Survival Improvement of Transplant Eligible Patients with Newly Diagnosed Multiple Myeloma in Two Consecutive Randomized Phase III Trials: Long-Term Follow up of GEM05 and GEM12 Trials

Introduction: In 2006 the Spanish Group (PETHEMA/GEM) conducted a randomized trial (GEM05menos65, NCT00461747) for transplant eligible patients with newly diagnosed multiple myeloma showing a significant improvement in progression free survival with induction with VTD compared to TD and combination chemotherapy plus bortezomib (VBMCP/VBAD/B) (Blood 2012) followed by maintenance (Leukemia 2017). In 2013 a randomized trial with VRD as pretransplant induction (GEM2012menos65, NCT1916252) (Blood 2019) followed by maintenance therapy (GEM2014MAIN, NCT02406144) were conducted (Blood 2023). We report here the long-term results of the GEM05 trial and compared with the GEM2012/GEM2014 studies.

Methods: the GEM05 trial enrolled 389 patients between April, 2006 and August 5, 2009. Patients were randomized to receive three induction regimens: six 4-week cycles of thalidomide and dexamethasone vs. six 4-week cycles of VTD (thalidomide 200 mg daily; dexamethasone 40 mg on days 1-4 and 9-12 plus intravenous [iv] bortezomib 1.3 mg/m2 on days 1, 4, 8 and 11) vs. combination chemotherapy plus bortezomib (4 cycles of alternating VBMCP and VBAD chemotherapy followed by two cycles of iv bortezomib [VBMCP-VBAD/B]). All patients were planned to undergo ASCT with melphalan 200 mg/m2 (MEL-200) followed by maintenance therapy with thalidomide/bortezomib (TV) vs. thalidomide alone (T) vs. alfa-2b-interferon (IFN) for 3 years. GEM2012 was conducted from September, 2013 to November, 2015 and included 458 patients. Induction therapy consisted of 6 cycles of VRD (subcutaneous bortezomib 1.3 mg/m2 on days 1, 4, 8, and 11 of each cycle; lenalidomide 25 mg/d on days 1 to 21; and dexamethasone 40 mg on days 1 to 4 and 9 to 12 at 4-week intervals). Then, patients were randomized to receive conditioning with BuMEL vs. MEL-200. Patients who achieved at least minimal response were included in the GEM14MAIN trial and randomized to receive maintenance therapy with lenalidomide and dexamethasone (Rd) or ixazomib plus Rd for at least 2 years. Patients harboring del17p, t(4;14) and/or t(14;16) were considered as high-risk cytogenetics (HR) and those without these cytogenetic abnormalities as standard-risk (SR). Patient characteristics at diagnosis and prognostic factors such as ISS, plasmacytomas and cytogenetics were similar in both, GEM05 and GEM2012 trials.

Results: After a median follow-up of 184.9 months (15.1 years), VTD resulted in a significantly longer PFS when compared with TD and VBMCP/VBAD/B (50.4 vs 28.4 vs 34.9 months, p=0.007) and in a significantly longer OS (10.5 vs 7.0 vs 7.5 years, p=0.02). At 15 years, 37.8% vs 25.7% vs 18.9% of the patients were alive with VTD vs TD vs VBMCP/VBAD/B. Maintenance with TV was associated with a better PFS (52.9 vs 42.7 vs 33.7 months, p=0.031) and better OS (9.3 vs 8.6 vs 6.9 years, p=0.05) from transplant than T and IFN. With a median follow-up of 101 months (8.1 years) these results were significantly improved in the GEM2012 study, with a median PFS of 77.5 months (p<0.001) and OS at 8 years of 70%, 58%, 47% and 45% with VRD, VTD, TD and VBMCP/VBAD/B, respectively (p<0.001). Patients with SR-cytogenetics had a PFS of 90 vs 53.3 vs 30.1 vs 43.2 months (p<0.001) and a median OS not reached vs 13.3 vs 9.4 vs 7.8 years (p<0.001) with VRD, VTD, TD and VBMVP/VBAD/V, respectively. In patients with HR-cytogenetics, no benefit in PFS (23 vs 15.3 vs 13.9 months, p=0.28) or OS (3 vs 4.3 vs 2.4 yrs, p=0.657) where observed with VTD, TD or VBMCP/VBAD. However, a significant improvement were observed with VRD, with a median PFS of 51.5 months (p<0.01) and OS not reached (p=0.005).

Conclusions: After over 15 years of follow-up, patients receiving VTD induction displayed a significantly longer OS than those receiving TD or VBMCP/VBAD/V. Of interest, patients with SR cytogenetics were those who benefit most of VTD while no differences in OS were observed in patients with HR cytogenetics between the 3 arms. VRD has improved the results obtained with VTD, with a median PFS of 77.5 vs 50.4 months and an OS at 8 years of 70% vs 58%. Patients who benefit most of VRD compared to VTD were those with HR cytogenetics. Finally, the incorporation of anti-CD38 monoclonal antibodies to VRD will likely result in further improvement of long-term outcome and in the fraction of operational cure.