Key Ideas

AL amyloidosis remains a frequently missed, "sneaky" diagnosis, but the treatment landscape is genuinely transforming: a novel CAR T-cell product designed specifically for this fragile population is showing rapid, deep responses, a kappa-specific anti-amyloid-fibril antibody has shown an all-cause mortality benefit, and bispecific antibodies are opening new options both in relapsed amyloidosis and in extramedullary myeloma, a historically underserved and aggressive subset.

Borrowing From Myeloma, and a Shift Toward Bispecifics

Because BCMA is highly expressed on malignant plasma cells generally, including in AL amyloidosis, many BCMA-targeted therapies developed for multiple myeloma are increasingly being applied across other plasma cell disorders. Bispecific antibodies in particular are seeing growing use, including for extramedullary myeloma, a rare, aggressive subset in which myeloma cells exit the bone marrow and settle into soft tissue organs.

Why AL Amyloidosis Is So Often Missed

AL amyloidosis is genuinely one of the "sneaky" diseases, masquerading as many other conditions, and patients often reach a specialist only after developing full-blown heart failure and kidney failure. The practical takeaway: whenever a patient presents with nonspecific symptoms (unexplained weight loss, shortness of breath, generally "not doing well" without a clear explanation), checking a total protein, serum immunofixation, and free light chains is warranted, and if any plasma cell disorder is found, amyloidosis should be on the differential, with tissue biopsy pursued early. Early biopsy is genuinely key to catching this disease before organ damage becomes severe.

Frontline Treatment: Daratumumab-CyBorD Remains Standard

The ANDROMEDA trial established daratumumab plus cyclophosphamide-bortezomib-dexamethasone (Dara-VCd) as the standard frontline regimen for AL amyloidosis. Five-year follow-up data, presented at ASH and subsequently published in Blood, showed that the composite endpoint (a combination of organ progression, treatment change, and death) was met in favor of the daratumumab combination: roughly 60% versus 33% event-free at 5 years for the daratumumab-containing regimen compared with the triplet used previously, nearly doubling this measure. An overall survival benefit with the daratumumab combination was also observed. This doublet targeting the underlying plasma cell clone remains the frontline standard.

A First CAR T-Cell Product Purpose-Built for a Fragile Population

NXC-201, evaluated in the multicenter NEXICART-2 trial, is the first CAR T-cell product studied specifically in AL amyloidosis. Because these patients tend to be sicker and less able to tolerate the toxicity of conventional CAR T-cell products, particularly patients with underlying heart failure, NXC-201 was sterically optimized specifically to reduce cytokine release syndrome (CRS) risk.

Results presented at ASH by Dr. Heather Landau (Memorial Sloan Kettering) were striking: at a median follow-up of about 8 months, nearly all patients had a rapid, deep drop in their free light chains (the immunoglobulin fragments that form amyloid deposits), with most patients achieving a complete hematologic response, and most evaluable patients also showing organ responses, meaning improvement in heart, kidney, and liver function. CRS was low-grade, occurred early, and resolved quickly, typically after a single dose of tocilizumab. Given the need for particular caution around cardiac toxicity in this population, only two patients experienced atrial arrhythmia flares, both easily controlled. This program is moving forward with additional clinical trials and will likely be considered for FDA approval in the future; for now, it represents a genuinely promising, if still investigational, option.

Anti-Amyloid-Fibril Antibodies: Real Progress, With an Important Caveat

Rather than targeting the plasma cell that produces the amyloid precursor, anti-fibril antibodies target the misfolded protein itself, the amyloid deposits already present in organs. Two antibodies have been studied in this space, with very different outcomes. One (birtamimab) did not meet its primary endpoint in a large phase 3 trial, and its development has been halted. The other, anselamimab (formerly known as CAEL-101), was studied in combination with quadruplet plasma-cell-directed therapy (Dara-VCd) and showed an improvement in all-cause mortality, but importantly, only in patients with kappa light chain amyloidosis; patients with lambda light chain disease did not show the same benefit. This is a real limitation, since lambda light chain amyloidosis is more common than kappa in most amyloidosis populations. If approved, anselamimab will likely be positioned as an addition to standard plasma-cell-directed therapy specifically for kappa light chain patients, rather than as a universal option.

