Advanced age, organ damage and adverse events negatively affect survival of myeloma patients receiving novel agents: A meta-analysis of 1435 individual patient data from 4 randomized clinical trials

Background Multiple myeloma (MM) is the most relevant hematologic tumor in the elderly population. Median age at diagnosis is 70 years; 37% of patients are older than 75 years and 30% of patients present at diagnosis at least one co-morbid condition. The introduction of novel agents, bortezomib, thalidomide and lenalidomide, have changed the treatment paradigm of elderly MM, but side effects are frequent and full-drug doses less tolerated. Up to 90% of at least one serious adverse event (AE), with a subsequent 40% of drug discontinuation has been reported. Aims. A retrospective analysis evaluating 1435 individual patient data from 4 European phase III trials was conducted. We analyzed the impact of age, organ damage, treatment-related AEs and drug discontinuation as predictors of outcome. Methods. Patients with newly diagnosed MM, not eligible for autologous transplantation due to age (≥65 years) or co-morbidities, received melphalan-prednisone (MP), MP-thalidomide (MPT), MP-bortezomib (VMP), bortezomib-thalidomide-prednisone (VTP) or VMP-thalidomide (VMPT). Patients enrolled in the GISMM-2001 MP vs. MPT (331 patients), HOVON 49 MP vs. MPT (333 patients), GEM05MAS VMP vs. VTP (260 patients) and GIMEMA MM0305 VMP vs. VMPT (511 patients) trials were included in this meta-analysis. Trials were registered at ClinicalTrials.gov or controlled-trials.com. Results. Of the 1435 patients analysed, 332 did not receive novel agents (MP), 332 received thalidomide (MPT), 387 bortezomib (VMP), 384 thalidomide and bortezomib (VTP/ VMPT). Patients ≥75 years were 36%, equally distributed in the 4 groups. The proportion of patients with ISS III was lower in the MP group; renal failure was higher in the MP and MPT groups, due to less stringent selection of these protocols. The incidence of any grade 3-4 non-hematologic AEs was 29%, higher in MPT (43%) compared with VMP (24%) or VTP/VMPT (32%) groups. The most frequent were infections (10%), peripheral neuropathy (8%), cardiac (6%) and gastro-intestinal complications (5%). Drug discontinuation for toxicity was 27%, higher in MPT (35%) compared with VMP (16%) or VTP/VMPT (29%) groups.After a median follow-up of 33 months (95% Confidence Interval [CI] 10-56 months), 513/1435 patients (36%) died, the median overall survival was 50 months (95% CI 46-60 months). The causes of death were disease progression (76%) and toxic effects (24%), mainly infections, cardiac complications, second primary malignancies, and venous thromboembolism. The risk of death was increased in patients ≥75 years (Hazard Ratio [HR] 1.44, 95% CI 1.20-1.72,