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Answers in AL Amyloidosis
Answers in AL Amyloidosis Diagnosis and Treatment to Optimize Personalized Care

Released: March 31, 2026

Anita D'Souza
Anita D'Souza, MD, MS
Jeffrey Zonder
Jeffrey Zonder, MD
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Key Takeaways
  • Diagnosing AL amyloidosis at an early stage requires a systematic approach with laboratory testing, multimodal cardiac assessment, and a confirmatory tissue biopsy with amyloid subtyping.  
  • Emerging treatment options for AL amyloidosis span multiple therapeutic classes, including plasma cell–directed therapies, BCMA-targeted immunotherapies, BCL-2 inhibitors, and anti–amyloid fibril antibodies, and will require careful patient selection based on disease biology, organ involvement, and prior therapy.
  • Long-term outcomes depend not only on achieving deep hematologic responses but also on coordinated multidisciplinary care to manage persistent cardiac, renal, gastrointestinal, and other organ-related complications.

Introduction
During the live webinar, “Transformative Advances and the Future of Personalized Care—Insights From the 2025 Hematology Meeting,” expert faculty discussed data from groundbreaking clinical studies presented at the American Society of Hematology Annual Conference in December 2025 and ongoing areas of emerging therapeutics in amyloid light-chain (AL) amyloidosis. In this ClinicalThought commentary, Anita D’Souza, MD, MS, and Jeffrey Zonder, MD, translate the findings into their own practice by discussing patient cases and providing their perspectives on important topics, highlighting future clinical implications in this area.

A 68‑year‑old patient presents with progressive fatigue and exertional dyspnea. During the past year, the patient also has developed mild lower extremity edema, intermittent diarrhea, and bilateral carpal tunnel syndrome. Echocardiogram shows preserved ejection fraction with diastolic dysfunction, and routine laboratory studies are otherwise unremarkable. When a patient presents with the symptoms in the case described above, how would you approach assessing the patient for AL amyloidosis?

Anita D’Souza, MD, MS:
When AL amyloidosis is suspected in a patient presenting with multisystem symptoms, I employ a systematic diagnostic approach using laboratory testing, cardiac biomarkers, and imaging. It is important to consider these tests alongside a patient’s history and physical examination findings while remembering what defines the high-risk populations: older adults, Black patients, and those who have a known plasma cell or lymphoproliferative clonal disease. Following the approach outlined will reduce the time between symptom onset and diagnosis, allowing patients to start treatment much earlier.

Beginning with laboratory testing, patients should undergo comprehensive screening for abnormal monoclonal proteins (or M-proteins), a serum free light chain assay, and urine protein electrophoresis with immunofixation performed. Specific to cardiac biomarkers, serum N-terminal pro-B-type natriuretic peptide (NT-proBNP) and troponin can suggest cardiac involvement.

If M-protein and laboratory testing confirm a plasma cell disorder, a tissue biopsy is required to confirm the diagnosis of AL amyloidosis. Sampling the abdominal fat pad combined with a bone marrow biopsy has a high sensitivity for AL amyloidosis. If the initial biopsy is negative but clinical suspicion remains high, a subsequent biopsy should occur on the target organ where amyloid involvement is suspected, like the kidneys, heart, or liver. Amyloid deposition is confirmed with Congo red or thioflavin T–positive or thioflavin S–positive staining of the tissue samples. Following confirmation of tissue amyloid deposition, timely amyloid subtyping with methods, such as mass spectrometry or immunohistochemistry, is also important.

Noninvasive cardiac imaging plays a key role in identifying cardiac involvement in AL amyloidosis. An echocardiogram that uses ultrasound to evaluate the heart can also provide important clues, including low-voltage QRS complexes, pseudoinfarct patterns, and arrhythmias. Echocardiography, particularly with strain imaging, can show other signs of cardiac involvement, like diastolic dysfunction, left ventricular hypertrophy, or thickened interventricular septum, especially when accompanied by an apical sparing (characteristic “cherry on top”) pattern. Cardiac MRI with contrast can show multiple clues, including increased extracellular volume, a higher native T1 values, and the classic delayed gadolinium enhancement pattern.

