Key considerations when selecting treatment for patients with AL amyloidosis
The first highlight article from the 18th International Symposium on Amyloidosis (ISA) 2022 is an overview of the Satellite Symposium, “Navigating the patient journey in AL amyloidosis: a multidisciplinary” presented by Giovanni Palladini from the Amyloidosis Research and Treatment Center, University of Pavia and IRCCS Fondazione Policlinico San Matteo, Italy on Monday 6 September 2022 in Heidelberg, Germany.
Professor Giovanni Palladini opened his lecture by observing that amyloid light-chain (AL) amyloidosis is both a haematological and an organ disease. This fact can help inform treatment decisions for AL amyloidosis, because healthcare professionals can follow the efficacy of treatments with biomarkers specific to haematologic and organ response.
A rapid and clinically significant reduction in the amyloid protein (free-light chains) is essential to achieving beneficial haematologic and organ responses. As Professor Giovanni Palladini stated, “The deeper [reduction] the better, the quicker the better”. One month is the ideal window to achieve amyloid reduction.
Treatment selection in AL amyloidosis is determined by several interacting factors:
- Expected efficacy (response speed, rate, and duration)
- Characteristics of the clone (size, chromosomal abnormalities)
- Access to drugs (clinical trials)
- Severity of organ involvement (biomarkers)
- Specific contraindications (renal failure, neuropathy)
- ‘Frailty’ (age, comorbidities)
- Patient’s preference (occupation, family issues)
First-line treatment that is well-chosen can trigger early improvement of organ dysfunction, permitting consideration of more aggressive second-line treatments
Guideline recommendations: treatment selection for AL amyloidosis
Step 1. Assess patient eligibility for autologous stem-cell transplant (ASCT)
The first step in treatment selection for AL amyloidosis, based on clinical practice and guidelines1,2, is to assess patient eligibility for autologous stem-cell transplant (ASCT). In many European countries, ASCT is a second-line treatment. Well-selected patients for ASCT can reduce patient mortality. Biomarkers, patient age (≤65 years of age), and residual organ dysfunction are key inclusion criteria for ASCT1.
Induction is a sequential response-driven approach offering patients ASCT, only if they show an unsatisfactory response following a bortezomib-based regimen ± daratumumab, for 2–4 cycles1. If the patient responds well to induction treatment (‘complete response’, CR), there is an option to observe without ASCT1.
In most cases of ASCT, patients receive melphalan 200 mg. Lower doses of melphalan can be used in patients with lower glomerular filtration rates. The endpoint of ASCT is haematologic ‘very good partial response’ (VGPR)1.
Step 2. Assess specific comorbidities in people who are not transplant candidates
The most common comorbidity in AL amyloidosis is neuropathy. Neuropathy can prevent patients from using bortezomib2.
If there is no evidence of neuropathy, the standard of care for cardiac stage I-IIIa is Dara-CyBorD (daratumumab-cyclophosphamide, bortezomib, dexamethasone). If this first option is not available, CyBorD, or BMDex (bortezomib, melphalan, dexamethasone), can be considered. In cardiac-stage IIIb, first-option is dose modified Dara-CyBorD, or daratumumab single agent2.
In there is evidence of neuropathy, for all cardiac stages, first option is daratumumab single agent2.
In ANDROMEDA, a phase 3 trial of daratumumab plus CyBorD versus CyBorD, higher rates for haematologic, cardiac and renal responses, including VGPR and CR, were shown for daratumumab plus CyBorD3.
Professor Giovanni Palladini noted that access to Dara-CyBorD is still limited in specific populations, such as pre-treated patients, or patients with comorbidities.
Step 3. Assess response to treatment
Reduction in free-light chains should be assessed for improvements in organ dysfunction using the BNP (brain natriuretic peptide) biomarker.
Grading of organ response is a new development in the AL amyloidosis field. Greater reduction in biomarkers of organ damage is associated with longer patient survival. Professor Giovanni Palladini opined that these markers should be carefully monitored during patient follow-up.
