The Evolving Landscape of Anti-Clonal Therapy in Newly Diagnosed Systemic Light-Chain (AL) Amyloidosis: Evidence- and Time-Based Comparison with Multiple Myeloma

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript provides a comprehensive and timely review of the therapeutic evolution in systemic AL amyloidosis, effectively contrasting it with the faster-paced developments in multiple myeloma (MM). The comparative timeline between the two entities is particularly illustrative. Overall, the work is of high quality; however, several minor editorial refinements and critical updates to the clinical data (reflecting findings from late 2024 and 2025) are required to ensure the manuscript reflects the current state of the art.

Specific Comments

Major(scientific)：

The author currently mentions the 2021 accelerated approval of D-VCd. However, on November 19, 2025, the FDA granted traditional approval to daratumumab and hyaluronidase-fihj (Darzalex Faspro) in combination with VCd based on the final analysis of the ANDROMEDA trial. This significant regulatory update should be included in Section 2.3 to reflect the current standard of care.

The discussion on staging (Mayo 2004/European modification) would benefit from mentioning the newly validated AL International Staging System (AL-ISS). This system defines an "ultra-poor risk" group, Stage IIIC (characterized by NT-proBNP ≥ 8500 ng/L and high-sensitivity Troponin T ≥ 50 ng/L with a Global Longitudinal Strain ≥ -9%). Since this group has a median survival of only approximately 7 months even in the daratumumab era, its identification is crucial for risk-adapted therapy and should be included in this review article.

In Section 2.3 or the Discussion, the status of anti-fibril monoclonal antibodies needs updating. The Phase 3 AFFIRM-AL trial (NCT04973137) of birtamimab was discontinued in May 2025 after failing to meet its primary endpoint of time to all-cause mortality. Similarly, CAEL-101 (anselamimab) did not meet its primary endpoints in the CARES program. These results underscore the ongoing challenge of amyloid clearance and the continued reliance on deep hematologic response, and should be referred in this comprehensive article.

 

Minor（Editorial, typographical）：

Lines 62–64 & 66: The abbreviations "(hem)", "(car)", and "(RW)" are used only once or twice. For better readability, I suggest spelling out "hematologic response," "cardiac response," and "real-world" throughout the text.

Lines 113 & 251: "TE" (Transplant Eligible) appears only twice. I recommend spelling it out at both occurrences to maintain clarity for a broad hematological audience.

Lines 199 & 225: "TI" (Transplant Ineligible) should be spelled out at its first occurrence on Line 199.

Lines 103 & 105: Melphalan is inconsistently abbreviated as "MF" and "M". Please standardize to "M" as per current international guidelines (e.g., IMWG).

Lines 142 & 217: Regarding belantamab mafodotin, please use "Belamaf" consistently throughout the manuscript.

Line 192: The nomenclature "VAd" (bortezomib, adriamycin, dexamethasone) could be confused with the historical "VAD" (vincristine, adriamycin, dexamethasone). Given that vincristine is generally avoided in AL amyloidosis due to neurotoxicity, please explicitly define VAd at its first mention as (bortezomib, Adriamycin, and dexamethasone) to ensure clinical accuracy.

Line 171: "maily" should be corrected to "mainly".

Line 238: The section heading "3. Discussion" is a numbering error and should be changed to "4. Discussion".

Comments for author File: Comments.pdf

Author Response

Thank you for the kind review. Please see the attached file.

Author Response File: Author Response.pdf

Reviewer 2 Report

Comments and Suggestions for Authors

This paper is highly significant, focusing on anticlonal therapy for newly diagnosed systemic light-chain (AL) amyloidosis. However, the following additional amyloidosis differential diagnoses should be described: (1) In systemic AL amyloidosis, M protein misfolds to form insoluble amyloid fibrils, which deposit in various organs and cause organ failure. The primary focus of treatment is killing the plasma cells that produce the amyloid that deposits in organs. Amyloid deposited in organs is broken down over a considerable period of time through self-cleaning. (2) In systemic AL amyloidosis, deposition of insoluble amyloid fibrils in the heart significantly reduces the heart's diastolic function, leading to heart failure and a very poor prognosis. (3) Familial amyloidosis, a differential diagnosis, is a condition in which a mutated transthyretin protein (TTR) due to a genetic mutation (mainly the TTR gene) causes the transthyretin (TTR) protein to more easily convert from a tetramer to a monomer, forming amyloid. It is an autosomal dominantly inherited disease in which amyloid fibrils are formed and deposited in organs throughout the body. Treatment options include liver transplantation, nucleic acid drugs that suppress amyloid precursor production in the liver, and stabilizers. (4) Senile amyloidosis, a differential diagnosis, is a progressive disease in which wild-type transthyretin protein aggregates with age and deposits in systemic tissues, including the heart. It primarily affects men over 70, causing heart failure, arrhythmia, carpal tunnel syndrome, and other conditions. The primary treatment is oral stabilizers such as tafamidis.

Author Response

Thank you for your kind comments. Please see the attached file.

Author Response File: Author Response.pdf