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A. Larocca et al.
frailty, as well as the patient’s compliance and treatment preference should be considered when choosing treatment. Our results highlight the importance of performing FISH analysis in all cases of NDMM for risk stratification. Treatment decisions in elderly patients ineligible for trans- plant are extremely complex, since they should take into consideration not only the biology and the stage of the dis- ease, but also the characteristics of patients (frailty status, comorbidities, hospitalization, concomitant medications, social support, compliance) and goals of care (depth of response or disease control). Therefore, both VMP and Rd are valid options for transplant-ineligible NDMM. Nevertheless, VMP could be preferred in patients with high-risk cytogenetics and severe renal insufficiency, whereas continuous Rd could be the treatment of choice in standard-risk patients, particularly those over 75 years, or if oral administration and avoidance of peripheral neuropa-
thy are major considerations.
The results of this analysis are based on a selected popu-
lation, including patients enrolled in clinical trials. Nevertheless, an ongoing trial will prospectively compare these two standard treatments, VMP and continuous Rd, and the impact of cytogenetics on outcomes in an unselect- ed population of patients ≥65 years with MM in every day clinical practice (Real MM trial, ClinicalTrials.gov Identifier: NCT03829371).
Better treatment options and newer combinations are needed for high-risk disease. Recent trials incorporating the first-in-class monoclonal antibody anti-CD38 daratumum- ab combined with VMP (Dara-VMP)23 or Rd (Dara-Rd)24 showed that these regimes significantly reduced the risk of progression or death by 50% and 44%, respectively, as compared to standard VMP (Dara-VMP vs. VMP: median PFS not reached vs. 18.1 months, HR=0.50, 95% CI: 0.38- 0.65) and Rd (Dara_Rd vs. Rd: median PFS not reached vs. 31.9 months, HR=0.56, 95% CI: 0.43-0.73). The benefit of Dara-VMP and Dara-Rd was evident in most of the sub- groups analyzed; however the addition of daratumumab did not seem not to overcome the poor prognosis of high- riskpatients.
Ongoing trials testing multi-drug combinations including IMiD, second-generation PI, such as carfilzomib and ixa- zomib, and monoclonal antibodies in the frontline setting will evaluate and, potentially, improve the outcome of high-risk patients.
Acknowledgments
The authors are grateful to the investigators of all participating sites and the patients who took part in the source studies. The authors also thank the data managers Debora Caldarazzo and Angela Jiang, and the nurses Rosalia Capobianco and Giacomo Castorina from the Torino site.
References
1. Palumbo A, Anderson K. Multiple myeloma. N Engl J Med 2011;364(11):1046-1060.
2. Howlader N, Noone A, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2014. Bethesda, US-MD.
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 Off J Eur Soc Med Oncol. 2017;28(Suppl_4):iv52-iv61.
4. San-Miguel JF, Schlag R, Khuageva NK, et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. N Engl J Med. 2008;359(9):906-917.
5. San-Miguel JF, Schlag R, Khuageva NK, et al. Persistent overall survival benefit and no increased risk of second malignancies with bortezomib-melphalan-prednisone versus melphalan-prednisone in patients with pre- viously untreated multiple myeloma. J Clin Oncol. 2013;31(4):448-455.
6. Benboubker L, Dimopoulos MA, Dispenzieri A, et al. Lenalidomide and dex- amethasone in transplant-ineligible patients with myeloma. N Engl J Med. 2014;371(10): 906-917.
7. Facon T, Dimopoulos MA, Dispenzieri A, et al. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma. Blood. 2018;131(3):301- 310.
8. Greipp PR, San Miguel J, Durie BGM, et al. International staging system for multiple myeloma. J Clin Oncol. 2005;23(15):3412- 3420.
9. Sonneveld P, Avet-Loiseau H, Lonial S, et al. Treatment of multiple myeloma with high- risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955-2962.
10. Avet-Loiseau H, Hulin C, Benboubker L, et
al. Impact of cytogenetics on outcomes of transplant-ineligible patients with newly diagnosed multiple myeloma treated with continuous lenalidomide plus low-dose dex- amethasone in the first (MM-020) Trial. Blood. 2015;126(23): 730.
11. Larocca A, Dold SM, Zweegman S, et al. Patient-centered practice in elderly myeloma patients: an overview and consensus from the European Myeloma Network (EMN). Leukemia. 2018;32(8):1697-1712.
12. Palumbo A, Bringhen S, Rossi D, et al. Bortezomib-melphalan-prednisone-thalido- mide followed by maintenance with borte- zomib-thalidomide compared with borte- zomib-melphalan-prednisone for initial treatment of multiple myeloma: a random- ized controlled trial. J Clin Oncol. 2010;28 (34):5101-5109.
13. Palumbo A, Bringhen S, Larocca A, et al. Bortezomib-melphalan-prednisone-thalido- mide followed by maintenance with borte- zomib-thalidomide compared with borte- zomib-melphalan-prednisone for initial treatment of multiple myeloma: updated follow-up and improved survival. J Clin Oncol. 2014;32(7):634-640.
14. Bringhen S, Larocca A, Rossi D, et al. Efficacy and safety of once-weekly borte- zomib in multiple myeloma patients. Blood. 2010;116(23):4745-4753.
15. Magarotto V, Bringhen S, Offidani M, et al. Triplet vs doublet lenalidomide-containing regimens for the treatment of elderly patients with newly diagnosed multiple myeloma. Blood. 2016;127(9):1102-1108.
16. Carpenter JR, Kenward MG. Multiple Imputation and its Application. Chichester, UK: John Wiley & Sons, Ltd. 2015.
17. Bartlett JW, Seaman SR, White IR, Carpenter JR. Multiple imputation of covariates by fully conditional specification: accommodat- ing the substantive model. Stat Methods Med Res. 2015;24(4):462-487.
18. Quartagno M, Carpenter JR. Multilevel mul- tiple imputation in presence of interactions, non-linearities and random slopes. 49th Scientific Meeting of the Italian Statistical Society.
19. Palumbo A, Bringhen S, Mateos M-V, et al. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: an International Myeloma Working Group report. Blood. 2015;125(13):2068-2074.
20. Larocca A, Salvini M, De Paoli L, et al. Efficacy and feasibility of dose/schedule- adjusted Rd-R vs. continuous Rd in elderly and intermediate-fit newly diagnosed multi- ple myeloma (NDMM) patients: RV-MM-PI- 0752 phase III randomized study. 2018;132(Suppl 1):305.
21. Durie BGM, Hoering A, Abidi MH, et al. Bortezomib with lenalidomide and dexam- ethasone versus lenalidomide and dexam- ethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): a randomised, open-label, phase 3 trial. Lancet. 2017;389(10068):519- 527.
22. Bringhen S, Mateos MV, Zweegman S, et al. Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 ran- domized trials. Haematologica. 2013;98(6): 980-987.
23. Mateos M-V, Dimopoulos MA, Cavo M, et al. Daratumumab plus bortezomib, melpha- lan, and prednisone for untreated myeloma. N Engl J Med 2018;378(6):518-528.
24. Facon T, Kumar SK, Plesner T, et al. Phase 3 randomized study of daratumumab plus lenalidomide and dexamethasone (D-Rd) versus lenalidomide and dexamethasone (Rd) in patients with newly diagnosed mul- tiple myeloma (NDMM) ineligible for trans- plant (MAIA). Blood. 2018;132(Suppl 1):LBA-2.
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