Donor Lymphocyte Infusion to Enhance the Graft-versus-Myeloma Effect

Round 1

Reviewer 1 Report

The authors present a review on the potential utility of donor lymphocyte infusion (DLI) in the setting of allogeneic hematopoetic SCT (alloSCT) against multiple myeloma (MM). As a consequence of recent major developments of anti-myeloma therapies, notably those of antibody-based new drugs (anti-CD38) and advanced generation compounds of major classes of targeted therapies, the applicability and indication of alloSCT has continuously shrunk in MM. Thus, in my opinion, even a review of alloSCT in MM would not expect extraordinary attention (no citation yet on Gharton et al. JCM since July 2020 in PubMed). Accordingly, in my view, the topic of the current manuscript being a sub-topic of the alloSCT in MM does not represent a particularly burning issue within the MM field. This statement is also illustrated by the fact that the reference list of this manuscript which is in general an important commodity of a review is particularly outdated (see below).

Major criticism:

1. Out of the total 49 references, the new ones are represented as follows: 2020: n=2 (both in the MDPI journal JCM); 2019: n=1 (1 JCM); 2018: n=1; 2017: n=3; 2016: n=1; 2015: n=2. A total of 10/49, 20%.
2. Conceptually, I would first present the prophylactic setting followed by the salvage setting.
3. It is overly detailed to describe a single study in a single paragraph as it is currently done from section 2, line 53 up to line 170.
4. Results presented in Tables 1 and 2 are never comparative and encompass small cohorts. The tables should also contain study years.
5. Subsection 6.3. (line 290) is off topic, not related to DLI.
6. I do not find it particularly elegant to describe in detail in a separate subsection 6.4. (line 310) an earlier study published by the authors in 2009 that did not receive a particularly large attention with a total of 20 citations in PubMed.

Minor comments:

1. Line 210 reference is missing.
2. Line 310: “Another….” is out of context.
3. English proficiency could be improved.

Author Response

see attachment

Author Response File: Author Response.pdf

Reviewer 2 Report

This is a comprehensive and well written review of DLI as used following allogeneic transplantation in Multiple Myeloma. The difficulty of concluding how to use this method is obvious. Allogeneic transplantation is today only rarely used in MM and consequently studies on DLI include few patients and prospective trial, including reasonable numbers of patients, are mainly lacking.

Overall comment:

 In light of the increasing use of CAR T cells it would be of interest if the authors would express a brief view at the end about this approach, and possibly in relation to allogenic transplantation followed by DLI. Allo CAR-T are now already produced and used in some clinical trials. Could Donor-CAR-T cells be a substitute or complement for DLI. Some lines about allogeneic CAR-T seems appropriate

Minor comments:

1. Acute and chronic GVHD seem differently important for outcome after DLI . Thus the authors should always indicate if they mean acute or chronic. It is not always done ( e.g. aGVHD or cGVHD)
2. ASCT is in the literature practically always used for autologous transplantation. I would have preferred AlloSCT as short form for allogeneic transplantation.
3. I assume that the only T-cell dose ( > 1x108/kg) of prognostic importance means total dose. Please clarify where not written ( e.g. line 61)
4. Line 89 : 95 DLI course (range 1-7). Not clear. Please clarify.
5. Table 1 Grade 3-4 should be given within brackets. I assume that the effect of Grade 1-2 is very different from that of Grade 3-4
6. Page 5 Lines 6.7 Clarify –does not read OK
7. Page 5 Lines 210 – 218 Reference?

Author Response

see attachment

Author Response File: Author Response.pdf

Reviewer 3 Report

The authors showed donor lymphocyte infusion (DLI) is useful therapeutic option for multiple myeloma via enhancing the graft-versus-myeloma effect in patients underwent allogeneic stem cell transplantation in this review. They also  showed that the prophylactic use is advantageous to obtain better outcome compared with the salvage use. Although the background of DLI is widely explained and the comparison between the salvage settings and the prophylactic settings is fairly depicted, the advantage and disadvantage of DLI after allogeneic stem cell transplantation should be more precisely explained.

Specific comments

1. The authors should show the outcome in patients underwent tandem autologous peripheral blood stem cell transplantation (PBSCT). Furtheromore, the authors should show the outcome in patients underwent single or tandem autologous PBSCT followed by the treatment of novel agents as the maintenance therapy.
2. The authors should compare the efficacy of DLI with that of other specific immunotherapies such as CAR-T, CAR-NK, bispecific antibodies, etc., showing the advantage and disadvantage of
3. The sentence from line 203 to 204 is incomplete (i.e., no verb).
4. The word of immune in line 208 is adjective. Is it immunity or immune response?

Author Response

See attachment

Author Response File: Author Response.pdf

Round 2

Reviewer 1 Report

The text amendments are acceptable. However, concerning my major criticism, i.e. the "outdatedness" of the entire topic and the high prevalence of old references has not been addressed at all. It is not particularly elegant to prompt the reviewer in the response letter to contribute to the manuscript by amending the reference list.

The careful re-evaluation of the reference list is still suggested and further efforts should be made to make the manuscript more actual.

Author Response

The text amendments are acceptable. However, concerning my major criticism, i.e. the "outdatedness" of the entire topic and the high prevalence of old references has not been addressed at all. It is not particularly elegant to prompt the reviewer in the response letter to contribute to the manuscript by amending the reference list.

The careful re-evaluation of the reference list is still suggested and further efforts should be made to make the manuscript more actual.

Answer: References were updated on alloSCT in general and immunotherapy in the Introduction and Conclusion. We agree with the reviewer that, unfortunately, for DLI there are no specific updated references highlighting the limitations of DLI use and this review and also point to the importance of patient identification.