Salvage autologous transplant and lenalidomide maintenance vs. lenalidomide/dexamethasone for relapsed multiple myeloma: the randomized GMMG phase III trial ReLApsE.

The role of salvage high-dose chemotherapy and autologous stem cell transplantation (sHDCT/ASCT) for relapsed and/or refractory multiple myeloma (RRMM) in the era of continuous novel agent treatment has not been defined. This randomized, open-label, phase III, multicenter trial randomized patients with 1st-3rd relapse of multiple myeloma (MM) to a transplant arm (n = 139) consisting of 3 Rd (lenalidomide 25 mg, day 1-21; dexamethasone 40 mg, day 1, 8, 15, and 22; 4-week cycles) reinduction cycles, sHDCT (melphalan 200 mg/m2), ASCT, and lenalidomide maintenance (10 mg/day) or to a control arm (n = 138) of continuous Rd. Median PFS was 20.7 months in the transplant and 18.8 months in the control arm (HR 0.87; 95% CI 0.65-1.16; p = 0.34). Median OS was not reached in the transplant and 62.7 months in the control arm (HR 0.81; 95% CI 0.52-1.28; p = 0.37). Forty-one patients (29%) did not receive the assigned sHDCT/ASCT mainly due to early disease progression, adverse events, and withdrawal of consent. Multivariate landmark analyses from the time of sHDCT showed superior PFS and OS (p = 0.0087/0.0057) in patients who received sHDCT/ASCT. Incorporation of sHDCT/ASCT into relapse treatment with Rd was feasible in 71% of patients and did not significantly prolong PFS and OS on ITT analysis while patients who received sHDCT/ASCT may have benefitted.

Cyclophosphamide-based stem cell mobilization in relapsed multiple myeloma patients: A subgroup analysis from the phase III trial ReLApsE.

OBJECTIVE: Analysis of the efficiency and toxicity of cyclophosphamide-based stem cell mobilization in patients with relapsed multiple myeloma (RMM). METHODS: Peripheral blood stem cells (PBSCs) were mobilized with high dose cyclophosphamide (2 g/m2 daily on days 1 and 2) and G-CSF plus pre-emptive/rescue plerixafor in RMM patients (first to third relapse) treated within the ReLApsE trial of the German-Speaking Myeloma Multicenter Group (GMMG). RESULTS: Mobilization was initiated with high-dose cyclophosphamide (HD-CY) and G-CSF in 30 patients. Fifteen patients received additional pre-emptive/rescue administration of plerixafor. Stem cell collection was successful (≥2×106 CD34+ cells per kg bw) in 77% (23/30 patients). Patients with prior high-dose melphalan collected a significantly lower median total number of PBSCs than patients without prior high-dose melphalan (3.3×106 vs 17×106 CD34+ cells/kg bw). Toxicity of HD-CY was frequent with 12 serious adverse events (SAE) in 37% of patients (11/30 patients). Infections accounted for the majority of SAE reports. In two patients, SAEs were lethal (septic shock). CONCLUSIONS: These data proof feasibility of PBSC collection at relapse but emphasize the importance of collection and storage of additional PBSC transplants during first-line treatment when mobilization is more efficient and less toxic.

Rationale and design of the German-Speaking Myeloma Multicenter Group (GMMG) trial ReLApsE: a randomized, open, multicenter phase III trial of lenalidomide/dexamethasone versus lenalidomide/dexamethasone plus subsequent autologous stem cell transplantation and lenalidomide maintenance in patients with relapsed multiple myeloma.

BACKGROUND: Despite novel therapeutic agents, most multiple myeloma (MM) patients eventually relapse. Two large phase III trials have shown significantly improved response rates (RR) of lenalidomide/dexamethasone compared with placebo/dexamethasone in relapsed MM (RMM) patients. These results have led to the approval of lenalidomide for RMM patients and lenalidomide/dexamethasone has since become a widely accepted second-line treatment. Furthermore, in RMM patients consolidation with high-dose chemotherapy plus autologous stem cell transplantation has been shown to significantly increase progression free survival (PFS) as compared to cyclophosphamide in a phase III trial. The randomized prospective ReLApsE trial is designed to evaluate PFS after lenalidomide/dexamethasone induction, high-dose chemotherapy consolidation plus autologous stem cell transplantation and lenalidomide maintenance compared with the well-established lenalidomide/dexamethasone regimen in RMM patients. METHODS/DESIGN: ReLApsE is a randomized, open, multicenter phase III trial in a planned study population of 282 RMM patients. All patients receive three lenalidomide/dexamethasone cycles and--in absence of available stem cells from earlier harvesting--undergo peripheral blood stem cell mobilization and harvesting. Subsequently, patients in arm A continue on consecutive lenalidomide/dexamethasone cycles, patients in arm B undergo high dose chemotherapy plus autologous stem cell transplantation followed by lenalidomide maintenance until discontinuation criteria are met. Therapeutic response is evaluated after the 3(rd) (arm A + B) and the 5(th) lenalidomide/dexamethasone cycle (arm A) or 2 months after autologous stem cell transplantation (arm B) and every 3 months thereafter (arm A + B). After finishing the study treatment, patients are followed up for survival and subsequent myeloma therapies. The expected trial duration is 6.25 years from first patient in to last patient out. The primary endpoint is PFS, secondary endpoints include overall survival (OS), RR, time to best response and the influence of early versus late salvage high dose chemotherapy plus autologous stem cell transplantation on OS. DISCUSSION: This phase III trial is designed to evaluate whether high dose chemotherapy plus autologous stem cell transplantation and lenalidomide maintenance after lenalidomide/dexamethasone induction improves PFS compared with the well-established continued lenalidomide/dexamethasone regimen in RMM patients. TRIAL REGISTRATION: ISRCTN16345835 (date of registration 2010-08-24).

Impact of unbalanced minor route versus major route karyotypes at diagnosis on prognosis of CML.

Major route additional cytogenetic aberrations (ACA) at diagnosis of chronic myeloid leukaemia (CML) indicate an increased risk of progression and shorter survival. Since major route ACA are almost always unbalanced, it is unclear whether other unbalanced ACA at diagnosis also confer an unfavourable prognosis. On the basis of 1348 Philadelphia chromosome-positive chronic phase patients of the randomized CML study IV, we examined the impact of unbalanced minor route ACA at diagnosis versus major route ACA on prognosis. At diagnosis, 1175 patients (87.2 %) had a translocation t(9;22)(q34;q11) and 74 (5.5 %) a variant translocation t(v;22) only, while a loss of the Y chromosome (-Y) was present in addition in 44 (3.3 %), balanced or unbalanced minor route ACA each in 17 (1.3 %) and major route ACA in 21 (1.6 %) cases. Patients with unbalanced minor route ACA had no significantly different cumulative incidences of complete cytogenetic remission or major molecular remission and no significantly different progression-free survival (PFS) or overall survival (OS) than patients with t(9;22), t(v;22), -Y and balanced minor route karyotypes. In contrast, patients with major route ACA had a shorter OS and PFS than all other groups (all pairwise comparisons to each of the other groups: p ≤ 0.015). Five-year survival probabilities were for t(9;22) 91.4 % (95 % CI 89.5-93.1), t(v; 22) 87 % (77.2-94.3), -Y 89.0 % (76.7-97.0), balanced 100 %, unbalanced minor route 92.3 % (72.4-100) and major route 52.2 % (28.2-75.5). We conclude that only major route, but not balanced or unbalanced minor route ACA at diagnosis, has a negative impact on prognosis of CML.