Analyses from prospective trials applying upfront high dose melphalan (200 mg/m2, HDM) and autologous blood stem cell transplantation (ASCT) up to 70 years (yrs) of age in the era of novel agents are rare.
The multicenter, phase III GMMG-MM5 trial included newly-diagnosed, transplant-eligible patients up to 70 yrs of age.
n = 601 patients (expanded intention-to-treat cohort, ITT) were equally randomized to receive induction therapy with either PAd (bortezomib/doxorubicin/dexamethasone) or VCD (bortezomib/cyclophosphamide/dexamethasone). Thereafter, first HDM/ASCT, and in case of less than near complete response (<nCR), a tandem HDM/ASCT was performed, followed by lenalidomide (LEN) consolidation, and either LEN maintenance therapy (MT) for a fixed duration of 2 years (LEN-2Y) or until achievement of CR (LEN-CR). Age groups were distributed as follows: n = 353/58.7% (≤60 yrs, S1), n = 107/17.8% (61–65 yrs, S2) and n = 141/23.5% (66–70 yrs, S3). Similar proportions of patients in each age group received LEN-CR/LEN-2Y MT: S1: 52.1/47.9% vs. S2: 45.8/54.2% vs. S3 48.2/51.8% (p = 0.46).
The rate of renal impairment at baseline (RI, serum creatinine ≥2 mg/dl), was similar between the three age groups (RI, S1: 12.5 vs. S2: 15.9 vs. S3: 15.6%, p = 0.54), but baseline glomerular filtration rate (GFR) expectedly declined among age groups (median GFR, S1/S2/S3: S1: 103.9, S2: 81.9, S3: 75.6 ml/min, p < 0.001). International staging system (ISS) III, but not revised ISS III, was more common among S2 / S3 (ISS III, S1/S2/S3: 24.4/31.8/31.9%, p = 0.04; rISS III, S1/S2/S3: 13.2/16.0/11.4%, p = 0.15). The median time to premature withdrawal from study was similar between the age groups S1, S2 and S3: 14.1 vs. 18.0 vs. 13.6 months (log-rank p = 0.79), respectively. A similar proportion of the ITT of each age group received a first HDM/ASCT: S1: 85.3 vs. S2: 89.7 vs. S3: 87.2% (p = 0.52). Neither PFS nor OS differed significantly between the three age groups (PFS: log-rank p = 0.73, S2/3 vs. S1: hazard ratio [HR] = 1.11/1.01, p = 0.43/0.94 and OS: log-rank p = 0.54, S2/3 vs. S1: HR = 1.22/1.15, p = 0.32/0.45). This effect was independent on LEN MT strategy (S1 vs. S2 vs. S3; PFS: LEN-2Y/LEN-CR: log-rank p = 0.99/0.45; OS: LEN-2Y/LEN-CR: log-rank p = 0.63/0.62). Mortality without MM relapse/progression (NRM) and corresponding time-to-progression (TTP) from randomization applying a competing risks model were similar between the age groups (NRM/TTP: Graýs p = 0.25/0.83). Very good partial response or better (≥VGPR) after LEN consolidation were similar (S1: 75.8% vs. S2: 84.7% vs. S3: 79.8%, p = 0.20) as was the proportion of patients beginning LEN MT (all LEN-2Y groups and in case of not achieving a CR in LEN-CR groups): S1: 61.8 vs. S2: 61.7 vs. S3: 56.0% (p = 0.49). LEN MT for at least 12 months was applied in S1: 64.7 vs. S2: 66.7 vs. S3: 59.5% (p = 0.61) of patients. Overall toxicity profile during the whole study treatment was altered in S2 and S3 vs. S1: at least one adverse event (AE, only if ≥3°, and ≥2° for infections, cardiac disorders, neuropathy or thromboembolic events; according to NCI CTCAE version 4.0) was observed in S1: 81.7% vs. S2: 90.7% vs. S3: 87.9% (p = 0.04).
Our present subgroup implies that HDM/ASCT and LEN MT can be applied safely up to the age of 70 years. PFS, OS and TTP/NRM are comparable to younger patient cohorts. Therefore, we suggest that transplant-eligible patients up to age of 70 years may receive upfront HDM/ASCT and LEN MT if they are considered transplant-eligible.