Monitoring schedule during and after treatment
In treatment monitoring, CR or VGPR plus organ response at 6–12 months is insufficient; a ‘deep’ organ response is also needed. The concept of ‘haematologic treatment relapse’ in the AL amyloidosis setting is not yet defined in the field.
If CR or VGPR plus organ response at 6–12 months, VGPR after 2 cycles, and PR after 1 cycle, is not evident, Professor Giovanni Palladini suggested that rescue therapy, based on daratumumab, ixazomib, or venetoclax, among others, be considered.
For managing AL amyloidosis, healthcare professionals are ‘well armed’. A standard of care has been developed, although further clinical trials of new agents are needed, especially for patients exposed to daratumumab, or those with comorbidities. Collaborative studies are required to determine treatment endpoints, and a definition of haematologic relapse.
- Sanchorawala V, Boccadoro M, Gertz M, Hegenbart U, Kastritis E, Landau H, et al. Guidelines for high dose chemotherapy and stem cell transplantation for systemic AL amyloidosis: EHA-ISA working group guidelines. Amyloid. 2022;29(1):1–7.
- Wechalekar AD, Cibeira MT, Gibbs SD, Jaccard A, Kumar S, Merlini G, et al. Guidelines for non-transplant chemotherapy for treatment of systemic AL amyloidosis: EHA-ISA working group. Amyloid. 2022:1–15.
- Kastritis E, Palladini G, Minnema MC, Wechalekar AD, Jaccard A, Lee HC, et al. Daratumumab-Based Treatment for Immunoglobulin Light-Chain Amyloidosis. New Eng J Med. 2021;385(1):46–58.
- A Study to Evaluate the Efficacy and Safety of CAEL-101 in Patients With Mayo Stage IIIb AL Amyloidosis. 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT04512235.
- A Study to Evaluate the Efficacy and Safety of CAEL-101 in Patients With Mayo Stage IIIa AL Amyloidosis. 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT04504825.
- A Study to Evaluate the Efficacy and Safety of Birtamimab in Mayo Stage IV Patients With AL Amyloidosis. 2022. Available at: https://clinicaltrials.gov/ct2/show/NCT04973137.
- Gertz MA, Tripuraneni R, Kinney GG. Birtamimab in Patients with Mayo Stage IV AL Amyloidosis: Rationale for Confirmatory Affirm-AL Phase 3 Study Design. Blood. 2021;138:2754.
- Edwards CV, Rao N, Bhutani D, Mapara M, Radhakrishnan J, Shames S, et al. Phase 1a/b study of monoclonal antibody CAEL-101 (11-1F4) in patients with AL amyloidosis. Blood. 2021;138(25):2632–2641.
- Valent J, Zonder JA, Liedtke M, Silowsky J, Kurman MR, Daniel E, et al. Safety and Tolerability of Cael-101 in Combination with Anti-Plasma Cell Dyscrasia Therapy in Patients with AL Amyloidosis: 1-Year Results from an Open-Label Phase 2 Trial. Blood. 2021;138:468.
- Gertz MA, Landau H, Comenzo RL, Seldin D, Weiss B, Zonder J, et al. First-in-Human Phase I/II Study of NEOD001 in Patients With Light Chain Amyloidosis and Persistent Organ Dysfunction. J Clin Oncol. 2016;34(10):1097–1103.
- Gertz MA, Cohen AD, Comenzo RL, Du Mond C, Kastritis E, Landau HJ, et al. Results of the phase 3 VITAL study of NEOD001 (Birtamimab) plus standard of care in patients with light chain (AL) amyloidosis suggest survival benefit for mayo stage IV patients. Blood. 2019;134:3166.
- FDA. DARZALEX FASPRO® Highlights of Prescribing information. 2022. Available at: https://www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf.
- Vaxman L, Gertz M. Recent Advances in the Diagnosis, Risk Stratification, and Management of Systemic Light-Chain Amyloidosis. Acta Haematol. 2019;141(2):93–106.
- Ciberia MT, Ortiz-Pérez JT, Quintana LF, Fernádez de Larrea C, Tovar N, Bladé J. Supportive Care in AL Amyloidosis. Acta Haematol. 2020;143(4):335–342.
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