What Is Genomic High-Risk Myeloma?
Round 1
Reviewer 1 Report
This is a well written and well organized manuscript that deals with genetic prognostic markers of multiple myeloma. The paper is of interest to all working on the field of plasma cell disorders.
I see only two shortcomings of the manuscript. The first one is not due to the authors intent but rather due to lack of detailed information: much of the genetic prognostication is done on newly diagnosed disease and only a sparse information is presented on relapsed/refractory myeloma. This is a pity, as most physicians treat a lot more relapsed patients as opposed to newly diagnosed. Broadening the scope of the paper with more data about relapsed and/or refractory disease would definitely further strengthen the paper.
I have found only one important information lacking from the manuscript: recently evidence has been provided also in the myeloma field with respect to the different splice isoform of the p53 protein (Rojas et al, 2022).
Author Response
We thank the reviewer for their comments. In response we have added in a section on relapsed MM, detailing the mechanisms of resistance to IMiDs and novel immunotherapies. We have also added in a statement on different splice isoforms of TP53 as an additional mechanism of gene dysregulation in the TP53 section.
Reviewer 2 Report
This is a very well written review of the current status of what constitutes high risk MM. The review covers very well the current understanding of this issue in great detail but the review remains readable and will serve as a terrific reference article. My only critique would be line 211 on page 5, which implies SMM is only stratified by clinical data, as current smoldering myeloma risk stratification schemas do include FISH and cytogenetic data ( see for example https://doi.org/10.1038/s41408-020-00366-3). The scope of the work is limited to a description and frequency of various types of mutations but does not deal with any clinical implications or treatment recommendations, which may disappoint some readers. However, the myeloma treatment landscape is changing rapidly and any such guidance might quickly become outdated
Author Response
We thank the reviewer for their comments. The reviewer is correct that current SMM guidelines do include translocations, gain 1q and del13q. Therefore, we have modified the text accordingly to incorporate this into the sentence.
Round 2
Reviewer 1 Report
My comments were well addressed.
Reviewer 2 Report
appreciate edits that authors have made, especially section on relapsed and refractory myeloma
