Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group.

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Abstract

The clinical outcome of multiple myeloma (MM) is heterogeneous. A simple and reliable tool is needed to stratify patients with MM. We combined the International Staging System (ISS) with chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization after CD138 plasma cell purification and serum lactate dehydrogenase (LDH) to evaluate their prognostic value in newly diagnosed MM (NDMM).

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A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1.

John Shaughnessy, Fenghuang Zhan, Bart Burington … (2007)

To molecularly define high-risk disease, we performed microarray analysis on tumor cells from 532 newly diagnosed patients with multiple myeloma (MM) treated on 2 separate protocols. Using log-rank tests of expression quartiles, 70 genes, 30% mapping to chromosome 1 (P < .001), were linked to early disease-related death. Importantly, most up-regulated genes mapped to chromosome 1q, and down-regulated genes mapped to chromosome 1p. The ratio of mean expression levels of up-regulated to down-regulated genes defined a high-risk score present in 13% of patients with shorter durations of complete remission, event-free survival, and overall survival (training set: hazard ratio [HR], 5.16; P < .001; test cohort: HR, 4.75; P < .001). The high-risk score also was an independent predictor of outcome endpoints in multivariate analysis (P < .001) that included the International Staging System and high-risk translocations. In a comparison of paired baseline and relapse samples, the high-risk score frequency rose to 76% at relapse and predicted short postrelapse survival (P < .05). Multivariate discriminant analysis revealed that a 17-gene subset could predict outcome as well as the 70-gene model. Our data suggest that altered transcriptional regulation of genes mapping to chromosome 1 may contribute to disease progression, and that expression profiling can be used to identify high-risk disease and guide therapeutic interventions.

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Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.

Michele Cavo, Paola Tacchetti, Francesca Patriarca … (2010)

Thalidomide plus dexamethasone (TD) is a standard induction therapy for myeloma. We aimed to assess the efficacy and safety of addition of bortezomib to TD (VTD) versus TD alone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma. Patients (aged 18-65 years) with previously untreated symptomatic myeloma were enrolled from 73 sites in Italy between May, 2006, and April, 2008, and data collection continued until June 30, 2010. Patients were randomly allocated (1:1 ratio) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily for the first 14 days and 200 mg daily thereafter) plus dexamethasone (40 mg daily on 8 of the first 12 days, but not consecutively; total of 320 mg per cycle), either alone or with bortezomib (1·3 mg/m(2) on days 1, 4, 8, and 11). The randomisation sequence was computer generated by the study coordinating team and was stratified by disease stage. After double autologous stem-cell transplantation, patients received two 35-day cycles of their assigned drug regimen, VTD or TD, as consolidation therapy. The primary endpoint was the rate of complete or near complete response to induction therapy. Analysis was by intention to treat. Patients and treating physicians were not masked to treatment allocation. This study is still underway but is not recruiting participants, and is registered with ClinicalTrials.gov, number NCT01134484, and with EudraCT, number 2005-003723-39. 480 patients were enrolled and randomly assigned to receive VTD (n=241 patients) or TD (n=239). Six patients withdrew consent before start of treatment, and 236 on VTD and 238 on TD were included in the intention-to-treat analysis. After induction therapy, complete or near complete response was achieved in 73 patients (31%, 95% CI 25·0-36·8) receiving VTD, and 27 (11%, 7·3-15·4) on TD (p<0·0001). Grade 3 or 4 adverse events were recorded in a significantly higher number of patients on VTD (n=132, 56%) than in those on TD (n=79, 33%; p<0·0001), with a higher occurrence of peripheral neuropathy in patients on VTD (n=23, 10%) than in those on TD (n=5, 2%; p=0·0004). Resolution or improvement of severe peripheral neuropathy was recorded in 18 of 23 patients on VTD, and in three of five patients on TD. VTD induction therapy before double autologous stem-cell transplantation significantly improves rate of complete or near complete response, and represents a new standard of care for patients with multiple myeloma who are eligible for transplant. Seràgnoli Institute of Haematology at the University of Bologna, Bologna, Italy. Copyright © 2010 Elsevier Ltd. All rights reserved.

