Advancements in Multiple Myeloma Therapies: A Comprehensive Review by Disease Stage

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript presents a detailed and structured review of the advancements in multiple myeloma (MM) therapies, categorized by disease stage. It offers a comprehensive analysis of therapeutic modalities, including targeted therapies, CAR-T therapy, monoclonal antibodies, and bone-modifying agents. The authors should be commended for the breadth of topics covered and their effort in compiling relevant recent data.

Strengths:

1. Comprehensive Scope:

   • The manuscript effectively covers various therapeutic approaches, linking them to the stages of MM progression.
   • The discussion of novel therapies such as bispecific antibodies and immunocytokines adds value by addressing cutting-edge treatments.

2. Clarity and Organization:

   • The division by disease stages (early, advanced, and relapse) facilitates a clear understanding of treatment paradigms.

3. Scientific Rigor:

   • Citations of key studies and clinical trials enhance the scientific robustness of the manuscript.

4. Figures and Tables:

   • Figures like the mechanisms of action for proteasome inhibitors, monoclonal antibodies, and bispecific antibodies are visually explanatory and support the textual content.

Weaknesses and Recommendations:

1. Literature Gaps:

   • Some sections, particularly on the role of CAR-T therapy and monoclonal antibodies in the early stages of MM, could benefit from additional discussion on limitations or challenges, such as accessibility, cost, and patient eligibility.

   Recommendation: Include a brief discussion on the barriers to implementing novel therapies and the disparities in access globally.

2. Redundancy:

   • The description of mechanisms (e.g., proteasome inhibitors) is repeated in several places. Consolidating these descriptions can improve readability.

   Recommendation: Streamline mechanistic details into a single section to avoid redundancy.

3. Incomplete Analysis of Toxicities:

   • While adverse effects of treatments like bisphosphonates and proteasome inhibitors are mentioned, the manuscript lacks a comparative discussion on the safety profiles of newer therapies.

   Recommendation: Add a table or subsection summarizing the safety profiles and toxicities of major treatment classes for easy reference.

4. Figure Quality and Labels:

   • Figures are informative but could be better integrated into the discussion. Some labels and legends lack clarity.

   Recommendation: Ensure all figures are legible, and their legends are sufficiently descriptive. Place figures close to the relevant text for easier comprehension.

5. References:

   • There are instances of incomplete or outdated citations (e.g., the 2016 WHO classification of MM stages could be updated with newer guidelines).

   Recommendation: Review and update references to include the latest guidelines and pivotal studies.

6. Editorial Issues:

   • There are minor typographical and grammatical errors throughout the manuscript.

   Recommendation: Perform a thorough proofreading to ensure linguistic accuracy and consistency.

Summary of Revisions:

1. Expand the discussion of barriers to the implementation of novel therapies.
2. Consolidate repetitive mechanistic details into one cohesive section.
3. Add a comparative analysis of safety profiles for major therapeutic classes.
4. Improve figure clarity and integrate them better within the text.
5. Update and verify the reference list.
6. Conduct a final editorial check for language and formatting issues.

Finally, this reviewer personally misses some insights on the evidence that MM grow and progress through continuous interaction with the surrounding microenvironment. Emerging evidence suggests that angiogenesis and immunosuppression often arise concurrently as a result of this interplay. Therefore, combining anti-angiogenic therapy with immunotherapy holds promise for shifting the tumor microenvironment dynamics and enhancing treatment outcomes. Please incorporate a brief mention of the role of angiogenesis in multiple myeloma progression. Highlight how the bone marrow microenvironment promotes angiogenesis through factors like VEGF and FGF, contributing to disease pathogenesis. Mention that anti-angiogenic therapies are emerging as a complementary approach in MM treatment. Include a subsection discussing anti-angiogenic agents, such as thalidomide, lenalidomide, and VEGF inhibitors. Evaluate their potential as adjuncts to standard treatments and their ability to modulate the bone marrow microenvironment, reducing tumor burden and improving patient outcomes. Highlight ongoing trials or recent data supporting their efficacy (please refer to PMID: 29568363 and expand the intro and discussion).

