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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.

Intensive upfront therapy in newly-diagnosed multiple myeloma (MM) including induction therapy (IT), high-dose melphalan (MEL200), and autologous blood stem cell transplantation (ASCT) followed by consolidation and/or maintenance is mostly restricted to patients up to 65 years of age. Prospective phase III trial data in the era of novel agents for patients up to 70 years of age are not available. The GMMG-MM5 trial included 601 patients between 18 and 70 years of age, divided in three groups for the present analysis: ≤60 years (S1, n= 353), 61–65 years (S2, n= 107) and 66–70 years (S3, n= 141). Treatment consisted of a bortezomib-containing IT, MEL200/ASCT, consolidation, and maintenance with lenalidomide. Adherence to treatment was similar among patients of the three age groups. Overall toxicity during all treatment phases was increased in S2 and S3 compared to S1 (any adverse event/any serious adverse event: S1:81.7/41.8% vs. S2:90.7/56.5% vs. S3:87.2/68.1%, p= 0.05/<0.001). With respect to progression-free survival (log-rank p= 0.73), overall survival (log-rank p= 0.54) as well as time-to-progression (Gray’s p= 0.83) and non-relapse mortality (Gray’s p= 0.25), no differences were found between the three age groups. Our results imply that an intensive upfront therapy with a bortezomib-containing IT, MEL200/ASCT, lenalidomide consolidation, and maintenance should be applied to transplant-eligible MM patients up to 70 years of age.

The MM5 trial aimed at demonstrating a progression-free survival (PFS) difference in continued vs. response-adapted (in case of complete response, CR) lenalidomide (LEN) maintenance therapy (MT) in newly diagnosed, transplant-eligible multiple myeloma (MM). Patients were equally randomized to receive induction therapy with PAd (bortezomib/doxorubicin/dexamethasone) or VCD (bortezomib/cyclophosphamide/dexamethasone), high-dose melphalan and autologous blood stem cell transplantation, and LEN consolidation, followed by either LEN MT for a fixed duration of 2 years (LEN-2Y) or until achievement of CR (LEN-CR, intention-to-treat population n= 502): arms A1:PAd + LEN-2Y (n= 125), B1:PAd + LEN-CR (n= 126), A2:VCD + LEN-2Y (n= 126), B2:VCD + LEN-CR (n= 125). In the LEN-CR group (B1 + B2), n= 88/17.5% patients did not start or discontinued LEN MT due to CR. There was no PFS (p= 0.60, primary endpoint) nor overall survival (OS) (p= 0.15) difference between the four study arms. On pooled LEN MT strategies, OS (hazard ratio, hazard ratio [HR] = 1.42, p= 0.03) but not PFS (HR = 1.15, p= 0.20) was shorter in LEN-CR (B1 + B2) vs. LEN-2Y (A1 + A2) groups. PFS was shortened on landmark analyses from the start of LEN MT in patients being in CR in the LEN-CR group (LEN-CR vs. LEN-2Y, HR = 1.84, p= 0.02). OS from first progression was shortened in the LEN-CR vs. LEN-2Y group (HR = 1.60, p= 0.01). LEN MT should be applied beyond CR for at least 2 years.