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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

Kevin Boyd, Fiona Ross, Laura Chiecchio … (2011)

The association of genetic lesions detected by FISH with survival was analyzed in 1069 patients with newly presenting myeloma treated in the Medical Research Council (MRC) 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 PFS and OS in multivariate analysis were +1q21, del(17p13) and an adverse 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 1 adverse lesion and a high risk group defined by the co-segregation of >1 adverse lesion. This genetic grouping was independent of the 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.

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Author and article information

Journal

Journal ID (iso-abbrev): J. Clin. Oncol.

Title: Journal of clinical oncology : official journal of the American Society of Clinical Oncology

ISSN (Electronic): 1527-7755

ISSN (Print): 0732-183X

Publication date (Electronic): Sep 10 2015

Volume: 33

Issue: 26

Affiliations

[1 ] Antonio Palumbo, Stefania Oliva, Simona Caltagirone, Sara Bringhen, and Francesca Gay, University of Torino, Azienda Ospedaliero-Universitaria Città della Salute della Salute e della Scienza di Torino; Roberto Passera, University of Torino, Torino; Massimo Offidani, Clinica di Ematologia, AUO Ospedali Riuniti di Ancona, Ancona; Pellegrino Musto, Istituto di Ricovero e Cura a Carattere Scientifico, Referral Cancer Center of Basilicata, Rionero in Vulture; Maria T. Petrucci, Sapienza University of Rome, Rome; Elena Zamagni and Michele Cavo, Istituto di Ematologia Seragnoli, Università di Bologna, Bologna, Italy; Hervé Avet-Loiseau and Michel Attal, Institut Claudius Regaud, L'Institut Universitaire du Cancer de Toulouse-Oncopole, Toulouse; Thierry Facon, Service des Maladies du Sang, Hôpital Claude Huriez, Centre Hospitalier Regionale et Universitaire Lille, Lille; Philippe Moreau, University Hospital Hotel-Dieu, Nantes, France; Henk M. Lokhorst, VU University Medical Center, Amsterdam; Pieter Sonneveld, Erasmus MC, Rotterdam, the Netherlands; Hartmut Goldschmidt, University Hospital and National Center for Tumor Diseases Heidelberg, Heidelberg, Germany; Laura Rosinol, Hospital Clínic, Institut Clínic d'Investigacions Biomèdiques Ausgust Pi i Sunyer, Barcelona; Juan José Lahuerta, Hospital Universitario 12 de Octubre, Madrid; Jésus San Miguel, Clínica Universidad de Navarra, Centro de Investigaciones Médicas Aplicadas, IDISNA, Pamplona, Spain; Paul Richardson and Kenneth C. Anderson, Jerome Lipper Multiple Myeloma Center, Dana-Farber Cancer Institute, Boston, MA; Shaji Kumar and S. Vincent Rajkumar, Mayo Clinic, Rochester, MN; Sagar Lonial, Winship Cancer Institute, Emory University, Atlanta, GA; Robert Z. Orlowski, The University of Texas MD Anderson Comprehensive Cancer Center, Houston, TX; Gareth Morgan, Myeloma Institutes for Research Therapy, University of Arkansas for Medical Sciences, Little Rock, AR; Brian G.M. Durie, Cedars-Sinai Comprehensive Canc

Article

Publisher Item ID: JCO.2015.61.2267 Mid ID: NIHMS747695

DOI: 10.1200/JCO.2015.61.2267

PubMed ID: 26240224

SO-VID: 3eda7802-3fa7-481c-a7f4-1fd99a848e93

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Revised International Staging System for Multiple Myeloma: A Report From International Myeloma Working Group.

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Most cited references 15

A validated gene expression model of high-risk multiple myeloma is defined by deregulated expression of genes mapping to chromosome 1.

Bortezomib with thalidomide plus dexamethasone compared with thalidomide plus dexamethasone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma: a randomised phase 3 study.

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

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