Age and organ damage correlate with poor survival in myeloma patients: meta-analysis of 1435 individual patient data from 4 randomized trials

Abstract

Thalidomide and bortezomib are extensively used to treat elderly myeloma patients. In these patients, treatment-related side effects are frequent and full drug doses difficult to tolerate. We retrospectively analyzed data from 1435 elderly patients enrolled in 4 European phase III trials including thalidomide and/or bortezomib. After a median follow up of 33 months (95%CI: 10-56 months), 513 of 1435 patients (36%) died; median overall survival was 50 months (95%CI: 46-60 months). The risk of death was increased in patients aged 75 years or over (HR 1.44, 95%CI: 1.20-1.72; P<0.001), in patients with renal failure (HR 2.02, 95%CI: 1.51-2.70; P<0.001), in those who experienced grade 3-4 infections, cardiac or gastrointestinal adverse events during treatment (HR 2.53, 95%CI: 1.75-3.64; P<0.001) and in those who required drug discontinuation due to adverse events (HR 1.67, 95%CI; 1.12-2.51; P=0.01). This increased risk was restricted to the first six months after occurrence of adverse events or drug discontinuation and declined over time. More intensive approaches, such as the combination of bortezomib-thalidomide, negatively affected outcome. Bortezomib-based combinations may overcome the negative impact of renal failure. Age 75 years or over or renal failure at presentation, occurrence of infections, cardiac or gastrointestinal adverse events negatively affected survival. A detailed geriatric assessment, organ evaluation and less intense individualized approaches are suggested in elderly unfit subjects.

Figure 1.

Cumulative incidence of grade 3–4 AEs and of drug discontinuation accounting for competing events (death and progressive disease). (A) Cumulative incidence of grade 3–4 non-hematologic toxicities. (B) Cumulative incidence of grade 3–4 infections, cardiac or gastrointestinal toxicities. (C) Cumulative incidence of drug discontinuation.

Figure 2.

Overall survival according to baseline patient conditions. (A) Kaplan-Meier overall survival curves in patients younger or equal/older than 75 years in whole population and within the different treatment groups in the forest plot (results are shown, on a log10 scale, for analysis adjusted for gender, International Staging System and serum creatinine). Interaction test (heterogeneity) P=0.0041. (B) Overall survival in patients with or without renal failure (serum creatinine ≥ or < 2 mg/dL) in whole population and within the different treatment groups in the forest plot (results are shown, on a log10 scale, for analysis adjusted for gender, age and International Staging System. Interaction test (heterogeneity) P=0.65. Hazard ratios higher than 1 indicate a higher risk of death. The I bars represent 95% confidence intervals. MP: melphalan and prednisone; MPT: melphalan, prednisone and thalidomide; VMP: melphalan, prednisone and bortezomib; VTP/VMPT: bortezomib, thalidomide, prednisone/bortezomib, melphalan, prednisone, thalidomide.

Figure 3.

Impact of treatment-related complications on overall survival. (A) Impact of grade 3 to 4 non-hematologic toxicity in whole population and within the different treatment groups within the first 6 months after the occurrence of event in the forest plot (results are shown, on a log10 scale, for analysis adjusted for age, gender, International Staging System and serum creatinine). Interaction test (heterogeneity) P=0.79. (B) Impact of grade 3 to 4 infections, cardiac, or gastrointestinal adverse events in whole population and within the different treatment groups within the first 6 months after the occurrence of event in the forest plot (results are shown, on a log10 scale, for analysis adjusted for age, gender, International Staging System and serum creatinine). Interaction test (heterogeneity) P=0.52. (C) Impact of drug discontinuation due to grade 3–4 adverse events in whole population and within the different treatment groups within the first 6 months after the occurrence of event in the forest plot (results are shown, on a log10 scale, for analysis adjusted for age, gender, International Staging System and serum creatinine). Interaction test (heterogeneity) P=0.14. Hazard ratios higher than 1 indicate a higher risk of death. The I bars represent 95% confidence intervals. MP: melphalan and prednisone; MPT: melphalan, prednisone and thalidomide; VMP: melphalan, prednisone and bortezomib; VTP/VMPT: bortezomib, thalidomide, prednisone/bortezomib, melphalan, prednisone, thalidomide.

Figure 4.

Hazard ratios for deaths for any cause, according to presence (vs. absence) of risk factors, treated as time-dependent variables. Results are shown on a log10 scale, for analysis adjusted for treatment and International Staging System (multivariate analysis). Hazard ratios higher than 1 indicate a higher risk of death. The I bars represent 95% confidence intervals. AEs: Adverse Events. *Impact on overall survival within the first 6 months after the occurrence of the event.