Investigational Monoclonal Antibodies in the Treatment of Multiple Myeloma: A Systematic Review of Agents under Clinical Development

Round 1

Reviewer 1 Report

The authors review the different modalities of mAbs under clinical development in the treatment of Multiple Myeloma. MM has been particularly difficult target even for the immune-oncological agents due to high relapse rates. Nevertheless, there are several agents in development targeting MM and it is critical to have a comprehensive review of all the clinical studies in the phase1/II. The authors have presented an overall comprehensive review of the different non-FDA approved agents targeting MM. The search strategy is adequate covering all different databases and the data extraction technique employed is appropriate to the study. The authors screened the unique records by reading the titles and excluded majority of the studies. It is not clear from figure 1 or the text what were some of the criteria chosen to screen articles based on their titles. The reviewer also thinks that it would be beneficial to the readers if the authors included the isotypes of the different mAbs listed in Tables 1 & 2. Other that these few suggestions, following minor points needs to be addressed –

·       Rephrase line 98

·       Abstract line 25 – change the size of font for ‘clinical benefit rate’

·       Line 27 – define ORR as it being used for the first time in the abstract

·       Lines 48 – 56, change the period after each bulleted point to comma

·       Line 91 – the title needs sectioning

Author Response

We would like to thank the reviewer for pointing out our mistakes in the manuscript. We tried to fix those problems which obviously improved our manuscript. We have also used professional English language services to improve the manuscript as well.

1. It is not clear from figure 1 or the text what were some of the criteria chosen to screen articles based on their titles.

We have added the following italics lines to explain which articles we excluded based on reading titles:

"After excluding 335 duplicates, we read titles and abstracts of the remaining 2395 articles and excluded further 2298 articles which were review articles, expert opinions, preclinical studies, monoclonal antibodies targeting cancers other than MM and studies on daratumumab and Elotuzumab."

2. The reviewer also thinks that it would be beneficial to the readers if the authors included the isotypes of the different mAbs listed in Tables 1 & 2. 

Response: We have added isotypes of monoclonal antibodies in table 1 & 2.

3. Rephrase line 98

 Response: We have rephrased line 98 as follows:

"For representing clinical outcome, we collected complete response (CR), stable disease (SD), partial response (PR), progressive disease (PD), overall survival (OS) and progression-free survival (PFS) rates."

4. Abstract line 25 – change the size of font for ‘clinical benefit rate’

Response: We have changed the size of the font.

5. Line 27 – define ORR as it being used for the first time in the abstract

Response: We have added the overall response rate (ORR) in the abstract.

6. Lines 48 – 56, change the period after each bulleted point to comma

Response: We have changed periods to commas after each bulleted point.

7.  Line 91 – the title needs sectioning

Response: We have added section as follows, "2.3. Study selection and data extraction"

Author Response File: Author Response.docx

Reviewer 2 Report

Iftikhar et al provide a review article on novel antibodies in MM. The authors mainly focus on compounds which yet has to be  approved by the FDA. This overview is interesting.

M y (minor) comments are:

Abstract: line 25: Please use a uniform fond size

line 31: (…) are warranted.

Line 65: add: ELOQUENT 3

Table 1: Please provide author, year, and journal name

Page 14 line 20: Update citation with: Dimopoulos MA, Dytfeld D, Grosicki S et al (2018) Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl JMed 378:1811–1822

GRP78 Line 82: Please also reference: Rasche et al, A GRP78-directed monoclonal antibody recaptures response in refractory multiple myeloma with extramedullary involvement, Clinical Cancer Res 2015

Line 164: Please briefly discuss the toxicity concerns with PD-1/IMiD combinations that made the FDA to stop the respective trials

Future prospective therapies: The paragraphs on BiTEs and bispecific antibodies need improvement. What is the difference between BiTEs vs. BiAb vs. BiFabs? The authors should consider a figure explaining the respective molecular basis and mode of action.

Line 196: add the positive efficacy data for the Amgen BiTE presented by Topp MS et al. at ASH 2018.

Author Response

We would like to thank the reviewer for pointing out our mistakes in the manuscript. We tried to fix those problems which improved our manuscript. We have also used professional English language services to improve the manuscript as well.

1. Abstract: line 25: Please use a uniform font size

Response: We have changed the font to make it uniform.

2. Line 31: (…) are warranted.

Response: We have changed "is" to "are" in the manuscript.

3. Line 65: add: ELOQUENT 3

Response: We have added the data and reference to the manuscript.

4. Table 1: Please provide author, year, and journal name

Response: We have mentioned journal names in both tables. 

5. Page 14 line 20: Update citation with: Dimopoulos MA, Dytfeld D, Grosicki S et al (2018) Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl JMed 378:1811–1822

Response: We would apologize for not being able to update ur manuscript with this citation. Possibly due to change in page and line structure, we couldn`t find the correct place to update this citation.

6. GRP78 Line 82: Please also reference: Rasche et al, A GRP78-directed monoclonal antibody recaptures response in refractory multiple myeloma with extramedullary involvement, Clinical Cancer Res 2015

Response: We have added the reference to the manuscript.

7. Line 164: Please briefly discuss the toxicity concerns with PD-1/IMiD combinations that made the FDA to stop the respective trials   

Response: We have added the toxicity concerns that made the FDA stop respective trials.               

8. Future prospective therapies: The paragraphs on BiTEs and bispecific antibodies need improvement. What is the difference between BiTEs vs. BiAb vs. BiFabs? The authors should consider a figure explaining the respective molecular basis and mode of action.

Response: We would like to thank you for pointing out the potential improvement point in the manuscript. BITE`s and BiFabs are different kinds of BiAb with a slightly different mechanism of action. We have merged these groups together and tried to explain it in a better and clear format. We have also added a figure “Figure 1” with a link to the original figure at the end of the manuscript.

9. Line 196: add the positive efficacy data for the Amgen BiTE presented by Topp MS et al. at ASH 2018.

Response: We have added the data provided by Topp MS et al at ASH in our manuscript.

Author Response File: Author Response.docx