Future Developments in the Treatment of AL Amyloidosis
Abstract
:1. Introduction
2. Therapies Targeting the Plasma Cell Clone
2.1. Current Treatment Algorithm
2.2. IgM-Amyloidosis
2.3. Clonal Characteristics of Plasma Cells and BCL2 Inhibition
2.4. Antibody Drug Conjugates
Belantamab Mafodotin
2.5. Bispecifics Active in MM also Relevant in AL Amyloidosis
2.6. Chimeric Antigen Receptor (CAR) T-Cells
2.7. Pathway Directed Therapy
2.7.1. BRAF Inhibitors and MEK Inhibitors
2.7.2. PI3K/AKT Pathway Directed Therapies
2.7.3. Transcription Factor Directed Therapies
2.8. New Immunomodulatory Agents (IMiDs)
2.9. TLX66
3. Special Considerations; Toxicity Associated with Anti-Clonal Therapies
4. Treatment Strategies Targeting Immunoglobulin mRNA
5. Anti-Amyloid Targeting Treatment Options
5.1. Targeting Amyloid Formation and Dissolution
5.2. Targeting Amyloid Deposits
6. Future Combinations and Treatment Algorithms
7. Conclusions
Author Contributions
Funding
Institutional Review Board Statement
Informed Consent Statement
Conflicts of Interest
References
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Name | Mechanism of Action | Study Phase | Results in Patients with AL Amyloidosis | Comments |
---|---|---|---|---|
Venetoclax | BCL-2 inhibitor | Phase III (in MM) | Yes in retrospective studies ORR: 81%, CR/VGPR: 78%, Organ response rate: 83% | Only in patients with t(11;14) |
Liftasoclax | BCL-2 inhibitor | Phase I/II (in MM and AL) | No, only in patients with myeloma | Only in patients with t(11;14) |
Belantamab mafodotin | Anti-BCMA ADC | Phase II (in AL) | Study is recruiting | Ocular toxicity of concern |
Milatuzumab doxorubicin | Anti-CD56 | Phase I (in MM) | No, only in patients with myeloma | |
Indatuximab ravtansine | Anti-CD138 | Phase I/IIa (in MM) | No, only in patients with myeloma | |
Talquetamab | BiTEs (GP3C5D/ CD3 on T cells) | Phase I | No, only in patients with myeloma | |
Cevostamab | BiTEs (FcRH5/CD3) | Phase I | No, only in patients with myeloma | |
Idecaptagene cicleucel | BCMA targeting CAR-T cells | Phase II | No, only in patients with myeloma | Toxicity is a concern–selected patients only |
Ciltacabtagene autoleucel | BCMA targeting CAR-T cells | Phase I/IIa | No, only in patients with myeloma | Toxicity is a concern–selected patients only |
Tisagenlecleucel | CD19 CAR T-cell | Approved for RR B-cell precursor acute Lymphoblastic leukemia and large B-cell lymphoma | Ongoing phase II studies in B-cell lymphomas to include also indolent diseases | Future option for IgM amyloidosis |
Axicabtagene ciloleucel | CD19 CAR-T-cell | Approved for RR large B-cell lymphoma | ||
Brexucabtagene autoleucel, | CD19-CAR-T-cell | Approved for RR mantle cell Lymphoma and B-cell precursor acute lymphoblastic leukemia | ||
Lisocabtagene maraleucel | CD19 CAR-T cell | Approved for RR Large B-cell Lymphomas | ||
Iberdomide (CC-220) | IMiDs | Phase II | No, only in patients with myeloma | |
CC-92480 | IMiDs | Phase I/II | No, only in patients with myeloma | |
Encorafenib and binimetinib | Dual BRAF and MEK inhibitor | Phase II | No, only in patients with myeloma | In patients with BRAF V600E mutation |
TLX66 | Bone marrow conditioning agent | Phase I/II (in AL) | Yes, hemResponse in 7/9 patients | Potential as a conditioning regimen for patients otherwise ineligible for high dose therapy |
Cael-101 | Amyloid targeting | Phase 3 | Yes, cardiac response: 67%, renal response: 50% | Phase 2 data available, ongoing phase 3 study in newly diagnosed patients with stage 3 disease |
Birtamimab | Amyloid targeting | Phase 3 | Yes, 50% relative risk reduction for all-cause mortality for Mayo stage IV patients | Initial phase 2 data positive, not confirmed in randomized phase 2 and phase 3. Under evaluation in stage IV (Mayo 2012) based on positive results in post hoc analysis |
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Theodorakakou, F.; Fotiou, D.; Dimopoulos, M.A.; Kastritis, E. Future Developments in the Treatment of AL Amyloidosis. Hemato 2022, 3, 131-152. https://doi.org/10.3390/hemato3010012
Theodorakakou F, Fotiou D, Dimopoulos MA, Kastritis E. Future Developments in the Treatment of AL Amyloidosis. Hemato. 2022; 3(1):131-152. https://doi.org/10.3390/hemato3010012
Chicago/Turabian StyleTheodorakakou, Foteini, Despina Fotiou, Meletios A. Dimopoulos, and Efstathios Kastritis. 2022. "Future Developments in the Treatment of AL Amyloidosis" Hemato 3, no. 1: 131-152. https://doi.org/10.3390/hemato3010012