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Welcome to Managing Myeloma, I am Michele Cavo from Bologna University School of Medicine, Italy. I will review three abstracts that were recently selected for oral presentation at the past EHA Meeting in Stockholm. In particular, I will review the final analysis of the phase 3 GIMEMA trial comparing bortezomib, thalidomide, and dexamethasone versus thalidomide and dexamethasone, incorporated into double autologous stem cell transplantation. I will also discuss the results of the phase 3 ALCYONE trial comparing bortezomib, melphalan, and prednisone (VMP) versus daratumumab plus VMP for transplant-ineligible myeloma patients. Finally, I will review the updated efficacy analysis of a phase 2 trial comparing carfilzomib, lenalidomide, and dexamethasone versus carfilzomib, cyclophosphamide, and dexamethasone. Thank you for viewing this activity.
If we move to the first study, the GIMEMA trial as previously mentioned was aimed at comparing three cycles of bortezomib, thalidomide, dexamethasone (VTD) with three cycles of thalidomide and dexamethasone as induction before, and the same regimen given also as consolidation after double autologous stem cell transplantation (ASCT), for transplant-eligible patients with newly diagnosed multiple myeloma. This final analysis was performed with a median follow-up of 10 years. On an intention-to-treat basis, the median progression-free survival (PFS) was approximately five years for patients randomized to VTD as induction and consolidation plus double ASCT, in comparison with 41 months for patients randomized to thalidomide and dexamethasone plus double ASCT. The progression-free survival benefit with VTD and double ASCT was retained across almost all pre-specified subgroups of patients, including patients with standard-risk and high-risk cytogenetic profiles, as conventionally defined. Importantly, at the time of the analysis, the estimated rate of overall survival at 10 years was 60% for patients randomized to VTD, as compared to patients randomized to TD who had overall survival rate of the 46% (the difference between the two groups was statistically significant). Again, the overall survival benefit with VTD plus double ASCT was retained across many pre-specified subgroups of patients. Secondary study endpoints were PFS2 and time to second antimyeloma therapy. In this case, randomization to VTD offered a significant benefit in terms of prolonged PFS2 and time to second antimyeloma therapy. Therefore, the conclusion is that VTD as induction and consolidation plus double ASCT significantly extended the progression-free survival and overall survival for newly diagnosed transplant-eligible myeloma patients, with a benefit retained in the majority of patients with low- or high-risk disease-related characteristics.
Moving to the second abstract, the oral presentation was related to the phase 3 ALCYONE trial. The ALCYONE trial was a large study for transplant-ineligible myeloma patients and was aimed at comparing bortezomib, melphalan, prednisone (VMP) versus VMP plus daratumumab. The primary study endpoint was progression-free survival, and the first interim analyses reported at the past ASH meeting showed significantly longer progression-free survival with the dara-VMP versus VMP. This study was aimed at evaluating the outcomes of patients randomized to the control group or the experimental treatment arm according to age, since patients were stratified based on age (higher or lower than 75 years). By the end of cycle 9, which was the planned number of cycles of VMP or dara-VMP followed by dara as maintenance therapy for patients randomized to the dara-VMP arm of the study, more VMP-treated patients discontinued the therapy due to progressive disease or adverse events in comparison with the dara-VMP arm. The longer exposure to dara-VMP was retained in younger and older patients (lower or higher than 75 years of age). The median cumulative dose of bortezomib actually received was related to the probability to complete the nine planned cycles, and it was the highest for younger patients randomized to dara-VMP and the lowest for older patients who were randomized to the control VMP treatment. With a median follow-up of approximately 16 months, the progression-free survival benefit with the dara-VMP versus VMP was retained in both age subgroups. The addition of dara to VMP reduced by approximately 50% the risk of progression in comparison with the control VMP treatment. What about overall response rates and the rates of complete response (CR)? Significantly higher rates of CR were observed with the dara-VMP versus VMP in patients older than 75 years, as well as in patients younger than 75 years of age. In both groups, the rate of CR or higher was approximately 40% with the dara-VMP versus approximately 25% with VMP. Patients were also monitored for minimal residual disease (MRD) negativity. With the threshold of 10-5, the probability of getting MRD negativity was four times higher for patients receiving dara-VMP in comparison with the VMP. The MRD negativity rate for both age groups treated with dara-VMP was in the range between 22% and 24%, versus a 6% to 8% MRD negativity rate for patients randomized to VMP. The toxicity profile was consistent with that seen in the overall patient population with the new safety signal, even in the older patient population. Therefore, this sub-analysis does confirm the benefit of the addition of the daratumumab to the standard of care VMP in transplant-ineligible myeloma patients with newly diagnosed multiple myeloma. It also highlights how a benefit – in terms of increased progression-free survival, overall response rate, complete response rate, and MRD negativity – was seen in patients older or younger than 75 years. In particular, this is the first phase 3 trial showing the probability of getting MRD negativity in approximately 1/5 of newly diagnosed multiple myeloma patients older than 75.
Moving to the final abstract, as previously mentioned, the presentation was about the updated response analysis of the FORTE trial which was aimed at comparing carfilzomib, lenalidomide, dexamethasone (KRd) as induction before and consolidation after single autologous stem cell transplantation, versus carfilzomib combined with cyclophosphamide and dexamethasone (KCd) as induction four cycles before and consolidation four cycles after a single transplant. A third arm of the study evaluated 12 cycles of KRd with the transplant delayed at the time of relapse. For the purpose of this analysis, patients in the KRd plus transplant arm were pooled together with those randomized to 12 cycles of KRd. The analysis was performed after the first four cycles of KRd versus KCd. KRd was related to a significantly higher rate of complete response or stringent complete response in comparison with KCd; 14% versus 4% (statistically significant difference). Even when the analysis was focused on the rate of at least very good partial response (VGPR), there was statistically significant difference in terms of VGPR or higher rate favoring KRd in comparison with KCd. When the two treatment groups were compared according to MRD negativity by flow cytometry, the rate of MRD negativity after four cycles of KRd therapy was significantly higher in comparison with four cycles of KCd therapy; 56% versus approximately 30%. This trial does confirm that the best partner for a proteasome inhibitor (PI) – even a second-generation PI such as carfilzomib – is an immunomodulatory agent (IMiD), in comparison with an alkylating agent such as cyclophosphamide.
Tacchetti P, Patriarca F, Petrucci M, et al. A Triplet Bortezomib- and Immunomodulator-Based Therapy Before and After Double ASCT Improves Overall Survival of Newly Diagnosed MM Patients: Final Analysis of Phase 3 GIMEMA-MMY-3006 Study. EHA 2018. Abstract S105.
San-Miguel J, Iida S, Blade J, et al. Daratumumab Plus Bortezomib-Melphalan-Prednisone (VMP) in Elderly (≥75 Years of Age) Patients with Newly Diagnosed Multiple Myeloma Ineligible for Transplantation (ALCYONE). EHA 2018. Abstract S107.
Gay F, Scalabrini DR, Belotti A, et al. Updated Efficacy and MRD Data According to Risk-Status in Newly Diagnosed Myeloma Patients Treated with Carfilzomib Plus Lenalidomide or Cyclophosphamide: Results from the FORTE Trial. EHA 2018. Abstract S109.