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 downregulated 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. (Blood.

The mechanisms by which multiple myeloma (MM) cells migrate and home to the bone marrow are not well understood. In this study, we sought to determine the effect of the chemokine SDF-1 (CXCL12) and its receptor CXCR4 on the migration and homing of MM cells. We demonstrated that CXCR4 is differentially expressed at high levels in the peripheral blood and is down-regulated in the bone marrow in response to high levels of SDF-1. SDF-1 induced motility, internalization, and cytoskeletal rearrangement in MM cells evidenced by confocal microscopy. The specific CXCR4 inhibitor AMD3100 and the anti-CXCR4 antibody MAB171 inhibited the migration of MM cells in vitro. CXCR4 knockdown experiments demonstrated that SDF-1-dependent migration was regulated by the PI3K and ERK/ MAPK pathways but not by p38 MAPK. In addition, we demonstrated that AMD3100 inhibited the homing of MM cells to the bone marrow niches using in vivo flow cytometry, in vivo confocal microscopy, and whole body bioluminescence imaging. This study, therefore, demonstrates that SDF-1/CXCR4 is a critical regulator of MM homing and that it provides the framework for inhibitors of this pathway to be IntroductionMultiple myeloma (MM) is the second most prevalent hematologic malignancy; it remains incurable, and the median survival time is 3 to 5 years. 1,2 It is characterized by the presence of multiple lytic lesions and widespread involvement of the bone marrow at diagnosis, implying a continuous (re)circulation of MM cells in the peripheral blood and (re)entrance into the bone marrow. 1 Studies have demonstrated the presence of circulating malignant plasma cells in more than 70% of patients diagnosed with MM. 3,4 Migration of cells through the blood to the bone marrow niches requires active navigation, a process termed homing.Chemokines are small chemoattractant cytokines that bind to specific G-protein-coupled 7-span transmembrane receptors present on the plasma membranes of target cells. [5][6][7] Chemokines play a central role in lymphocyte trafficking and homing. [8][9][10][11] One of the most extensively studied chemokines in migration is SDF-1 and its receptor, CXCR4. 12,13 SDF-1 is primarily produced by stromal cells. CXCR4 is expressed on the surfaces of normal cells such as hematopoietic stem cells and T and B lymphocytes and on malignant cells such as breast cancer cells and lymphoid malignancies. 6,11,[14][15][16] To date, the role of CXCR4 in homing of MM cells to the bone marrow has not been fully elucidated. Inhibitors of CXCR4, such as AMD3100 (AnorMED, Toronto, ON, Canada), have been shown to induce the mobilization of stem cells. 17,18 AMD3100 (AnorMED) is a bicyclam molecule that reversibly blocks the binding of CXCR4 with SDF-1. 19 Because SDF-1/CXCR4-dependent signaling differs between cell types and between malignant and normal counterparts, 20 it is critical to investigate the unique role of CXCR4/SDF-1 in MM. In this study, we sought to determine the effect of CXCR4 and its specific inhibitor, AMD3100, on the migration and in vivo ...

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Summary 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 × 106 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.