Author Response

Please see attached document

Author Response File: Author Response.docx

Reviewer 2 Report

Comments and Suggestions for Authors

 

This is an interesting review and the paper is generally well written and structured but the text needs better English grammar. Moreover, the manuscript  has other  shortcomings. Below I have provided numerous remarks on the text as it is

 

often redundant and long-winded. In several instances I also suggested to cite more relevant and recent literature. Furthermore I made additional suggestions for more in-depth analyses of the clinical studies reported. Given these shortcomings the manuscript requires major revisions.

 

1) Please add page numbers.

2) In the Abstract check the verb “curated” (line 14).

3) Table 1 needs to be completed according to the lines 74-75 (check and/or…).

4) Please clarify sentence (P3, lines 94-95); what “biomarkers” do you mean?

5) P4, lines 123-124.This is a very vague statement; the words “physician reviews” need to be modified and more relevant and recent references need to be added;

6) P5, line 175 Please check “inturn”. Moreover please update the “Bisphosphonates” 3.1.1 subsection by adding the following Ref.:  

Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis: A Living Systematic Review and Network Meta-analysis for the American College of Physicians. Ann Intern Med 2024 Jun;177(6):eL230118. doi: 10.7326/L24-0118

Pharmacologic Treatment of Primary Osteoporosis or Low Bone Mass to Prevent Fractures in Adults: A Living Clinical Guideline From the American College of Physicians Ann Intern Med. 2023 Feb;176(2):224-238. doi: 10.7326/M22-1034. 

7) The text of the Figure 1 is not readable and the figure legend is too long. Please use a brief title.

8) P8, lines 260-282 Please summerize in a few lines in order to introduce the Figure 2 (line 275) and Bortezomib and Carfilzomib (line 284).

9) Please check the paragraph (P9, lines 307-312) “positions”??

10) The legend of the figure 2 is too long, please summerize and detail in the paragraph 3.2.1.

11) Please delete lines 348-354 because redundant.

12) Please re-write “CAR-T Therapy” subsection by providing an overview of a) the importance of therapy respect to others and b) recent advances in CAR-T Therapy. See:

Mailankody S, Matous JV, Chhabra S, Liedtke M, Sidana S, Oluwole OO, Malik S, Nath R, Anwer F, Cruz JC. Allogeneic BCMA-targeting CAR T cells in relapsed/refractory multiple myeloma: phase 1 UNIVERSAL trial interim results. Nat Med. 2023;29(2):422–9.

Du Z, Zhu S, Zhang X, Gong Z, Wang S. Non-conventional allogeneic Anti-BCMA chimeric Antigen receptor-based Immune Cell therapies for multiple myeloma treatment. Cancers (Basel) 2023, 15(3).

13) In the “Relapse” Section delete lines 400-405 because redundant.

14) Please move the text of lines 440-444 after the first occurence of “ bortezomib” (line 424 after the fullstop).

15) Please join the subsection 4.1.2. to the previous one (4.1.1. Bispecific antibodies (BsAbs)).

16) Please check line 492.

17) Please join the subsection 4.2.1. to the previous one (4.2. Immunocytokine therapy).

18) P16 line 501 please replace the word “attaches” with “binds”.

19) Please join the subsection 4.2.3. to the previous one (4.2.2).Moreover detail MS advantages respect to the traditional SPE and add references.

Comments for author File: Comments.pdf

Comments on the Quality of English Language

The authors need a native English-speaking co-author to thoroughly revise the grammar of this manuscript

Author Response

Please see the attached document.

-----the point by point response-----

1) Please add page numbers.
Page numbers added on top right corner.

2) In the Abstract check the verb “curated” (line 14).
The verb “curated” has been replaced with “recommended course of treatment” (line 15)

3) Table 1 needs to be completed according to the lines 74-75 (check and/or…).
Table 1 has been modified to accommodate the and/or clause mentioned in lines 80-82

4) Please clarify sentence (P3, lines 94-95); what “biomarkers” do you mean?
The mentioned biomarkers (line 106) have been defined in lines 107-108

5) P4, lines 123-124.This is a very vague statement; the words “physician reviews” need to be modified and more relevant and recent references need to be added.
The term “physician reviews” has been replaced by referencing the relevant authors making the recommendation specifically in line 138.

