Complete Response (CR) with Total Therapy 2 (TT2) for Multiple Myeloma (MM): Low Frequency in Case of Prior MGUS without Adverse Consequences for Survival - Yet Critical for Disease Control in Presumed “De Novo” MM.

Background: It is now widely accepted that stringently defined CR is a prerequisite for durable EFS and OS also in MM.

Patients and Methods: The results of TT2 (4 cycles of intensive induction prior to and consolidation chemotherapy after tandem autotransplant) have recently been reported (ASCO 2005), demonstrating a significantly higher CR rate and longer EFS but not OS among those randomized to thalidomide. Baseline laboratory variables and the clinical history off 668 patients enrolled in TT2 were examined for their potential impact on CR and, in turn CR’s impact on EFS and OS. The Kaplan-Meier method was used to estimate EFS and OS. Cox regression was used to evaluate multivariate factors of CR, EFS, and OS; the prognostic value of CR and 1^st and 2^nd transplants were modeled as time-dependent covariates in order to adjust for the guarantee time associated with reaching these treatment markers.

Results: Of 668 patients enrolled, 45 had a documented history of prior MGUS (n=22) or smoldering MM (SMM) (n=23); 20 had a prior solitary plasmacytoma (SPC) of bone. 2-yr estimates of CR (negative immunofixation, normal bone marrow) were 47% for the 588 without history of preceding SPC/MGUS/SMM, 55% for SPC and 22% for the MGUS/SMM groups. EFS and OS at 4 yrs were 57% and 71%, independent of a preceding disorder. Multivariate analysis revealed faster onset and higher frequency of CR with only light chain MM (HR, 2.6; p<.001), in the absence of MGUS/SMM (HR, 1.8; p=.049), and with thalidomide (HR, 1.7: p<0.001). Cytogenetic abnormalities (CA), del13q14 and amp1q21, while adversely affecting EFS/OS, did not influence CR. On multivariate analysis for EFS and OS accounting, in addition to baseline variables, also for T, CR, 1^st and 2^nd transplant, and pre-MM history of MGUS/SMM, we observed that patients attaining a CR had significantly improved EFS and OS independent of key baseline variables (amp1q21, del13q14, CA, LDH, albumin) and treatment markers (T, 1^st and 2^nd transplants).

Conclusion: We confirm that documented MGUS/SMM pre-MM is associated with lower CR rate without impacting survival negatively, probably implying the re-establishment of the precursor condition. For the remainder, CR was critical for prolonged survival. Gene expression analysis is applied to recognize, in the absence of prior history, those patients likely having evolved from MGUS and thus contribute fundamentally to a distinction of “de novo” MM from “MGUS-evolved MM”. Those results will be presented at the meeting.