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.

The impact of prior malignancies on second malignancies and survival in MM patients: a population-based study.

In the present study, we aimed to evaluate 2 hypotheses. First, we hypothesize that prior malignancy is a proxy for genetic susceptibility that could be a risk factor for subsequent malignancy development in multiple myeloma (MM) patients. Second, we hypothesize that survival after MM is influenced by a prior malignancy. All patients diagnosed with MM from 1 January 1973 to 31 December 2010 were identified from the Swedish Cancer Register. Cox regression model was used to calculate hazard ratios (HRs) and 95% confidence intervals (CIs) where prior malignancy was compared in MM patients who developed a subsequent malignancy and MM patients who did not. In another Cox regression model, survival was compared in MM patients with and without a prior malignancy diagnosis. A total of 19 791 patients were diagnosed with MM. Patients with a prior malignancy diagnosis had a significantly increased risk of developing a subsequent malignancy compared with MM patients without (HR 1.42, 95% CI 1.23-1.65, P < .001). MM patients with a prior malignancy diagnosis had a significant 1.21-fold increased risk of death (95% CI 1.115-1.26, P < .001) compared with MM patients without. MM patients with 2 or more prior malignancy diagnoses had a 1.34-fold increased risk of death (95% CI 1.19-1.52, P < .001). In this large population-based study, we report that prior malignancy increases the risk of subsequent malignancy development in MM patients. Furthermore, we found that prior malignancy negatively impacts survival and that >1 prior malignancy reduces survival even further.

Transplantation for Multiple Myeloma.

Multiple myeloma is a disorder characterized by accumulation of malignant plasma cells in the bone marrow, hypercalcemia, monoclonal protein, and end organ damage. Recently newer generation proteosome inhibitors, monoclonal antibodies and novel agents have been approved by FDA, which is undoubtedly increasing life expectancy of the patients. However, hematopoietic stem cell transplantation still remains the cornerstone of the treatment. In this chapter, we are discussing the autologous stem cell transplant, allogeneic stem cell transplant and total therapy trials with outcomes.