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

Purpose: To determine whether a reduction in the intensity of Total Therapy (TT) reduces toxicity and maintains efficacy.Experimental Design: 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/m2/d for 4 days.Results: Grade ≥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 4.5 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.Conclusions: 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. Clin Cancer Res; 23(11); 2665-72. ©2016 AACR.

Completion of premaintenance phases in total therapies 2 and 3 improves clinical outcomes in multiple myeloma: an important variable to be considered in clinical trial designs.

BACKGROUND: Total Therapy (TT) programs are complex and their execution over the course of several years is fraught with patient attrition due to failure and toxicity of therapy and patient/physician acceptance. METHODS: The impact of completion versus noncompletion of intended treatment steps was examined in protocols TT2 (n=668) and TT3 (n=303) on overall survival (OS) and event-free survival (EFS). RESULTS: By using appropriate landmarks of 36 months with TT2 and 18 months with TT3, representing the maxima to completion of premaintenance phases, postconsolidation OS was superior for 211 patients completing versus 311 patients not completing premaintenance steps on TT2 (P=.001), which also pertained to the 161 patients completing versus 47 not completing intended treatment steps on TT3 (P=.01). On multivariate analysis that included all patients, completion of therapy independently favored longer OS and EFS in the context of both standard prognostic factors and gene expression profiling-defined risk; in addition, TT3 prolonged EFS over results obtained with TT2. CONCLUSIONS: 1) Completion of intended therapy was a significant independent variable conferring superior OS and EFS in TT programs; and 2) after adjusting for completion of therapy, EFS was still superior with TT3 versus TT2, supporting the beneficial role of bortezomib included in TT3. Collectively, these data point to the importance of designing clinical trials that balance the treatment requirements for disease control with host acceptance and tolerance.

Incorporating bortezomib into upfront treatment for multiple myeloma: early results of total therapy 3.

Total therapy 3 incorporated bortezomib into a melphalan-based tandem transplant regimen for 303 newly diagnosed patients with myeloma. Induction chemotherapy prior to and consolidation chemotherapy after transplants each consisted of two cycles of VTD-PACE (bortezomib, thalidomide, dexamethasone and 4-d continuous infusions of cis-platin, doxorubicin, cyclophosphamide, etoposide); 3-year maintenance comprised monthly cycles of VTD in the first and TD in the remaining years. The median age was 59 years (age >64 years, 28%). A minimum of 20 x 10(6) CD34 cells/kg was collected in 87% of patients; 83% completed both transplants, and only 5% suffered a treatment-related death. At 24 months, 83% had achieved near-complete remission, which was sustained in 88% at 2 years from its onset. With a median follow-up of 20 months, 2-year estimates of event-free and overall survival were 84% and 86% respectively. The 44 patients who experienced an event more often had a high-risk gene array profile, cytogenetic abnormalities and indicators of high lactate dehydrogenase, beta-2-microglobulin, creatinine and International Staging System stage. Toxicities of grade > 2 included thrombo-embolic events in 27% and peripheral neuropathy in 12%. Results of this phase-2 study demonstrated that bortezomib could be safely combined with multi-agent chemotherapy, effecting near-complete remission status and 2-year survival rates in more than 80% of patients.