Nonrandom recurrent chromosomal abnormalities are ubiquitous in multiple myeloma (MM) and include, among others, translocations of the immunoglobulin heavy chain locus (IgH). IgH translocations in MM ...result in the up-regulation of oncogenes, and include more commonly t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16)(q32;q23). Based on the recurrent nature of these translocations and their finding since the early stages of the plasma cell (PC) disorders, we hypothesized that they would confer biologic and clinical variability. In addition, deletions of 13q14 and 17p13 have also been associated with a shortened survival. We used cytoplasmic Ig—enhanced interphase fluorescent in situ hybridization to detect deletions (13q14 and 17p13.1), and translocations involving IgH in 351 patients treated with conventional chemotherapy entered into the Eastern Cooperative Oncology Group clinical trial E9486/9487. Translocations were frequently unbalanced with loss of one of the derivative chromosomes. The presence of t(4; 14)(p16;q32) (n = 42; 26 vs 45 months, P < .001), t(14;16)(q32;q23) (n = 15; 16 vs 41 months, P = .003), – 17p13 (n = 37; 23 vs 44 months, P = .005), and – 13q14 (n = 176; 35 vs 51 months, P = .028) were associated with shorter survival. A stratification of patients into 3 distinct categories allowed for prognostication: poor prognosis group (t(4;14)(p16;q32), t(14; 16)(q32;q23), and – 17p13), intermediate prognosis (– 13q14), and good prognosis group (all others), with median survivals of 24.7, 42.3, and 50.5 months, respectively (P < .001). This molecular cytogenetic classification identifies patients into poor, intermediate, and good risk categories. More importantly it provides further compelling evidence that MM is composed of subgroups of patients categorized according to their underlying genomic aberrations.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Lenalidomide is an immunomodulatory drug (IMiDs) with clinical efficacy in multiple myeloma (MM) and other late B-cell neoplasms. Although cereblon (CRBN) is an essential requirement for IMiD action, ...the complete molecular and biochemical mechanisms responsible for lenalidomide-mediated sensitivity or resistance remain unknown. Here, we report that IMiDs work primarily via inhibition of peroxidase-mediated intracellular H2O2 decomposition in MM cells. MM cells with lower H2O2-decomposition capacity were more vulnerable to lenalidomide-induced H2O2 accumulation and associated cytotoxicity. CRBN-dependent degradation of IKZF1 and IKZF3 was a consequence of H2O2-mediated oxidative stress. Lenalidomide increased intracellular H2O2 levels by inhibiting thioredoxin reductase (TrxR) in cells expressing CRBN, causing accumulation of immunoglobulin light-chain dimers, significantly increasing endoplasmic reticulum stress and inducing cytotoxicity by activation of BH3-only protein Bim in MM. Other direct inhibitors of TrxR and thioredoxin (Trx) caused similar cytotoxicity, but in a CRBN-independent fashion. Our findings could help identify patients most likely to benefit from IMiDs and suggest direct TrxR or Trx inhibitors for MM therapy.
•IMiDs inhibit TrxR-mediated intracellular decomposition of H2O2 and caused oxidative stress in MM cells.•MM cells with lower antioxidative capacity were more vulnerable to lenalidomide-induced H2O2 accumulation and its associated cytotoxicity.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The precise molecular mechanism of action and targets through which thalidomide and related immunomodulatory drugs (IMiDs) exert their antitumor effects remains unclear. We investigated the role of ...cereblon (CRBN), a primary teratogenic target of thalidomide, in the antimyeloma activity of IMiDs. CRBN depletion is initially cytotoxic to human myeloma cells, but surviving cells with stable CRBN depletion become highly resistant to both lenalidomide and pomalidomide, but not to the unrelated drugs bortezomib, dexamethasone, and melphalan. Acquired deletion of CRBN was found to be the primary genetic event differentiating isogenic MM1.S cell lines cultured to be sensitive or resistant to lenalidomide and pomalidomide. Gene expression changes induced by lenalidomide were dramatically suppressed in the presence of CRBN depletion, further demonstrating that CRBN is required for lenalidomide activity. Downstream targets of CRBN include interferon regulatory factor 4 (IRF4) previously reported to also be a target of lenalidomide. