Page 233 - Haematologica April 2020

(hazard ratio for progression-free survival=0.96; hazard ratio for overall survival=1.81). In this non-ran- domized analysis, VMP and Rd-R were equally effective in younger (≤75 years), standard-risk patients, while older ones (>75 years) benefited more from Rd-R. In high-risk patients, VMP improved progres- sion-free survival and overall survival irrespective of age. The source trials are registered at ClinicalTrials.gov (NCT01063179 and NCT01093196).
First-line therapy in elderly MM patients
Introduction
Multiple myeloma (MM) is a disease that occurs pre- dominantly in the elderly: the median age at diagnosis is 71 years and two-thirds of patients are over 65 years of age.1,2 Elderly patients, defined as those older than 65-70 years of age, are usually considered ineligible for high- dose chemotherapy and autologous stem-cell transplanta- tion (ASCT).3 In Europe, standard initial therapy of older patients consists of either a triplet regimen including bortezomib-melphalan-prednisone (VMP) administered in a fixed-duration schedule, or a doublet combination of lenalidomide (25 mg) and dexamethasone (Rd), adminis- tered continuously until progression or intolerance.3 The VISTA trial demonstrated that VMP was superior to mel- phalan-prednisone both in terms of progression-free sur- vival [PFS: 21.7 vs. 15.2 months, hazard ratio (HR)=0.56; P<0.001] and overall survival (OS: 56.4 vs. 43.1 months, HR=0.69; P<0.001).4,5 The FIRST trial showed that contin- uous Rd significantly prolonged the median PFS (26 vs. 21.9 months, HR=0.69; P<0.001) and OS (59.1 vs. 49.1 months, HR=0.78; P=0.0023) compared to the median PFS and OS achieved with melphalan-prednisone-thalidomide (MPT).6,7 Based on the results of these two phase III stud- ies, both VMP and continuous Rd were approved by the European Medicine Agency as standard treatments for patients with newly diagnosed MM ineligible for ASCT.
The most important prognostic factors in MM are age and frailty, disease stage defined by the International Staging System (ISS),8 and chromosomal abnormalities, detected by fluorescent in situ hybridization (FISH). Patients harboring chromosomal abnormalities, including del(17p), t(4,14) and t(14,16), have a poor prognosis, with a higher risk of disease progression and death.9 Approximately 15-20% of patients with newly diagnosed MM present with at least one cytogenetic abnormality and constitute the so-called “high-risk” population.
Despite recent therapeutic advances in MM, the results obtained with novel agent-based regimens in patients with high-risk chromosomal abnormalities are unsatisfac- tory and the prognosis of these patients remains poor. Moreover, limited data are available on high-risk, trans- plant-ineligible MM patients treated with bortezomib or lenalidomide in first-line therapy. In the VISTA trial, patients with high- or standard-risk cytogenetics who received VMP had similar times to progression (median 19.8 vs. 23.1 months, HR=1.29; P=0.55) and OS (HR=1.00; P=0.99).4,5 In a subanalysis of the FIRST trial, which com- pared continuous Rd treatment until progression, Rd treat- ment for 72 weeks (Rd18) and MPT treatment, continuous Rd treatment resulted in PFS and OS benefits in compari- son with MPT; however, these benefits were largely due to the improvements in PFS and OS in patients without high-risk cytogenetics (median PFS 31.1 vs. 21.2 vs. 24.9 months for continuous Rd vs. Rd18 vs. MPT). Indeed, in the high-risk group, the longest PFS was observed with
Rd18 treatment (median 8.4 vs. 17.5 vs. 14.6 months for continuous Rd vs. Rd18 vs. MPT) while OS was similar across treatment arms.10
Unfortunately, VMP and Rd have never been formally compared in a randomized trial. Based on the different safety profiles of bortezomib and lenalidomide, borte- zomib is usually preferred in patients with advanced renal failure, while lenalidomide can be the drug of choice for patients with pre-existing neuropathy, or when oral ther- apy is preferable.11 Besides these considerations, VMP and Rd are equally recommended. Because a head-to-head comparison of VMP vs. Rd is lacking, the choice of first- line treatment of elderly MM patients is based mainly on the physician’s and patient’s preferences.
We previously published the results of two randomized, phase III studies investigating both VMP (GIMEMA-MM- 03-05)12–14 and Rd induction followed by lenalidomide maintenance (Rd-R) (EMN01)15 as upfront therapies for elderly, transplant-ineligible MM patients. In order to pro- vide clinicians with useful, and currently lacking, evidence that may help to tailor anti-myeloma treatment better in this population, we conducted a pooled, retrospective analysis comparing the efficacy of VMP and Rd-R in dif- ferent subgroups of elderly, transplant-ineligible MM patients, focusing on cytogenetic profile.
Methods
Study design and participants
We pooled the single data from two phase III studies, the GIMEMA-MM-03-05 (NCT01063179) and the EMN01 (NCT01093196) trials. Both trials enrolled patients with newly diagnosed MM who were older than 65 years of age or younger but ineligible for ASCT. Inclusion and exclusion criteria, as well as treatment details of the source studies, have been published previ- ously.12–15 Further details on study treatments and procedures are reported in the Online Supplementary Appendix. For this retrospec- tive, not pre-planned analysis, we selected only patients random- ized to VMP or Rd-R. The source studies were approved by the institutional review boards at each of the participating centers. All patients gave written informed consent before entering the source studies, which were performed in accordance with the Declaration of Helsinki.
Statistical analysis
The primary objective of this analysis was to compare PFS and OS (see Online Supplementary Appendix) in patients treated with VMP or Rd-R, adjusting for patient and disease characteristics at baseline.
Single data from the two studies were pooled together and ana- lyzed. Comparisons between different groups of patients were conducted using standard statistical tests. Time-to-event data were analyzed using the Kaplan–Meier method; survival curves were compared with the log-rank test. Results are presented as hazard ratios (HR), 95% confidence intervals (95% CI), and two-
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