Evaluation should also assess other organ involvement, including screening for albuminuria or elevated creatinine for kidney disease, elevated alkaline phosphatase or bilirubin for liver involvement, including a physical examination, and nerve conduction velocity studies for neuropathy. Screen patients with extensive bruising, such as periorbital purpura, for factor X deficiency, which can develop in patients with AL amyloidosis.

A 70-year-old man with relapsed AL amyloidosis after initial treatment presents with worsening cardiac and renal involvement. He now has organ damage and requires a personalized treatment strategy. What second-line therapy could you consider for this patient?

Anita D’Souza, MD, MS:
For newly diagnosed AL amyloidosis, daratumumab in combination with cyclophosphamide, bortezomib, and dexamethasone (Dara-CyBorD) is the current standard of care based on data from the phase III ANDROMEDA trial demonstrating superior hematologic and organ response rates compared with CyBorD alone. There are no approved therapies for relapsed or refractory AL amyloidosis, and treatment selection is guided by prior therapies, cytogenetic features such as t(11;14), organ involvement, and patient fitness. There are several effective therapies targeting plasma cell disorders approved in multiple myeloma that can be used in the relapsed AL amyloidosis setting. 

Retreatment with Dara-CyBorD can be considered in patients who had prior durable response to this regimen. Patients without prior anti-CD38 exposure can consider treatment with either Dara or isatuximab. For patients who have not previously received proteasome inhibitors, a bortezomib-based regimen is reasonable or carfilzomib can also be considered. Of importance, patients who have advanced cardiac involvement with relapsed AL amyloidosis, like this patient case, may not tolerate cardiotoxic drugs such as carfilzomib. For patients with t(11;14), the BCL-2 inhibitor venetoclax has demonstrated high activity and can be considered in this setting. Immunomodulatory drugs (IMiDs), such as lenalidomide and pomalidomide, as well as alkylating agents, like melphalan or bendamustine, may also be considered. Of note, IMiDs may increase cardiac biomarkers, such as NT-proBNP and troponin, despite hematologic response, and this effect should not be misinterpreted as disease progression or cardiotoxicity.

Jeffrey Zonder, MD:
BCMA is an established target in plasma cell dyscrasias and is an area of active investigation in AL amyloidosis. Although BCMA-targeted bispecific antibodies (teclistamab and elranatamab), CAR T-cell therapies (idecabtagene vicleucel and ciltacabtagene autoleucel), and antibody–drug conjugates (belantamab mafodotin) are approved for patients with multiple myeloma, these soon may be additional options for patients with AL amyloidosis.

Recent clinical trials have demonstrated promise for investigational BCMA-directed CAR T-cell therapy in relapsed or refractory AL amyloidosis. The BCMA-targeted CAR T-cell therapy NXC-201 has shown promising hematologic responses in phase I/II trials. The BCMA/CD19 dual-targeting CAR T-cell therapy AZD0120 is currently also in phase I/II trials and results are expected soon.

New BCMA-targeted bispecific T-cell engagers are also in development for patients with relapsed AL amyloidosis who have advanced cardiac involvement. For example, etentamig is a second-generation bispecific antibody with bivalent targeting of BCMA and CD3 but with lower affinity and a longer half-life, permitting monthly dosing. Etentamig showed promising efficacy in the dose escalation portion of phase I/II trial while also reporting a fairly low incidence of cytokine release syndrome, infections, and treatment-emergent hematologic adverse events (AEs).

There is also a new phase I study of ramantamig, a trispecific antibody that targets BCMA, GPRC5D, and CD3, that includes patients with relapsed or refractory AL amyloidosis. Trispecific antibodies have shown promise in multiple myeloma, so I am excited to see how this ends up working in AL amyloidosis. However, it is important to remember that GPRC5D has on-target off-tumor effects, so investigators will need to be on the lookout for skin, nail, taste, tongue, and gastrointestinal AEs that can happen with GPRC5D-targeted therapy.