Bispecific Antibodies Are Moving Into Amyloidosis

Real-world data from a multi-institutional consortium using BCMA-directed bispecific antibodies (such as elranatamab) in AL amyloidosis showed a response rate of roughly 76%, with a high rate of complete responses and organ responses as well. This has opened the door to dedicated prospective studies: a relapsed/refractory trial of elranatamab (a Pfizer BCMA bispecific) is now open in collaboration with Dana-Farber, and a frontline bispecific study is planned to open soon. The treatment paradigm for AL amyloidosis is shifting steadily toward greater incorporation of both bispecific antibodies and, eventually, anti-fibril antibodies, alongside continued use of subcutaneous approaches to existing agents that have shown good tolerability in this generally frailer patient population.

POEMS Syndrome: A Hard-to-Diagnose Syndrome With a Younger Patient Population

POEMS syndrome (polyneuropathy, organomegaly, endocrinopathy, M protein, skin changes) is genuinely difficult to diagnose, and patients frequently arrive after being evaluated by multiple specialists, often including neurology for the neuropathy component, before the diagnosis is made. Unlike myeloma, which typically presents in a patient's late 60s to early 70s, POEMS tends to present earlier, often in a patient's 50s.

Diagnosis requires two mandatory criteria (polyneuropathy and a monoclonal plasma cell disorder, almost always producing lambda light chain), plus at least one of three major criteria (which include Castleman disease, sclerotic bone lesions, and elevated VEGF), plus at least one of several minor criteria. Because the diagnosis doesn't strictly require detecting a large amount of monoclonal protein, any patient presenting with neuropathy should have a serum immunofixation performed; a positive result should prompt further workup for this syndrome, since it's frequently missed by clinicians (including in neurology, where cluster headache-type workups are sometimes pursued instead) who aren't specifically thinking about it.

Skin findings can be genuinely helpful for diagnosis and for monitoring treatment response over time: glomeruloid angiomas, acrocyanosis, hyperemia, and whitened fingernails are all characteristic. The neuropathy in POEMS can closely resemble chronic inflammatory demyelinating polyneuropathy (CIDP), but sural nerve sparing (seen in CIDP but not in POEMS) helps distinguish the two, alongside checking VEGF, which is quite specific (though not very sensitive) for POEMS when elevated in the right clinical context. A confirmed EMG showing true neuropathy is essential before making this diagnosis; a substantial number of patients referred with a presumed "neuropathy" turn out not to have one on formal testing.

Treatment is guided by disease burden: patients with only one or a few plasmacytomas and a clean bone marrow can often be cured with radiation targeted at the lesion alone, with cure rates above 70% in this scenario. Patients with two or more plasmacytomas, or with bone marrow involvement, require systemic treatment, generally followed by autologous stem cell transplant once patients have recovered enough from their neuropathy to tolerate it (many patients present quite debilitated, sometimes wheelchair-bound, making the timing of transplant an important individualized decision).

Extramedullary Myeloma: New Hope From Dual-Targeted Bispecifics

Extramedullary myeloma, where myeloma exits the bone marrow and involves organs such as the pancreas, muscle, or lung, is an aggressive subset historically associated with survival of only 3 to 4 months even with the best available therapy, and these patients have been chronically underrepresented in clinical trials, in part because many have nonsecretory or oligosecretory disease that's hard to monitor with standard blood tests.

A study combining the GPRC5D-directed bispecific antibody talquetamab with the BCMA-directed bispecific antibody teclistamab (the RedirecTT-1 trial) produced a response rate of roughly 79% to 80% in this population, compared with a historical response rate closer to 20-30% with older approaches, a genuinely dramatic improvement. Responses were seen even in patients previously treated with anti-BCMA therapy. This combination is now included in NCCN guidelines, and clinicians managing myeloma patients with extramedullary disease should strongly consider a bispecific combination approach, ideally alongside consideration of CAR T-cell therapy or a clinical trial where feasible.

