Bortezomib-based induction, high-dose melphalan and lenalidomide maintenance in myeloma up to 70 years of age

Abstract

Intensive upfront therapy in newly-diagnosed multiple myeloma (MM) including induction therapy (IT), high-dose melphalan (MEL200), and autologous blood stem cell transplantation (ASCT) followed by consolidation and/or maintenance is mostly restricted to patients up to 65 years of age. Prospective phase III trial data in the era of novel agents for patients up to 70 years of age are not available. The GMMG-MM5 trial included 601 patients between 18 and 70 years of age, divided in three groups for the present analysis: ≤60 years (S1, n = 353), 61-65 years (S2, n = 107) and 66-70 years (S3, n = 141). Treatment consisted of a bortezomib-containing IT, MEL200/ASCT, consolidation, and maintenance with lenalidomide. Adherence to treatment was similar among patients of the three age groups. Overall toxicity during all treatment phases was increased in S2 and S3 compared to S1 (any adverse event/any serious adverse event: S1:81.7/41.8% vs. S2:90.7/56.5% vs. S3:87.2/68.1%, p = 0.05/<0.001). With respect to progression-free survival (log-rank p = 0.73), overall survival (log-rank p = 0.54) as well as time-to-progression (Gray's p = 0.83) and non-relapse mortality (Gray's p = 0.25), no differences were found between the three age groups. Our results imply that an intensive upfront therapy with a bortezomib-containing IT, MEL200/ASCT, lenalidomide consolidation, and maintenance should be applied to transplant-eligible MM patients up to 70 years of age.

Fig. 1. Consort diagram.

Consort diagram is grouped by the three predefined age groups: ≤60 years (subgroup S1), 61–65 years (subgroup S2) and 66–70 years (subgroup S3). n/% numbers are from the intention-to-treat population of each age group. Light blue boxes indicate different trial sections or skipped therapy phases. Gray boxes summarize reasons for end of study between subsequent trial sections in the respective age groups S1, S2, and S3. For a detailed version of the consort diagram see Supplementary Fig. 1. ITT, intention-to-treat population; LEN, lenalidomide; MDS, myelodysplastic syndrome; MEL200, melphalan 200 mg/m²; ASCT, autologous blood stem cell transplantation; CR, complete response; AE, adverse event; PD, progressive disease.

Fig. 2. Progression-free, overall survival, time-to-progression, and non-relapse mortality from randomization.

a, b Progression-free and overall survival (PFS, OS) from randomization with respect to the three age groups: ≤60 years (S1), 61–65 years (S2), and 66–70 years (S3) including univariate Cox models comparing single age groups. c Cumulative incidence estimates of competing events progressive disease (PD, cause 1) vs. non-relapse mortality (NRM, cause 2) from randomization shown as incidence and survival curves, respectively, for the age groups S1, S2 and S3. PFS, progression-free survival; OS, overall survival; TTP, time-to-progression; NRM, non-relapse mortality; HR, hazard ratio; 95% CI, 95% confidence interval.

Fig. 3. Forest plots on subgroup analyses for progression-free and overall survival from randomization.

Forest plots on specific subgroups defined by baseline disease characteristics for a PFS and b OS from randomization. Age groups are defined as: ≤60 years (S1), 61–65 years (S2) and 66–70 years (S3). Renal insufficiency is defined as serum creatinine value of >177 μmol/l. Adverse cytogenetics were defined as at least one of the following aberrations: deletion17p13, translocation t(4;14), translocation t(14;16), gain 1q21 (>3 copies). PFS, progression-free survival; OS, overall survival; LDH, lactate dehydrogenase; ULN, upper limit of the normal; WHO, World Health Organization; IA p, interaction test p value.