Randomized Phase III Trial in Non-Transplant Eligible Patients with Newly Diagnosed Symptomatic Multiple Myeloma Comparing Melphalan-Prednisone-Thalidomide Followed By Thalidomide Maintenance (MPT-T) Versus Melphalan-Prednisone-Lenalidomide Followed By Maintenance with Lenalidomide (MPR-R); A Joint Study of the Dutch-Belgian Cooperative Trial Group for Hematology Oncology (HOVON) and the Nordic Myeloma Study Group (NMSG)

Background

Melphalan-based regimens, combined with Prednisone and Thalidomide (THAL)(MPT) or Bortezomib (V)(MPV), have been approved as standard therapy of non-transplant eligible newly diagnosed multiple myeloma (NDMM) patients. Similar to MPT and MPV also MP-Lenalidomide followed by Lenalidomide (LEN) maintenance (MPR-R) has a superior PFS compared to MP. We compared MPT followed by THAL maintenance (MPT-T) versus MPR-R in non-transplant eligible NDMM patients.

Study design

Patients were randomised to receive nine 4-weekly cycles of MPT (MEL 0.18 mg/kg days 1-4, PRED 2 mg/kg days 1-4 plus THAL 200 mg days1-28) followed by THAL maintenance 100 mg d1-28 until progression or nine cycles of MPR (MEL 0.18 mg/kg days 1-4, PRED 2 mg/kg days 1-4 plus LEN 10 mg days 1-21) followed by LEN maintenance 10 mg d1-21 until progression. In order to detect an improvement of progression free survival (PFS) with 90% power and a HR of 0.714 for patients receiving MPR-R, 668 patients had to be randomized. The study started in January 2009 and was closed for inclusion in October, 2012. This analysis is restricted to the first 560 eligible randomized patients, i.e. 280 per arm, including the minimum number of events (377) that were required for the primary endpoint.

Results

Patient characteristics are presented in table 1. The median follow up is 32.6 months. The results of FISH analysis on isolated plasma cells, being performed in 75% and 79% of patients treated with MPT-T and MPR-R respectively, are shown in table 1.

Complete response (CR) rates on protocol were 10% (MPT-T) vs. 13% (MPR-R), (p=0.43), ≥ very good partial response (VGPR) rates were 49% vs. 44% (p=0.31), and ≥ partial response (PR) rates were 82% vs. 83% (p=0.91). The median PFS was 20 months (95% CI; 18-23) for MPT-T vs. 22 months (95% CI; 19-27) for MPR-R (HR = 0.86, 95% CI = 0.70-1.05, p-value adjusted for ISS =0.14). The median overall survival (OS) was 49 months (95% CI; 43-54) for MPT-T vs. 50 months (95% CI; 45-54) for MPR-R (HR = 0.79, 95% CI = 0.60-1.05, p-value adjusted for ISS =0.11). Del(17p) was associated with a lower PR rate (OR=0.45, 95% CI 0.22-0.95, p=0.003), worse PFS (HR=1.74, 95% CI 1.20-2.54, p=0.007) and decreased OS (HR=1.98, 95% CI 1.19-3.28, p=0.01).

Grade ≥ 3 toxicity during induction and maintenance is presented in table 2. The dose intensity of THAL during induction was median 53% (mean 56%, SD 34%), vs. median 88% (mean 73%, SD 32%) for LEN during induction. There was a significantly higher discontinuation rate due to toxicity associated with THAL (28% within one year, and 58% within two years) vs LEN maintenance (10% within one year, and 16% within two years)(p<0.001). The median duration of THAL maintenance was 5 months, vs. median 16 months of LEN maintenance.

The incidence rates for second primary malignancies (SPM) were 3.3/100 patient years (MPT-T) and 2.4/100 patient years (MPR-R)(p=0.33), with 3 (MPT-T) and 6 (MPR-R) cases of AML/MDS and 18 (MPT-T) and 11 (MPR-R) solid tumors (excluding non-melanoma skin cancers).

Detailed analyses will be performed in order to allow cross trial comparisons.

Conclusions

Treatment of elderly NDMM patients with MPT followed by THAL maintenance or MPR followed by LEN maintenance resulted in similar PFS. In addition, response rates and OS were not significantly different. Discontinuation of maintenance therapy due to toxicity was significantly higher for THAL versus LEN and SPM incidence rates similar across the groups.

* Venous Thromboembolic Event including both deep venous thrombosis and pulmonary embolism

This trial was registered as EudraCT 2007-004007-34