Long-Term Follow-up Analysis of Progression-Free and Overall Survival in Newly Diagnosed Multiple Myeloma Patients from the GMMG Myeloma Registry Following the Randomized Phase III GMMG-HD6 Trial
Authors: Keller Anne-Valérie , Hajiyianni Marina , Kurre Eileen , Mai Elias Karl , Bertsch Uta , Benner Axel , Luntz Steffen , Raab Marc-Steffen , Besemer Britta , Michel Christian Sebastian , Schroers Roland , Fenk Roland , Salwender Hans , Blau Igor Wolfgang , Hänel Mathias , Mann Christoph , Goldschmidt Hartmut 
Published: December 2024

Abstract
Introduction:
Advances in the treatment of multiple myeloma (MM) have led to a significant improvement in prognosis. Nevertheless, prognosis of MM is heterogeneous depending on risk factors and treatment response. The German-speaking Myeloma Multicenter Group (GMMG) Myeloma Registry has collected long-term follow-up (FU) data from several trials (e.g. GMMG trials: MM5/HD6/HD7). Based on the GMMG HD6 study database we performed a long-term FU.
Patients and Methods:
The Myeloma Registry was activated on December 8, 2022. Currently 35 GMMG centers in Germany are participating. The first longtime FU data set included in the registry was the GMMG-HD6 trial. The GMMG-HD6 trial is a phase 3 trial which investigated the efficacy of the addition of the anti-SLAMF7 monoclonal antibody elotuzumab, to the standard induction andconsolidation therapy consisting of lenalidomide, bortezomib and dexamethasone (RVd) in transplant-eligible patients with newly diagnosed MM. The primary objective was determined best of four treatment strategies regarding progression-free survival (PFS) from randomization in newly diagnosed transplant eligible multiple myeloma patients. Secondary endpoints were evaluated which included overall survival (OS), follow-up time, the cause of death, the therapy free time after first progressive disease and treatment of the first relapse. For death cause a systematic classification of cause of death (COD) for MM (Mai et al., 2018) and the MedDRA terminology was applied.
Results:
Between June 2015 and September 2017, 564 patients were included in the GMMG- HD6 trial, of which 50 patients could not be included in the registry, for various reasons like lost to FU, withdrawal of informed consent, or physician decision. 436 patients were entered in the registry. Cut-off date of this analysis was on 31st December, 2023. The estimated median FU time was 85 months with a 95% CI [84.2;86.4]. PFS was not statistically significantly different between the four treatment arms (p=0.90, log-rank test), 5-year estimated PFS ratewas 52.0% (95% CI: 43.7% - 61.8%), 56.3% (95% CI: 48.4% - 65.5%), 48.0% (95% CI: 39.6% - 58.1%), 53.8% (95% CI: 45.6% - 63.5%) in the RVd/R, RVd/E-R, E-RVd/R, and E-RVd/E-R groups, respectively. Time to progression (TTP) was not statistically significantly different between the four treatment arms (p=0.92, Gray's test). Overall Survival (OS): 135 of 559 patients had died until the cut-off date. OS was not statistically significantly different between the four treatment arms (p=0.50, log-rank test). The median of OS was not reached in either arm. The causes of death were classified in four COD categories. (1A), 67% (n=90) were MM-dependent, (2), 9,5 % (n=13) MM-independent, (3), 9,5% (n=13) not attributable to (1)(2) and (4), 14% (n=19) unknown. Among 66% (n=90) MM-dependent (1) COD, 66,7 % (n=60) were MM progression-related (1A), 23,3 % (n=21) MM therapy-related (1B) and 10% (n=9) not attributable to (1A)/(1B) (1C). The most common MM-dependent SOC (1A), 58%, (n=53) were progressive disease and infections 26,4%, (n=24). The SOC category of MM therapy-related dependent (1B) was exclusive infections 14% (n=13). MM-independent cause of death COD (2)-(4) n=46 (34%), infections 30,4% (n=14) were the most frequent SOC followed by neoplasms (15,2 %, n=7) and vascular disorders (13 %, n=6). Treatment after first relapse: 183 of 559 patients had at least one first relapse. 62,7 % (n=89) patients with a first relapse were treated with the anti-CD38 monoclonal antibody daratumumab single and in combination of immunomodulators and/or proteasomes. 22,4 % patients with a first relapse did not require therapy and will be monitored onwards. Patients with first relapse without subsequent treatment had a median observation time of 30 month.
Conclusions:
The long-term follow-up of the HD6 in the registry confirmed that the addition of elotuzumab did not result in improved PFS or OS. Among the long-term FU, the majority of death was 67% MM-dependent of which 39% due to MM-progress-related and 15% MM-therapy related infections. The treatments after the first relapse shows a heterogeneous strategy where 62.7 % of the patients in the registry were treated with CD38 monoclonal antibody daratumumab alone or in combination with different proteasome inhibitors or immunomodulators.