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01-12-2021 | Multiple Myeloma | Research article

Comparison of monoclonal antibodies targeting CD38, SLAMF7 and PD-1/PD-L1 in combination with Bortezomib/Immunomodulators plus dexamethasone/prednisone for the treatment of multiple myeloma: an indirect-comparison Meta-analysis of randomised controlled trials

Authors: Wu Ye, Xia Wu, Xiaoyan Liu, Xue Zheng, Jili Deng, Yuping Gong

Published in: BMC Cancer | Issue 1/2021

Abstract

Background

Many clinical trials have assessed the effect and safety of monoclonal antibodies (MAbs) in combination with proteasome inhibitors or immunomodulators plus dexamethasone/prednisone for the treatment of multiple myeloma (MM). The treatment outcomes of comparing different MAbs in combination with the above-mentioned agents remained unclear. We performed the meta-analysis to indirectly compare the effect and safety of MAbs targeting CD38, SLAMF7, and PD-1/PD-L1 in combination with bortezomib/immunomodulators plus dexamethasone/prednisone for patients with MM.

Methods

We searched thoroughly in the databases for randomised controlled trials (RCTs) in which at least one of the three MAbs were included. We included eleven eligible RCTs with 5367 patients in the meta-analysis. Statistical analysis was carried out using StataMP14 and Indirect Treatment Comparisons software.

Results

We calculated hazard ratios (HRs) for overall survival (OS) and progression-free survival (PFS) and relative risk (RR) for overall response rate, complete response (CR) or better, very good partial response (VGPR) or better, VGPR, partial response, stable disease, and grade 3 or higher adverse events among the three groups. The HRs for PFS of the CD38 group vs SLAMF7 group, CD38 group vs PD-1/PD-L1 group, and SLAMF7 group vs PD-1/PD-L1 group were 0.662 (95%CI 0.543–0.806), 0.317 (95%CI 0.221–0.454), and 0.479 (95%CI 0.328–0.699), respectively. The HR for OS of the CD38 group vs SLAMF7 group was 0.812 (95%CI 0.584–1.127). The RR for CR or better in the CD38 group vs SLAMF7 group was 2.253 (95%CI 1.284–3.955). The RR for neutropenia of the CD38 group vs SLAMF7 group was 1.818 (95%CI 1.41–2.344).

Conclusions

Treatment with the CD38 group had longer PFS and better treatment response than that with the SLAMF7 or PD-1/PD-L1 group. In addition, the SLAMF7 group prolonged PFS compared with the PD-1/PD-L1 group and was associated with a lower incidence of grade 3 or higher neutropenia than the CD38 and PD-1/PD-L1 group. In conclusion, MAbs targeting CD38 are the best, followed by those targeting SLAMF7; MAbs targeting PD-1/PD-L1 are the worst when in combination with bortezomib/immunomodulators plus dexamethasone/prednisone for the treatment of MM.

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Morandi F, Horenstein AL, Costa F, Giuliani N, Pistoia V, Malavasi F. CD38: a target for immunotherapeutic approaches in multiple myeloma. Front Immunol. 2018;9:2722. https://doi.org/10.3389/fimmu.2018.02722.CrossRefPubMedPubMedCentral

Chini EN, Chini C, Espindola NJ, de Oliveira GC, van Schooten W. The pharmacology of CD38/NADase: an emerging target in Cancer and diseases of aging. Trends Pharmacol Sci. 2018;39(4):424–36. https://doi.org/10.1016/j.tips.2018.02.001.CrossRefPubMedPubMedCentral

van de Donk N, Usmani SZ. CD38 antibodies in multiple myeloma: mechanisms of action and modes of resistance. Front Immunol. 2018;9:2134. https://doi.org/10.3389/fimmu.2018.02134.CrossRefPubMedPubMedCentral

Malaer JD, Mathew PA. CS1 (SLAMF7, CD319) is an effective immunotherapeutic target for multiple myeloma. Am J Cancer Res. 2017;7(8):1637–41.PubMedPubMedCentral

Malaer JD, Marrufo AM, Mathew PA. 2B4 (CD244, SLAMF4) and CS1 (CD319, SLAMF7) in systemic lupus erythematosus and cancer. Clin Immunol. 2019;204:50–6. https://doi.org/10.1016/j.clim.2018.10.009.CrossRefPubMed

Chen J, Zhong MC, Guo H, Davidson D, Mishel S, Lu Y, et al. SLAMF7 is critical for phagocytosis of haematopoietic tumour cells via mac-1 integrin. NATURE. 2017;544(7651):493–7. https://doi.org/10.1038/nature22076.CrossRefPubMedPubMedCentral