For Patients

AL amyloidosis is a rare disease in which abnormal proteins produced by plasma cells misfold and deposit in organs, particularly the heart and kidneys, causing progressive damage. It's frequently missed early on because its symptoms (fatigue, weight loss, shortness of breath) can look like many other things, so patients often aren't diagnosed until the disease is more advanced. Anyone with unexplained, persistent symptoms like these, especially alongside any evidence of a plasma cell disorder, should be evaluated for this condition, ideally with an early tissue biopsy.

Treatment for AL amyloidosis is advancing quickly. The current standard combines an antibody drug (daratumumab) with chemotherapy, but newer options are emerging, including a CAR T-cell therapy specifically designed to be gentler for this often frailer patient population, and antibody-based drugs that target the amyloid deposits directly rather than just the cells producing them (though one such drug appears to work only for a specific subtype of the disease, called kappa light chain amyloidosis).

POEMS syndrome is a separate, rare, and often difficult-to-diagnose condition that combines nerve damage, organ enlargement, hormone problems, an abnormal blood protein, and skin changes. It's frequently mistaken for other neurological conditions before the correct diagnosis is made, so anyone with unexplained neuropathy should be tested for an abnormal blood protein as part of their workup.

Extramedullary myeloma, a rare and aggressive form of multiple myeloma that spreads outside the bone marrow into other organs, has historically had very poor outcomes, but a new combination of two antibody-based drugs has shown a dramatic improvement in response rates, offering real hope for a group of patients who previously had very limited options.

Anyone facing one of these rare diagnoses should ask their care team about referral to a center with specific experience in plasma cell disorders and amyloidosis, and about whether newer therapies or a clinical trial might apply to their situation.

Key Takeaways

  • AL amyloidosis is frequently missed early because its symptoms mimic many other conditions; checking serum immunofixation and free light chains, with early biopsy when a plasma cell disorder is found, is key to timely diagnosis.

  • Daratumumab plus CyBorD (ANDROMEDA regimen) remains the frontline standard for AL amyloidosis, with 5-year follow-up confirming both event-free and overall survival benefit.

  • NXC-201, a sterically optimized CAR T-cell product designed specifically for AL amyloidosis, has shown rapid, deep hematologic and organ responses with low-grade, manageable CRS in early trial data.

  • Anselamimab (CAEL-101), an anti-amyloid-fibril antibody, showed an all-cause mortality benefit only in kappa light chain amyloidosis, not lambda; a competing agent (birtamimab) failed its phase 3 trial.

  • POEMS syndrome is a hard-to-diagnose, plasma-cell-related syndrome presenting earlier in life than myeloma; serum immunofixation should be checked in any patient with unexplained polyneuropathy.

  • Extramedullary myeloma, historically associated with survival of only 3-4 months, is now showing response rates near 80% with the talquetamab-teclistamab bispecific combination (RedirecTT-1 trial), now included in NCCN guidelines.

References

  1. Kastritis E, Palladini G, Minnema MC, et al. Daratumumab-based therapy in newly diagnosed AL amyloidosis (ANDROMEDA), 5-year follow-up. Blood. 2025.

  2. Landau HJ, et al. Initial safety and efficacy data from NEXICART-2, the first US trial of NXC-201 CAR T-cell therapy in relapsed/refractory AL amyloidosis. Presented at 2025 ASH Annual Meeting. Abstract 696.

  3. Gertz MA, Cohen AD, Comenzo RL, et al. Birtamimab plus standard of care in light-chain amyloidosis: the phase 3 randomized placebo-controlled VITAL trial. Blood. 2023.

  4. Efficacy and safety of anselamimab in immunoglobulin light chain amyloidosis: results from the randomized CARES trials. J Clin Oncol. 2026.

  5. Kumar S, et al. Talquetamab plus teclistamab in relapsed or refractory multiple myeloma with extramedullary disease (RedirecTT-1). N Engl J Med. 2025.

  6. Dispenzieri A. POEMS syndrome: 2023 update on diagnosis, risk-stratification, and management. Am J Hematol. 2023.

  7. Khouri J, Nakashima M, Wong S. Update on the Diagnosis and Treatment of POEMS (Polyneuropathy, Organomegaly, Endocrinopathy, Monoclonal Gammopathy, and Skin Changes) Syndrome: A Review. JAMA Oncol. 2021;7(9):1383–1391. doi:10.1001/jamaoncol.2021.0586