Page 171 - 2018_12-Haematologica-web

Subgroup analyses of D-Rd vs. Rd in POLLUX
with high-risk disease. Although cross-study comparisons should be performed with caution, smaller differences in PFS and ORR between standard- and high-risk patients in the CASTOR study in patients treated with daratumum- ab and Vd were observed.31 Daratumumab-based combi- nations that include both a PI and an IMiD may further improve efficacy in patients with high-risk disease.
Prolonged treatment with D-Rd or Rd did not uncover new safety concerns, and the incidences of second pri- mary malignancies were balanced between study arms. While certain adverse events, such as cough, dyspnea, and pneumonia occurred more frequently with daratumumab, the percentage of patients that discontinued treatment due to adverse events was similar between groups (12.0% for D-Rd, 12.8% for Rd). Additionally, patients in the D-Rd group were treated for longer, with a median duration of 24.5 months versus 16.0 months in the Rd group, which likely contributed to the increase in rates for certain adverse events. Finally, the addition of a third drug to the standard of care Rd regimen did not have a negative effect on HRQoL.
Several limitations of the study should be noted. First, although balanced between treatment arms, only a subset of patient samples was collected for central cytogenetic testing as outlined in the Methods. Second, not all eligible patients with suspected CR or CR had available MRD data, and these patients were therefore conservatively classified as MRD positive. Based on the experiences obtained from this phase 3 study, continuous improve- ments in MRD testing are being implemented across ongoing and future daratumumab studies in multiple myeloma. Finally, based on the limitations of post hoc
analyses, the findings presented here require further con- firmation in future studies prospectively assessing the effi- cacy of D-Rd in these clinically relevant patient popula- tions.
In summary, these updated secondary subgroup analy- ses highlight the benefit of combining daratumumab with the standard of care regimen Rd in RRMM across exam- ined subgroups. The addition of daratumumab to Rd drove deep responses, as shown by achievement of MRD negativity in many patients. These results suggest that D-Rd is a highly effective and well-tolerated regimen that may be recommended for RRMM after first relapse and beyond.
Funding
This study was sponsored by Janssen Research & Development, LLC. The data sharing policy of Janssen Pharmaceutical Companies of Johnson & Johnson is available at https://www.janssen.com/clinical-trials/transparency. As noted on this site, requests for access to the study data can be submitted through Yale Open Data Access (YODA) Project site at http://yoda.yale.edu. JLK consulted for BMS, Janssen, Celgene, Karyopharm, and Pharmacyclics.
Acknowledgments
The authors wish to thank the patients participating in this study and their families, as well as the global network of inves- tigators, research nurses, study coordinators, and operations staff (including Sonali Trivedi, Jaime Bald, Xiang Qin, and Christopher Velas). Medical writing and editorial support were provided by Jason Jung, PhD, and Sima Patel, PhD, of MedErgy, and were funded by Janssen Global Services, LLC.
References
1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111(5):2516-2520.
2. Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mor- tality and outcomes in older patients. Leukemia. 2014;28(5):1122-1128.
3. Moreau P, San Miguel J, Sonneveld P, et al. Multiple myeloma: ESMO Clinical Practice Guidelines for diagnosis, treatment and fol- low-up. Ann Oncol. 2017;28(suppl 4):iv52- iv61.
4. NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines): multiple myeloma. Version 4. 2018. https://www.nccn.org/professionals/physi cian_gls/pdf/myeloma.pdf
5. Lin P, Owens R, Tricot G, Wilson CS. Flow cytometric immunophenotypic analysis of 306 cases of multiple myeloma. Am J Clin Pathol. 2004;121(4):482-488.
6. Santonocito AM, Consoli U, Bagnato S, et al. Flow cytometric detection of aneuploid CD38(++) plasmacells and CD19(+) B-lym- phocytes in bone marrow, peripheral blood and PBSC harvest in multiple myeloma patients. Leuk Res. 2004;28(5):469-477.
7. deWeersM,TaiYT,vanderVeerMS,etal. Daratumumab, a novel therapeutic human
CD38 monoclonal antibody, induces killing of multiple myeloma and other hematolog- ical tumors. J Immunol. 2011;1 86(3):1840- 1848.
8. Lammerts van Bueren J, Jakobs D, Kaldenhoven N, et al. Direct in vitro com- parison of daratumumab with surrogate analogs of CD38 antibodies MOR03087, SAR650984 and Ab79. Blood. 2014; 124(21):3474.
9. Overdijk MB, Verploegen S, Bogels M, et al. Antibody-mediated phagocytosis con- tributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma. MAbs. 2015;7(2):311-321.
10. Overdijk MB, Jansen JH, Nederend M, et al. The therapeutic CD38 monoclonal anti- body daratumumab induces programmed cell death via Fcgamma receptor-mediated cross-linking. J Immunol. 2016; 197(3):807- 813.
11. Krejcik J, Casneuf T, Nijhof IS, et al. Daratumumab depletes CD38+ immune- regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma. Blood. 2016;128(3):384-394.
12. McKeage K, Lyseng-Williamson KA. Daratumumab in multiple myeloma: a guide to its use as monotherapy in the EU. Drugs Ther Perspect. 2016;32(11):463-469.
13. McKeage K. Daratumumab: first global approval. Drugs. 2016;76(2):275-281.
14. Palumbo A, Chanan-Khan A, Weisel K, et
al. Daratumumab, bortezomib, and dex- amethasone for multiple myeloma. N Engl J Med. 2016;375(8):754-766.
15. Dimopoulos MA, Oriol A, Nahi H, et al. Daratumumab, lenalidomide, and dexam- ethasone for multiple myeloma. N Engl J Med. 2016;375(14):1319-1331.
16. Blair HA. Daratumumab: A review in relapsed and/or refractory multiple myelo- ma. Drugs. 2017;77(18):2013–2024.
17. DARZALEX® (daratumumab) injection, for intravenous use [package insert]. Horsham, PA: Janssen Biotech, Inc.; 2018.
18. Durie BGM, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006; 20(9):1467-1473.
19. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uni- form reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;117(18): 4691-4695.
20. McCudden C, Axel AE, Slaets D, et al. Monitoring multiple myeloma patients treated with daratumumab: teasing out monoclonal antibody interference. Clin Chem Lab Med. 2016;54(6):1095-1104.
21. Durie BG, Miguel JF, Blade J, Rajkumar SV. Clarification of the definition of complete response in multiple myeloma. Leukemia. 2015;29(12):2416-2417.
22. Sonneveld P, Broijl A. Treatment of relapsed and refractory multiple myeloma.
haematologica | 2018; 103(12)
2095