Pazina T, James AM, MacFarlane AT, Bezman NA, Henning KA, Bee C, et al. The anti-SLAMF7 antibody elotuzumab mediates NK cell activation through both CD16-dependent and -independent mechanisms. Oncoimmunology. 2017;6(9):e1339853. https://doi.org/10.1080/2162402X.2017.1339853.CrossRefPubMedPubMedCentral

Ishibashi M, Soeda S, Sasaki M, Handa H, Imai Y, Tanaka N, et al. Clinical impact of serum soluble SLAMF7 in multiple myeloma. Oncotarget. 2018;9(78):34784–93. https://doi.org/10.18632/oncotarget.26196.CrossRefPubMedPubMedCentral

Rosenblatt J, Avigan D. Targeting the PD-1/PD-L1 axis in multiple myeloma: a dream or a reality? BLOOD. 2017;129(3):275–9. https://doi.org/10.1182/blood-2016-08-731885.CrossRefPubMed

10.

Oliva S, Troia R, D'Agostino M, Boccadoro M, Gay F. Promises and pitfalls in the use of PD-1/PD-L1 inhibitors in multiple myeloma. Front Immunol. 2018;9:2749. https://doi.org/10.3389/fimmu.2018.02749.CrossRefPubMedPubMedCentral

11.

Lesokhin AM, Bal S, Badros AZ. Lessons learned from checkpoint blockade targeting PD-1 in multiple myeloma. Cancer Immunol Res. 2019;7(8):1224–9. https://doi.org/10.1158/2326-6066.CIR-19-0148.CrossRefPubMedPubMedCentral

12.

Zheng Y, Shen H, Xu L, Feng J, Tang H, Zhang N, et al. Monoclonal antibodies versus histone deacetylase inhibitors in combination with Bortezomib or Lenalidomide plus dexamethasone for the treatment of relapsed or refractory multiple myeloma: an indirect-comparison Meta-analysis of randomized controlled trials. J Immunol Res. 2018;2018:1–20.

13.

Kodama S, Fujihara K, Horikawa C, Harada M, Ishiguro H, Kaneko M, et al. Network meta-analysis of the relative efficacy of bariatric surgeries for diabetes remission. Obes Rev. 2018;19(12):1621–9. https://doi.org/10.1111/obr.12751.CrossRefPubMed

14.

Mateos MV, Cavo M, Blade J, Dimopoulos MA, Suzuki K, Jakubowiak A, et al. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): a randomised, open-label, phase 3 trial. LANCET. 2020;395(10218):132–41. https://doi.org/10.1016/S0140-6736(19)32956-3.CrossRefPubMed

15.

Spencer A, Lentzsch S, Weisel K, Avet-Loiseau H, Mark TM, Spicka I, et al. Daratumumab plus bortezomib and dexamethasone versus bortezomib and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of CASTOR. Haematologica. 2018;103:2079–87.CrossRef

16.

Dimopoulos MA, San-Miguel J, Belch A, White D, Benboubker L, Cook G, et al. Daratumumab plus lenalidomide and dexamethasone versus lenalidomide and dexamethasone in relapsed or refractory multiple myeloma: updated analysis of POLLUX. Haematologica. 2018;103:2088–96.CrossRef

17.

Dimopoulos MA, Lonial S, Betts KA, Chen C, Zichlin ML, Brun A, et al. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer Am Cancer Soc. 2018;124:4032–43.

18.

Attal M, Richardson PG, Rajkumar SV, San-Miguel J, Beksac M, Spicka I, et al. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): a randomised, multicentre, open-label, phase 3 study. Lancet. 2019;394(10214):2096–107. https://doi.org/10.1016/S0140-6736(19)32556-5.CrossRefPubMed

19.

Moreau P, Attal M, Hulin C, Arnulf B, Belhadj K, Benboubker L, et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study. Lancet. 2019;394:29–38.CrossRef

20.

Facon T, Kumar S, Plesner T, Orlowski RZ, Moreau P, Bahlis N, et al. Daratumumab plus Lenalidomide and dexamethasone for untreated myeloma. N Engl J Med. 2019;380(22):2104–15. https://doi.org/10.1056/NEJMoa1817249.CrossRefPubMed

21.

Mateos MV, Dimopoulos MA, Cavo M, Suzuki K, Jakubowiak A, Knop S, et al. Daratumumab plus Bortezomib, Melphalan, and prednisone for untreated myeloma. N Engl J Med. 2018;378(6):518–28. https://doi.org/10.1056/NEJMoa1714678.CrossRefPubMed

22.

