Randomized auto-transplant trial for low-risk myeloma

Purpose: To determine whether a reduction in the intensity of Total Therapy (TT) reduces toxicity and maintains efficacy. Experimental Design: 289 patients with gene expression profiling (GEP70)-defined low-risk multiple myeloma (LRMM) were randomized between a standard arm (TT4-S) and a light arm (TT4-L). TT4-L employed 1 instead of 2 inductions and consolidations. To compensate for potential loss of efficacy of TT4-L, bortezomib and thalidomide were added to fractionated melphalan 50mg/m2/d x 4. Results: Grade {greater than or equal to}3 toxicities and treatment-related mortalities were not reduced in TT4-L. Complete response (CR) rates were virtually identical (p=0.2; TT4-S, 59%: TT4-L, 61% at 2 years), although CR duration was superior with TT4-S (p=0.05; TT4-S, 87%;TT4-L, 81% at 2 years. With a median follow-up of 4.5yr, there was no difference in overall survival (OS) and progression-free survival (PFS). While metaphase cytogenetic abnormalities (CA) tended to be an adverse feature in TT4-S, as with predecessor TT trials, the reverse applied to TT4-L. Employing historical TT3a as training and TT3b as test set, 51 gene probes (GEP51) significantly differentiated the presence and absence of CA (q<0.0001), 7 of which function in DNA replication, recombination, and repair. Applying the GEP51 model to clinical outcomes, OS and PFS were significantly inferior with GEP51/CA in TT4-S; such difference was not observed in TT4-L. Conclusions: We identified a prognostic CA-linked GEP51 signature, the adversity of which could be overcome by potentially synergizing anti-MM effects of melphalan and bortezomib. These exploratory findings require confirmation in a prospective randomized trial.

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