Response-Adapted Lenalidomide Maintenance in Newly Diagnosed, Transplant-Eligible Multiple Myeloma: Results from the Multicenter Phase III GMMG-MM5 Trial

Background: The open-label, multicenter, randomized MM5 trial from the German-Speaking Myeloma Multicenter Group (GMMG) aimed at the investigation of the best treatment strategy with respect to progression-free survival (PFS) in newly diagnosed, transplant-eligible multiple myeloma (MM). Treatment strategies are defined by bortezomib (BTZ) and dexamethasone (DEX)-containing induction therapy (IT) with either doxorubicine (PAd) or cyclophosphamide (VCD), standard intensification with high-dose melphalan (HDM, 200mg/m²) and autologous blood stem cell transplantation (ASCT), lenalidomide (LEN) consolidation and maintenance treatment (MT) with LEN for 2 years (LEN-2Y) vs. LEN MT until achievement of a complete response (CR; LEN-CR).

Patients and Methods: Fivehundred and two patients were equally randomized between the four treatment arms: arm A1: PAd + LEN-2Y (n=125), arm A2: VCD + LEN-2Y (n=126), arm B1: PAd + LEN-CR (n=126) and arm B2: VCD + LEN-CR (n=125). HDM/ASCT was carried out according to standard procedures. Tandem HDM/ASCT was recommended if no near complete response or better (≥nCR) was achieved after first HDM/ASCT. Following HDM/ASCT, two cycles of LEN consolidation (25mg, d1-21, repeated d29) were applied. LEN MT was applied continuously as 10mg/d for the first 3 months. LEN dose was increased to 15mg/d thereafter if treatment was well tolerated. The primary endpoint reports on PFS. Secondary endpoints include overall survival (OS), response rates (Durie et al., Leukemia, 2006) and toxicity (Common Terminology Criteria for Adverse Events, version 4.0).

Results: The median follow-up was 60.1 months, 321 PFS / 162 OS events occurred. The ≥VGPR rates after consolidation were similar between the study arms: A1+B1 [PAd IT]: 81.2% vs. A2+B2 [VCD IT]: 77.2%, (p=0.38).

In the LEN-2Y arms A1/A2, 74% and 75% vs. 39% and 50% of patients in the LEN-CR arms B1/B2 started LEN MT. In the LEN-CR arms B1/B2, 25%/23% of patients did not start LEN MT after consolidation due to CR, and another 12%/10% of patients stopped LEN during MT due to CR. Two years of LEN MT on study were applied in 35%, 35%, 14% and 18% patients in the arms A1, A2, B1 and B2, respectively. Toxicity was significantly increased in the LEN-2Y arms (A1+A2) compared to the LEN-CR arms (B1+B2; relevant adverse events [AE], defined as ≥ grade 3 and infections, cardiac disorders, neuropathy and thromboembolic events ≥ grade 2; A1: 87.3% vs. A2: 91.3% vs. B1: 79.5% vs. B2: 77.4%, p=0.01), mainly because of an increased number of AE during LEN MT in the LEN-2Y arms (A1+A2: 77.6% vs. B1+B2: 58.2%, p<0.001). Infections (≥ grade 2) were the major AE during LEN MT (A1+A2: 52.7% vs. B1+B2: 32.3%, p<0.001).

The primary endpoint, PFS from randomization between the treatment arms was not significantly different (stratified log-rank test p=0.60) with a median PFS of 43.2 vs. 40.9 vs. 35.9 vs. 35.7 months in the arms A1, A2, B1 and B2, respectively. OS was significantly different (p=0.02) with a 36-months OS rate of 82.9 vs. 85.2 vs. 75.1 vs. 77.1% in the arms A1, A2, B1 and B2, respectively.

To compare LEN-CR/LEN-2Y treatment strategies, arms A1+A2 and B1+B2 were pooled. Yet, PFS was not significantly different comparing the LEN-CR vs. LEN-2Y groups (hazard ratio [HR]=1.15, 95% confidence interval [95%CI]: 0.93-1.44, p=0.20), but the LEN-2Y showed significantly better OS (HR=1.42, 95%CI: 1.04-1.93 p=0.03). On landmark analyses from the start of LEN MT, comparison of LEN-CR/LEN-2Y groups according to response after consolidation (CR/non-CR) revealed significantly shortened PFS (HR=1.84, 95%CI: 1.08-3.13, p=0.02) but not OS (HR=1.80, 95%CI: 0.74-4.36, p=0.19) for patients with CR in the LEN-CR group. Among non-CR patients, PFS and OS were similar in the LEN-CR vs. LEN-2Y groups (PFS/OS: HR=1.01/1.50, 95%CI: 0.72-1.41/0.90-2.50, p=0.97/0.12). In multivariate analyses, International Staging System stages (ISS) II/III (II/III: HR=1.45/1.66, p=0.02/0.002; vs. ISS stage I) and adverse cytogenetics (CA, defined as either deletion17p13 and/or translocation t(4;14) and/or gain 1q21; HR=1.97, p<0.001; vs. no CA) were associated with an adverse PFS.

Conclusions: This is the first randomized phase III trial providing data on the response-adapted administration of LEN MT in transplant-eligible MM. LEN MT beyond CR improved OS but not PFS and is associated with an increased toxicity. Our results suggest that LEN MT should be applied beyond the achievement of a CR.