Novel Developments in the Treatment of Multiple Myeloma-Associated Bone Disease

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

This another review on myeloma bone disease including new developments in the medical prevention and surgical treatment of osteolytic lesions with a special focus on the treatment of osteonecrosis of the jaw and on  new targets in the myeloma bone marrow environment. This review is well written and correctly updated. However some aspects of this paper have been recently developed in a review written by the IMW (Lancet Oncology2021) and reflect the generally adopted opinion. Therefore the authors should focus more on really newer aspects or address remaining questions   

For instance ,  osteonecrosis of the jaw after antiresorptive therapies has been studied many years ago and has generated a number of recommendations, and the most interesting in this the part of the paper is surgical treatment which contains some new considerations. Overall this part is too long (compared to the part on anti-resorptive agents) and should be focused mostly on new data. Moreover, I recommend to place it before the discussion on the duration of antiresorptive agents

 There are currently two questions regarding prevention with antiresorptive treatments

1) ZA vs Denosumab. The authors provided only general considerations regarding the choice between the two modalities. One on the important criteria is the cost of denosumab treatment versus generic ZA . Although some studies have suggested that denosumab could be cost-effective versus ZA, the authors should give an idea of this difference to correctly inform the reader. Considering in addition the question of stopping denosumab , the authors should try to be more precise in their recommendations , in particular in case of renal failure

2) Duration of ZA treatment. They authors suggest” that the treatment period may need to be prolonged”. In this regard, they do not mention the Danish study that was presented at the last IMW meeting in Athens, the preliminary results of which were in favor of prolonging the treatment for 4 years. However, another strategy is currently often proposed, ie to adapt the duration to the result achieved by the anti-myeloma treatment . In the MRC Myeloma IX trial the benefit of ZA was mostly for patients achieving less than VGPR. The impact of ZA therapy is less evident in patients achieving CR. Currently, not only more patients achieve CR, even transplant non eligible patients (with Daratumumab lenalidomide dexamethasone), but more profound responses (negative minimal residual disease) can be achieved with triplets and autologous transplantation, and even more frequently with quadruplets.Therefore the authors should at least address the question of the interest of long ZA treatment in patients who achieve minimal residual disease negativity and will enjoy long progression-survivals

Author Response

Reply to Reviewer 1:

Dear reviewer. Thank you for taking time to review our manuscript, and for your comments.

All changes can be more easily tracked in the uploaded and revised document, but are clarified further below with a point-to-point response.

 

With regards to your general considerations on placement and length of the section on osteonecrosis of the jaw after antiresorptive therapies, that part has been shortened in order to highlight only the important conclusions, and other parts rewritten to convey the same information in a shorter sentence. This makes for easier reading. In addition as you suggested, the part on duration of treatment with antiresorptives, as well as drug holidays have been moved to after the osteonecrosispart as suggested, and given its own headline “Antiresorptive agents and duration of treatment”. An excellent recommendation, and seems to give a more clear structure of the manuscript.

 

Comment 1: ZA vs Denosumab. The authors provided only general considerations regarding the choice between the two modalities. One on the important criteria is the cost of denosumab treatment versus generic ZA. Although some studies have suggested that denosumab could be cost-effective versus ZA, the authors should give an idea of this difference to correctly inform the reader. Considering in addition the question of stopping denosumab, the authors should try to be more precise in their recommendations , in particular in case of renal failure.

 

Response 1:  Agreed. These are important points that you point out, and the manuscript has been updated accordingly, see page 4, line 8-11 and page 6, and line 38-51.

 

Comment 2: Duration of ZA treatment. They authors suggest” that the treatment period may need to be prolonged”. In this regard, they do not mention the Danish study that was presented at the last IMW meeting in Athens, the preliminary results of which were in favor of prolonging the treatment for 4 years. However, another strategy is currently often proposed, i.e. to adapt the duration to the result achieved by the anti-myeloma treatment . In the MRC Myeloma IX trial the benefit of ZA was mostly for patients achieving less than VGPR. The impact of ZA therapy is less evident in patients achieving CR. Currently, not only more patients achieve CR, even transplant non eligible patients (with Daratumumab lenalidomide dexamethasone), but more profound responses (negative minimal residual disease) can be achieved with triplets and autologous transplantation, and even more frequently with quadruplets.Therefore the authors should at least address the question of the interest of long ZA treatment in patients who achieve minimal residual disease negativity and will enjoy long progression-survivals.

 

Response 2: Thank you for highlighting our presentation at IMS at Athens. We had not yet presented our data when we made this manuscript. But as you rightly point out, these are important data in regard to duration. We have thus added these new data, see page 6, line 11-15 . Furthermore, we have discussed them in the context of the data regarding response driven approach thus expanding this section of the manuscript. Please see line page 6, line 26-27.

 

Reviewer 2 Report

Comments and Suggestions for Authors

This is a very nice review.

I suggest the authors to also cite the following Refs and discuss them into the text for the completion of the paper:

Cancers (Basel). 2022 Jun 2;14(11):2768; Cancers (Basel). 2021 Jul 31;13(15):3877; Cancers (Basel). 2021 Mar 12;13(6):1257; Int J Mol Sci. 2021 Feb 27;22(5):2375; Blood Cancer J. 2020 Mar 2;10(3):25; Am J Hematol. 2019 Apr;94(4):400-407

Furthermore, a table describing the major bone targeted effects of novel anti-myeloma therapies have to be also included.

Author Response

Reply to Reviewer 2:

 

Dear reviewer. Thank you for taking time to review our manuscript, and for your comments.

All changes can be more easily tracked in the uploaded and revised document, but are clarified further below with a point-to-point response.

Comment 1: This is a very nice review. I suggest the authors to also cite the following Refs and discuss them into the text for the completion of the paper: Cancers (Basel). 2022 Jun 2;14(11):2768; Cancers (Basel). 2021 Jul 31;13(15):3877; Cancers (Basel). 2021 Mar 12;13(6):1257; Int J Mol Sci. 2021 Feb 27;22(5):2375; Blood Cancer J. 2020 Mar 2;10(3):25; Am J Hematol. 2019 Apr;94(4):400-407. Furthermore, a table describing the major bone targeted effects of novel anti-myeloma therapies have to be also included.

Response 1:

 

Thank you for pointing our attention to these very relevant articles. The two articles regarding microRNA has been added and discussed it the section “Antiresorptive agents and duration of treatment” in relation to a possible future noval patient tailored treatment, see page 6, lines 33 – 37. The consolidation with KRD study is discussed in section “Antiresorptive agents and duration of treatment”, see page 6, line 22. The REBUILD study is added and discussed in the section “Targeting the microenvironment”, see page 10, line 29-32. The two remaining studies are added in the section concerning the effect of proteasome inhibitors on bone formation, see page 10, line 16 and line 19. The table you suggest can be found at page 10 at the bottom.