Data from Adverse Metaphase Cytogenetics Can Be Overcome by Adding Bortezomib and Thalidomide to Fractionated Melphalan Transplants

Abstract

<div>Abstract<p><b>Purpose:</b> To determine whether a reduction in the intensity of Total Therapy (TT) reduces toxicity and maintains efficacy.</p><p><b>Experimental Design:</b> A total of 289 patients with gene expression profiling (GEP70)-defined low-risk multiple myeloma were randomized between a standard arm (TT4-S) and a light arm (TT4-L). TT4-L employed one instead of two inductions and consolidations. To compensate for potential loss of efficacy of TT4-L, bortezomib and thalidomide were added to fractionated melphalan 50 mg/m<sup>2</sup>/d for 4 days.</p><p><b>Results:</b> Grade ≥3 toxicities and treatment-related mortalities were not reduced in TT4-L. Complete response (CR) rates were virtually identical (<i>P</i> = 0.2; TT4-S, 59%; TT4-L, 61% at 2 years), although CR duration was superior with TT4-S (<i>P</i> = 0.05; TT4-S, 87%; TT4-L, 81% at 2 years). With a median follow-up of 4.5 years, there was no difference in overall survival (OS) and progression-free survival (PFS). Whereas metaphase cytogenetic abnormalities (CAs) 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), seven 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 a difference was not observed in TT4-L.</p><p><b>Conclusions:</b> We identified a prognostic CA-linked GEP51 signature, the adversity of which could be overcome by potentially synergizing anti–multiple myeloma effects of melphalan and bortezomib. These exploratory findings require confirmation in a prospective randomized trial. <i>Clin Cancer Res; 23(11); 2665–72. ©2016 AACR</i>.</p></div>