6) P5, line 175 Please check “inturn”. Moreover please update the “Bisphosphonates” 3.1.1 subsection by adding the following Ref.:
Effectiveness and Safety of Treatments to Prevent Fractures in People With Low Bone Mass or Primary Osteoporosis: A Living Systematic Review and Network Meta-analysis for the American College of Physicians. Ann Intern Med 2024 Jun;177(6):eL230118. doi: 10.7326/L24-0118
Pharmacologic Treatment of Primary Osteoporosis or Low Bone Mass to Prevent Fractures in Adults: A Living Clinical Guideline From the American College of Physicians Ann Intern Med. 2023 Feb;176(2):224-238. doi:10.7326/M22-1034.
P7, line 207 the word “inturn” has been replaced with “induces”. The suggested references for section 3.1.1, "Bisphosphonates," have been thoroughly reviewed. However, they do not provide any new or additional insights to enhance the section and therefore were not added.

7) The text of the Figure 1 is not readable and the figure legend is too long. Please use a brief title.
The figure legend and title for figure 1 have been shortened (lines 268-272).

8) P8, lines 260-282 Please summerize in a few lines in order to introduce the Figure 2 (line 275) and Bortezomib and Carfilzomib (line 284).
P10, lines 290-294 and lines 305-306 have been re-written and shortened in order to introduce Figure 2 (line 298) and Bortezomib and Carfilzomib (line 307) in as few words as possible.

9) Please check the paragraph (P9, lines 307-312) “positions”??
The sentence (P11, line 332) has been re-written and the word “positions” removed

10) The legend of the figure 2 is too long, please summerize and detail in the paragraph 3.2.1.
The legend of the figure 2 (lines 338-341) has been shortened and the details in the original document were kept in the “3.2.1 Proteasome Inhibitors” section that sufficiently explain the figure.

11) Please delete lines 348-354 because redundant.
The paragraph (in the original document lines 348-354) has been deleted.

12) Please re-write “CAR-T Therapy” subsection by providing an overview of a) the importance of therapy respect to others and b) recent advances in CAR-T Therapy.
P13, section 3.3 CAR-T Therapy (including 3.3.1) has been changed and 3.3.2 was added

13) In the “Relapse” Section delete lines 400-405 because redundant.
Lines 400-405 (in the original document) were deleted

14) Please move the text of lines 440-444 after the first occurence of “ bortezomib” (line 424 after the fullstop).
The text of lines 440-444 (in the original document) was moved to follow the sentence of “bortezomib” first occurrence (line 470) and are now in lines 473-479

15) Please join the subsection 4.1.2. to the previous one (4.1.1. Bispecific antibodies (BsAbs)).
Subsection 4.1.2. was joined to the previous one (4.1.1.) in line 515

16) Please check line 492.
Line 492 (in the original document) was checked and expanded into lines 543-545

17) Please join the subsection 4.2.1. to the previous one (4.2. Immunocytokine therapy).
Subsection 4.2.1. was joined with the previous one (4.2. Immunocytokine therapy) in line 545

18) P16 line 501 please replace the word “attaches” with “binds”.
The word “attaches” was replaced with the word “binds” in line 551

19) Please join the subsection 4.2.3. to the previous one (4.2.2). Moreover detail MS advantages respect to the traditional SPE and add reference.
Subsection 4.2.3. was joined with the previous one (4.2.2). An additional sentence about SPEP and MS has been added (lines 591-593)

Author Response File: Author Response.docx

Reviewer 3 Report

Comments and Suggestions for Authors

Kakarougkas A et al in a Review titled `Advancements in Multiple Myeloma Therapies. A Comprehensive Review by Disease Stage` describe current options for a therapeutical approach for a multiple myeloma. They are addressing the question of which of those options would be the best solution for this, still incurable disease.

The authors analyze each of the therapies with its advantages and disadvantages as a potential final curative option, since multiple myeloma is a disease known for its regression.

The article is well organized with detailed explanation of disease itself, current treatments gaps and they offer possible solution therapies that would overbridge these disadvantages.

The figures are of good quality.

The suggestion would be maybe to add more statistical data of the patients treated with each of the therapies described in the article.

 

Author Response

Please see the attached letter

Author Response File: Author Response.docx

Round 2

Reviewer 1 Report

Comments and Suggestions for Authors

The authors have clarified several of the questions I raised in my previous review. Most of the major problems have been addressed by this revision.