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High-dose busulfan plus melphalan failed to generate a progression-free survival benefit vs melphalan for autologous stem cell transplant conditioning in patients with newly diagnosed multiple myeloma after induction therapy.
High-dose busulfan (Busulfex) plus melphalan (Alkeran; BUMEL) failed to generate a progression-free survival (PFS) benefit vs melphalan 200mg/m2 (MEL200) for autologous stem cell transplant (ASCT) conditioning in patients with newly diagnosed multiple myeloma (NDMM) after induction therapy, according to results from the phase 3 GEM12meno65 trial (NCT01916252).1
Findings presented at the 19th Annual International Myeloma Society Meeting showed that at a median follow up of 84.4 months (95% CI, 82.1-85.6), the median PFS was not reached (NR) with BUMEL (95% CI, 68.8-NR) vs 75.3 months (95% CI, 59.3-NR) with MEL200 (HR, 0.880; 95% CI, 0.679-1.139; log-rank test P = .331). Median overall survival (OS) was reached in either arm. In all patients, the median PFS was 80.8 months (95% CI, 68.8-NR).
However, in certain subgroups of patients with NDMM, the BUMEL regimen achieved a significantly longer PFS compared with MEL200. This was especially true for patients with more than 1 risk factor.
GEM12meno65 follows results from 2 prospective studies, which signaled survival advantages with both the BUMEL and MEL200 regimens. First, in the IFM 95021 study of 8 Gy total body irradiation plus 140 mg/m2 of melphalan (MEL140) vs MEL200 inpatient with multiple myeloma, MEL200 showed a 21-month median event-free survival compared with 20.5 months in the MEL140 arm.2 Then, in a phase 3 study of BUMEL vs MEL200 (NCT01413178), BUMEL showed a median PFS of 64.7 months compared with 43.5 months with MEL200 (HR, 0.53; P = .02) in a NDMM population.3
In GEM12meno65, 458 patients were randomized to receive either MEL200 (n = 228) or BUMEL (n = 230). The primary end point of the study was PFS after ASCT in patients who received lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (VRD-GEM) as induction and consolidation therapy. A total of 208 patients in the MEL200 arm completed induction with VRD-GEM, as did 217 in the BUMEL arm. Then, 202 patients were treated with MEL200 and ASCT, and 194 had BUMEL and ASCT. Patients then went on to consolidation with VRD-GEM.
Treatment with VRD-GM was administered with lenalidomide 25 mg per day on days 1-21, bortezomib 1.3 mg/mg subcutaneously on days 1, 4, 8, and 11, and dexamethasone 40 mg orally on days 1-4 and 9-12. For BUMEL, patients received 3.2 mg/kg of busulfan with melphalan 140 mg/m2.
All patients included were 65 years of age or older with NDMM. Patients had measurable disease, an ECOG performance status of ≥ 2, and adequate organ function.
According to Joan Blade, MD, PhD, who presented the GEM12meno65 data, the 2 treatment arms were well balanced in terms of prognostic features. The key prognostic features used for subgroup analysis in this study were International Staging System (ISS) disease stage, lactate dehydrogenase (LDH) elevation, and cytogenetics like deletion 17p (del(17p), translocation 4:14 (t(4;14), and t(14;16).
Results showed responses after induction, transplant, and consolidation, as well as survival across the key prognostic subgroups, and safety.
Post-induction results showed that 34.1% of patients achieved minimal residual disease (MRD) negativity in the BUMEL arm compared with 31.1% in the MEL200 arm (P = .5). Complete responses (CRs) or higher responses to induction therapy occurred in 42.2% of the BUMEL arm vs 30.3% of the MEL200 arm (P = .1). Very good partial responses (VGPRs) or PRs were observed in 43% of the BUMEL arm vs 54.3% of the MEL200 arm (P = .018).
After transplant MRD negativity was shown in 55.2% of patients in the BUMEL arm vs 52% in the MEL200 arm (P = .6). One hundred twenty-three patients (53.5%) who were treated with BUMEL had ≥ CR compared with 43.0% of the MEL200 arm (P = .2). A VGPR or PR was observed in 32.2% of the BUMEL arm vs 38.1% of the MEL200 arm (P = .17).
Post consolidation results showed that 58.2% of patients in the BUMEL arm achieved MRD negativity vs 55.5% in the MEL200 arm (P = .6). At least a CR was achieved in 59.1% of the BUMEL group vs 53.1% in the MEL200 arm (P = .7). Finally, a VGPR or PR occurred in 23.9% of the BUMEL arm vs 28.5% of the MEL200 arm (P = .33).
Grade 1 through 4 toxicity was mostly similar between the 2 arms. However, grade 1 gastrointestinal (GI) events and grade 3 mucositis did show a significant difference. Specifically, 21.8% of the BUMEL experienced GI toxicity vs 10.8% of the MEL200 arm, and 17.8% had mucositis vs 9.8%, respectively. Graft failure occurred in 1 patient in the BUMEL compared with 0 in the MEL200 arm. The patient continued treatment after receiving cyclosporine. There were no deaths in the study associated with treatment.
Of the 458 patients in the study, 109 had stage III disease, 170 had stage II disease, and 179 had stage I disease. These 3 stages were compared in the subgroup analysis. Translocations, specifically t(14:16) were seen in 17 patients at baseline, and the subgroup analysis compared the 17 patients with translocation to the 377 patients without. Additionally, del(17p) was seen in 27 patients at baseline, and those patients were compared with the 355 who had no dels during the subgroup analysis.
The subgroup analysis showed that stage II had longer PFS vs stage III, and stage I (HR, 0.87; 95% CI, 0.67-1.13; P = .009). Moreover, having t(14:16) led to a shorter PFS compared with patients who had no translocations (HR, 0.10; 95% CI, 0.01-0.82; P < .01). Del(17p) was also associated with shorter PFS compared with no dels (HR, 0.31; 95% CI, 0.116-0.85; P < .03).
Subgroup analysis results also showed that PFS in patients with stage III disease was longer in the BUMEL arm vs the MEL200 arm, and with del(17p) vs no dels. However, patients with t(14;16) had a longer PFS when treated with MEL200 vs BUMEL.
“BUMEL results in a significantly longer progression-free survival, especially in those with more than one of the risk factors. We have to consider that the use of an intensified induction and consolidation with VRD-GEM, along with an intensive maintenance, resulted in a progression-free survival of 80 month, [which is the] longest reported so far. This may have diluted other potential difference between the 2 hide-dose regimens,” explained Blade, during his presentation.
According to Blade, a subsequent analysis is upcoming to follow patients for longer and determine how this study approach impacts the cure rate compared with another strategy.