Se Bell

A novel prognostic model in myeloma based on co-segregating adverse FISH lesions and the ISS: analysis of patients treated in the MRC Myeloma IX trial.

The association of genetic lesions detected by fluorescence in situ hybridization (FISH) with survival was analyzed in 1069 patients with newly presenting myeloma treated in the Medical Research Council Myeloma IX trial, with the aim of identifying patients associated with the worst prognosis. A comprehensive FISH panel was performed, and the lesions associated with short progression-free survival and overall survival (OS) in multivariate analysis were +1q21, del(17p13) and an adverse immunoglobulin heavy chain gene (IGH) translocation group incorporating t(4;14), t(14;16) and t(14;20). These lesions frequently co-segregated, and there was an association between the accumulation of these adverse FISH lesions and a progressive impairment of survival. This observation was used to define a series of risk groups based on number of adverse lesions. Taking this approach, we defined a favorable risk group by the absence of adverse genetic lesions, an intermediate group with one adverse lesion and a high-risk group defined by the co-segregation of >1 adverse lesion. This genetic grouping was independent of the International Staging System (ISS) and so was integrated with the ISS to identify an ultra-high-risk group defined by ISS II or III and >1 adverse lesion. This group constituted 13.8% of patients and was associated with a median OS of 19.4 months.

Minimal residual disease in myeloma by flow cytometry: independent prediction of survival benefit per log reduction

The detection of minimal residual disease (MRD) in myeloma using a 0.01% threshold (10(-4)) after treatment is an independent predictor of progression-free survival (PFS), but not always of overall survival (OS). However, MRD level is a continuous variable, and the predictive value of the depth of tumor depletion was evaluated in 397 patients treated intensively in the Medical Research Council Myeloma IX study. There was a significant improvement in OS for each log depletion in MRD level (median OS was 1 year for ≥10%, 4 years for 1% to <10%, 5.9 years for 0.1% to <1%, 6.8 years for 0.01% to <0.1%, and more than 7.5 years for <0.01% MRD). MRD level as a continuous variable determined by flow cytometry independently predicts both PFS and OS, with approximately 1 year median OS benefit per log depletion. The trial was registered at www.isrctn.com as #68454111.

Long-term Follow-up of MRC Myeloma IX Trial: Survival Outcomes with Bisphosphonate and Thalidomide Treatment

Purpose: Medical Research Council (MRC) Myeloma IX was a phase III trial evaluating bisphosphonate and thalidomide-based therapy for newly diagnosed multiple myeloma. Results were reported previously after a median follow-up of 3.7 years (current controlled trials number: ISRCTN68454111). Survival outcomes were reanalyzed after an extended follow-up (median, 5.9 years). Experimental Design: At first randomization, patients (N = 1,970) were assigned to bisphosphonate (clodronic acid or zoledronic acid) and induction therapies [cyclophosphamide–vincristine–doxorubicin–dexamethasone (CVAD) or cyclophosphamide–thalidomide–dexamethasone (CTD) followed by high-dose therapy plus autologous stem cell transplantation for younger/fitter patients (intensive pathway), and melphalan–prednisone (MP) or attenuated CTD (CTDa) for older/less fit patients (nonintensive pathway)]. At second randomization, patients were assigned to thalidomide maintenance therapy or no maintenance. Interphase FISH (iFISH) was used to analyze cytogenics. Results: Zoledronic acid significantly improved progression-free survival (PFS; HR, 0.89; P = 0.02) and overall survival (OS; HR, 0.86; P = 0.01) compared with clodronic acid. In the intensive pathway, CTD showed noninferior PFS and OS compared with CVAD, with a trend toward improved OS in patients with favorable cytogenics (P = 0.068). In the nonintensive pathway, CTDa significantly improved PFS (HR, 0.81; P = 0.007) compared with MP and there was an emergent survival benefit after 18 to 24 months. Thalidomide maintenance improved PFS (HR, 1.44; P < 0.0001) but not OS (HR, 0.96; P = 0.70), and was associated with shorter OS in patients with adverse cytogenics (P = 0.01). Conclusions: Long-term follow-up is essential to identify clinically meaningful treatment effects in myeloma subgroups based on cytogenetics. Clin Cancer Res; 19(21); 6030–8. ©2013 AACR.

United Kingdom Myeloma Forum (UKMF) position statement on the use of bendamustine in myeloma.

Bendamustine is a unique bifunctional alkylating agent with promising activity in myeloma. Despite the increasing number of studies demonstrating its efficacy in both the upfront and relapse settings, including patients with renal insufficiency, the optimal use of bendamustine, in terms of dosage, schedule and combination with other agents, has yet to be defined. It is currently licensed for use as frontline treatment with prednisolone for patients with myeloma who are unsuitable for transplantation and who are contraindicated for thalidomide and bortezomib. Studies in relapsed/refractory patients are currently ongoing with other combinations. Given the increasing data to date, the UK Myeloma Forum believes that bendamustine with steroids alone or in combination with a novel agent could be considered for patients with multiply relapsed myeloma. This document provides guidance for the use of bendamustine for patients with myeloma until the results of definitive studies are available.