Anita D’Souza, MD, MS:
Indeed, the BCMA-directed therapies have demonstrated encouraging activity in retrospective studies on their use in patients with relapsed or refractory AL amyloidosis. However, they have unique AEs that can lead to dose interruptions, dose modifications, and even death in some cases. Particularly for patients who have multiorgan involvement, the AEs associated with CAR T-cell therapy and T-cell engagers, such as cytokine release syndrome and immune effector cell–associated neurotoxicity syndrome, cytopenias, and an increased risk of long-term infection, can be challenging. I am looking forward to seeing more prospective clinical trials with BCMA-directed therapy for patients with AL amyloidosis including finite duration of therapy with BCMA bispecific antibodies.

Monoclonal antibodies targeting amyloid fibrils have been investigated as a strategy to directly clear deposited amyloid and improve organ function. One of these agents, birtamimab, was evaluated in the phase III AFFIRM-AL trial in patients with newly diagnosed, Mayo stage IV AL amyloidosis, but this study did not reach its primary or secondary endpoints and development has been discontinued.

More recently, the phase III CARES-301 and CARES-302 studies evaluated anselamimab in patients with Mayo stage IIIa and IIIb AL amyloidosis who were treatment naive. A recent press release revealed that although the primary endpoint (a hierarchical combination of time to all-cause mortality and frequency of cardiovascular hospitalizations) was not met, there was a prespecified subgroup of patients with AL amyloidosis that had a meaningful improvement in these endpoints.

Data suggest that t(11;14) translocations are present in 40% to 50% of patients with AL amyloidosis and was previously associated with worse prognosis. What current data show promise for this specific subpopulation of patients with AL amyloidosis?

Anita D’Souza, MD, MS:
Stem cell transplantation is an effective option for patients with AL amyloidosis, but only 15% to 20% of newly diagnosed patients with AL amyloidosis are eligible for transplant because of age, comorbidities, and extent of organ involvement. Retrospective studies suggest that patients with t(11;14) who undergo stem cell transplantation have similar outcomes to those without t(11;14), potentially mitigating the adverse prognostic impact associated with this cytogenetic abnormality. Of note is the ongoing phase III SWOG 2213 trial, which is randomizing patients who receive 3 cycles of Dara-CyBorD induction to consolidation with either high-dose melphalan and autologous stem cell transplant or 3 additional cycles of Dara-CyBorD, followed by maintenance Dara for all patients. The results of this trial will help clarify the role of upfront transplantation in the era of Dara-based therapy.

As mentioned earlier, BCL-2 inhibitors like venetoclax are a key treatment option for patients with t(11;14)-positive AL amyloidosis after standard therapy. Multiple retrospective single-center and multicenter studies have demonstrated high response rates and encouraging survival with venetoclax in this patient population. In terms of safety, infections have been manageable to date, although continued monitoring for cytopenias and infectious complications remains important.

Jeffrey Zonder, MD:
I agree. A prospective phase I/II trial is assessing venetoclax and dexamethasone in patients with t(11;14)-positive AL amyloidosis after ≥1 prior line of therapy, including an anti-CD38 antibody. Preliminary data of the first 12 patients showed an overall response rate of 92%, with a median time to best response of 0.9 months (within 1 cycle of starting treatment). In terms of AEs, so far, infections have been quite manageable with 1 patient reporting a grade 3 infection (COVID-19).

It is important to remember that multidisciplinary care is critical for optimal management of patients with AL amyloidosis. These patients are often frail because of significant organ involvement and related symptom burden. We are entering an era where advances in therapy have made deep hematologic responses achievable for most patients, but ongoing multidisciplinary support is necessary to manage long-term cardiac, gastrointestinal, renal, and other organ-related complications. 

Your Thoughts
How do you select and sequence individualized treatment for patients with AL amyloidosis in your practice?

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In your current practice, which of the following areas represents the greatest opportunity to improve care for patients with AL amyloidosis?

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