Tandem Transplantation in Multiple Myeloma Prolongs Survival, Predominantly in Patients Achieving Partial Remission after the First Cycle of High-Dose Therapy.
Authors: Nowrousian M.R. , Hoiczyk M. , Mueller S. , Schuett P. , Wrzeciono T. , Poser M. , Brandhorst D. , Welt A. , Hense J. , Flasshove Michael , Metz K.A. , Seeber S. , Moritz T. 
Published: October 2019

Abstract
Introduction. The group of patients (pts) with multiple myeloma (MM) who benefit from two cycles of high-dose (HD) melphalan (MP) has not yet been clearly defined. In this single-institution, nonrandomized study, we evaluate the long-term results of tandem HDMP and peripheral blood stem cell transplantation (PBSCT) in previously untreated pts and investigate the pretherapeutic and therapeutic factors predictive for survival.
Patients and treatment. From 2/94 to 10/05, 90 pts were included. Pt characteristics: Age median 53 (range 31–70, 29% >60 yrs), m/f 59/41%, MM stage I/II/III 5/23/72%, A/B 88/12% (Durie/Salmon), Bence Jones protein 42%, albumin <3.5 g/dL 13%, beta2-microglobulin (b2MG)>2.5 mg/mL 70%, CRP >5 mg/L 61%, IL2-receptor elevated 49%, and thymidine kinase>10 U/L 48%. 28% of pts received HD dexamethasone and 72% conventional-dose chemotherapy, mainly VAD-based, prior to intended 2 (administered 1–3) cycles of HD cyclophosphamide (CY) (2–3 g/m2, days 1+2) and 2 (administered 0–3) cycles of HDMP (100 mg/m2, days 1+2). HDCY cycles were supported by G-CSF or GM-CSF and HDMP cycles by autologous PBSC and G-CSF. PBSC were collected after the first or second cycle of HDCY.
Results. 14% (n=13) of pts received only CY, 30% (n=27) 1 cycle of HDMP, and 56% 2–3 cycles (n=47/3), depending on treatment complications, number of PBSC available, and patient compliance. 54% of pts achieved CR (defined as disappearance of myeloma protein in serum and urine and <5% myeloma cells in the bone marrow), 36% PR (defined as reduction of MM protein in serum >50% and in urine >90% from baseline), and 3% no change after completion of treatment. 7% of pts died during treatment. With a median follow-up of 5.8 yrs, the probability of overall survival (OS) for the entire group of pts was 48% and 41% at 5 and 7 yrs, respectively, and the probability of progression-free survival (PFS) 35% and 21%. In multivariate analysis, CRP ≤5 mg/L and b2MG ≤2.5 mg/mL were independent positive pretherapeutic parameters for OS and b2MG ≤2.5 mg/mL for PFS. Among the therapeutic factors, achievement of CR after completion of treatment and the use of tandem HDMP independently predicted prolonged OS and PFS. Pts who achieved CR had a median OS and PFS of 110 and 64 months, respectively, compared with 45 and 27 months in pts with PR or NC (p<.008, p<.001). The median OS and PFS in pts who received 2 cycles of HDMP were 110 and 44 months, respectively, compared with 49 and 20 months in pts with only 1 cycle (p<.023 and p<.028). Among the first group of pts, however, exclusively those with PR (n=22), and not those with CR (n=28), benefited from the second cycle of HDMP, with a median OS and PFS significantly increasing from 49 to 110 and 14 to 44 months (p<.028 and p<.013), respectively. The median OS in pts with CR after the first cycle of HDMP with (n=28) or without (n=10) a second cycle has not been reached at 10 yrs (p=.736), and the probability of PFS at 5 and 7 yrs in those with a second cycle was 60% and 48% and in those without a second cycle 50% and 17% (p=.207), respectively.
Conclusion. The results of this study clearly show a long-term benefit from tandem HDMP in pts with MM, including those age > 60 yrs. This benefit is particularly evident in pts achieving PR after the first cycle of HD treatment.