Dimopoulos MA, Oriol A, Nahi H, San-Miguel J, Bahlis NJ, Usmani SZ, et al. Daratumumab, Lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319–31. https://doi.org/10.1056/NEJMoa1607751.CrossRefPubMed

23.

Palumbo A, Chanan-Khan A, Weisel K, Nooka AK, Masszi T, Beksac M, et al. Daratumumab, Bortezomib, and dexamethasone for multiple myeloma. N Engl J Med. 2016;375(8):754–66. https://doi.org/10.1056/NEJMoa1606038.CrossRefPubMed

24.

Lonial S, Dimopoulos M, Palumbo A, White D, Grosicki S, Spicka I, et al. Elotuzumab therapy for relapsed or refractory multiple myeloma. N Engl J Med. 2015;373(7):621–31. https://doi.org/10.1056/NEJMoa1505654.CrossRefPubMed

25.

Jakubowiak A, Offidani M, Pegourie B, De La Rubia J, Garderet L, Laribi K, et al. Randomized phase 2 study: elotuzumab plus bortezomib/dexamethasone vs bortezomib/dexamethasone for relapsed/refractory MM. BLOOD. 2016;127(23):2833–40. https://doi.org/10.1182/blood-2016-01-694604.CrossRefPubMedPubMedCentral

26.

Dimopoulos MA, Dytfeld D, Grosicki S, Moreau P, Takezako N, Hori M, et al. Elotuzumab plus Pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018;379(19):1811–22. https://doi.org/10.1056/NEJMoa1805762.CrossRefPubMed

27.

Usmani SZ, Schjesvold F, Oriol A, Karlin L, Cavo M, Rifkin RM, et al. Pembrolizumab plus lenalidomide and dexamethasone for patients with treatment-naive multiple myeloma (KEYNOTE-185): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019;6(9):e448–58. https://doi.org/10.1016/S2352-3026(19)30109-7.CrossRefPubMed

28.

Mateos MV, Blacklock H, Schjesvold F, Oriol A, Simpson D, George A, et al. Pembrolizumab plus pomalidomide and dexamethasone for patients with relapsed or refractory multiple myeloma (KEYNOTE-183): a randomised, open-label, phase 3 trial. Lancet Haematol. 2019;6(9):e459–69. https://doi.org/10.1016/S2352-3026(19)30110-3.CrossRefPubMed

29.

Bonello F, D'Agostino M, Moscvin M, Cerrato C, Boccadoro M, Gay F. CD38 as an immunotherapeutic target in multiple myeloma. Expert Opin Biol Ther. 2018;18(12):1209–21. https://doi.org/10.1080/14712598.2018.1544240.CrossRefPubMed

30.

Yang WC, Lin SF. Mechanisms of drug resistance in relapse and refractory multiple myeloma. Biomed Res Int. 2015;2015:341430.PubMedPubMedCentral

31.

van de Donk N, Richardson PG, Malavasi F. CD38 antibodies in multiple myeloma: back to the future. BLOOD. 2018;131(1):13–29. https://doi.org/10.1182/blood-2017-06-740944.CrossRefPubMed

32.

Korkmaz S, Erdem S, Akay E, Tasdemir EA, Karaman H, Keklik M. Do PD-1 and PD-L2 expressions have prognostic impact in hematologic malignancies? Turk J Med Sci. 2019;49(1):265–71. https://doi.org/10.3906/sag-1706-194.CrossRefPubMedPubMedCentral

33.

Jelinek T, Paiva B, Hajek R. Update on PD-1/PD-L1 inhibitors in multiple myeloma. Front Immunol. 2018;9:2431. https://doi.org/10.3389/fimmu.2018.02431.CrossRefPubMedPubMedCentral

34.

Jelinek T, Mihalyova J, Kascak M, Duras J, Hajek R. PD-1/PD-L1 inhibitors in haematological malignancies: update 2017. Immunology. 2017;152(3):357–71. https://doi.org/10.1111/imm.12788.CrossRefPubMedPubMedCentral

Title: Comparison of monoclonal antibodies targeting CD38, SLAMF7 and PD-1/PD-L1 in combination with Bortezomib/Immunomodulators plus dexamethasone/prednisone for the treatment of multiple myeloma: an indirect-comparison Meta-analysis of randomised controlled trials
Authors: Wu Ye
Xia Wu
Xiaoyan Liu
Xue Zheng
Jili Deng
Yuping Gong
Publication date: 01-12-2021
Publisher: BioMed Central
Keywords: Multiple Myeloma
Immunomodulator
Neutropenia
Daratumumab
Dexamethasone
Published in: BMC Cancer / Issue 1/2021
Electronic ISSN: 1471-2407
DOI: https://doi.org/10.1186/s12885-021-08588-9

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