was designed for patients with multiple myeloma, but allowed [patients with AL amyloidosis] in it. There was some preliminary efficacy,⁴ which led to the current trial, which was the first CAR T-cell trial that was designed specifically for patients with AL amyloidosis.

How was the NEXICART-2 (NCT06097832) trial designed to investigate this therapy?

The current clinical trial was designed as a phase 1b/2 trial where we enrolled the first 3 patients at the lowest dose, and without any dose limiting toxicity, we escalated the dose. Forty-two patients have been treated with this product at [up to] 450 × 10⁶ BCMA-directed CAR T cells/kg and...there has been no dose-limiting toxicity, and the trial has now been completed.

How has this therapy performed in this trial?

In February, I reported on the first 23 patients,⁵ and at that time, based on the data cutoff, there was a 74% complete hematologic response rate, but several of the patients had met the end point of MRD [minimal residual disease] negativity in the bone marrow. What that means is that we expect those patients to evolve into complete hematologic responses, because we test the hematologic response by the serologic marker, and sometimes that takes some time to go away. The finding that the majority of patients who were tested at day 25 had no evidence by our most sensitive methods of any abnormal plasma cells in the bone marrow, and in fact we saw even at earlier time points, day 7 or day 14, that the free light chains normalized very rapidly in everybody with this product, [which] was very promising.

Could you discuss the tolerability observed with this CAR T product?

In the first 23 patients, 78% did experience cytokine release syndrome [CRS], which is a common toxicity in patients who get T-cell redirecting therapies, but that happened very quickly and very predictably in the first 24 to 48 hours and lasted a median of 1 day. It’s a very manageable toxicity, where patients get tocilizumab [Actemra], and it’s easily reversed. Due to the lymphodepleting chemotherapy, patients did experience very short-lived cytopenias, mostly neutropenia, but that recovered very quickly, and there were no episodes of neutropenic infection.

Otherwise…these patients did not experience any [immune effector cell–associated] neurotoxicity on this treatment. Delayed neurotoxicity has also been one of our most feared complications of current BCMA-directed CAR T cells…and we have pretty long follow-up for some of our earliest patients, and there is no evidence of delayed neurotoxicity in this patient population with this product.

Did anything else stand out to you about this trial that you found striking?

What was really impressive and different was what we saw was the patients who were sickest coming into the trial, who had high light chains or obvious organ progression due to their relapsing disease, experienced significant clinical benefit very rapidly—as soon as the light chains were controlled. I can’t say I’ve witnessed that with any other therapy that I’ve given. It’s remarkable and dramatic when patients who come in with escalating symptoms from their disease, and as soon as you turn off the ‘spigot’ of toxic light chains, they really improve quite a bit. It’s hard to understand, because we don’t get rid of the amyloid deposits that are already there, but I think the continuous toxic insult that they’re experiencing is a source of continuous insult to patients’ organs.

The other thing about CAR T cells is the liberty that our patients experience with having a one-and-done approach, meaning a single infusion result results in complete responses, and then the patients don’t have to experience ongoing therapy, which is what they’ve received and come to expect. Almost all of our therapies have been continuous for quite some time, and so there is benefit of liberating patients after a one-time investment. In this current clinical trial, we were hospitalizing everybody for 10 days after their infusion, so it was quite an investment in terms of time and commitment—yet, thereafter not having to come to the infusion center every week, or every other week, is a gift to these patients.

What are the next steps and how do you see the future of treating patients with AL amyloidosis?

There is no comparison to this kind of response in the relapsed setting, and that’s truly an area of unmet medical need, where we don’t have any products that are nearly as effective or safe for this patient population. We anticipate regulatory approval in the relapsed setting—I can’t say it’s guaranteed, but I’m hopeful that the regulators will understand that this data is transformative for this patient population, and then we’ll be able to offer it to other patients in this space, because it’s a challenging space to not have any effective or safe therapies. I believe that the company is planning an upfront study, because treating patients in the upfront setting with very effective single-infusion therapy that results in elimination of pathologic plasma cells and toxic light chains within 7 to 14 days would be very beneficial for this patient population. Time to response is an important end point for preserving organ function.

What do you feel is most crucial to be aware of in developing therapies for this disease?

The regulatory pathway to drug development in this disease has been exquisitely challenging. For multiple myeloma, 20 drugs [have been FDA approved] in the last 20 years, and we have a single approval for our [patients with AL amyloidosis], which has been quite sobering.

We’re studying BCMA-directed therapies in this space, and there are excellent response rates and safety profiles that are unprecedented, but regulators are mandating randomized clinical trials to prove the benefit of these transformative therapies. I find it a big issue when you have a rare disease to have to do a large, randomized trial, which can only be ethically done in the upfront setting, because there’s nothing approved in the relapsed setting. The result is that the drug companies are putting resources into doing these upfront trials with drugs that are potentially effective, and there is a void of trials or available therapies in the relapsed space because of the way our regulatory development pathway is constructed. Ideally, in a rare disease, accelerated approval based on single-arm phase 2 trials should be granted [for a therapy that] has a favorable safety profile and very deep hematologic responses, which is a surrogate for overall survival in this disease. It is [frustrating] that it will take more resources and years to make effective therapies available to patients.

Otherwise, I do think that the future will eventually be bright for our patients with AL amyloidosis. We have products that work and are safe, and I feel that our patients will benefit. Getting these products to patients is the current uphill battle.

REFERENCES

1. Landau H, Raza S, Rosenberg A, et al. First 20-patient safety and efficacy data from nexicart-2, the first U.S. trial of CAR-T in R/R light chain (AL) amyloidosis, NXC-201. Blood. 2025;146(suppl 1):696. doi:10.1182/blood-2025-696

2. Immix Biopharma announces 95% complete response rate in interim update from relapsed/refractory AL amyloidosis clinical trial NEXICART-2. News release. Immix Biopharma. May 21, 2026. Accessed June 22, 2026. https://tinyurl.com/4vu2zrav

3. Kastritis E, Palladini G, Minnema MC, et al. Daratumumab-based treatment for immunoglobulin light-chain amyloidosis. N Engl J Med. 2021;385(1):46-58. doi:10.1056/NEJMoa2028631

4. Lebel E, Kfir-Erenfeld S, Asherie N, et al. Feasibility of a novel academic anti-BCMA chimeric antigen receptor t-cell (CART) (HBI0101) for the treatment of relapsed and refractory AL amyloidosis. Blood. 2023;142(suppl 1):538. doi:10.1182/blood-2023-186450

5. Landau HJ, Raza S, Rosenberg A, et al. First 23-patient safety and efficacy data from Nexicart-2, the first U.S. trial of CAR-T in R/R light chain (AL) amyloidosis, Nxc-201. Transplant Cell Ther. 2026. 32(suppl 2):S4. doi:10.1016/j.jtct.2025.12.018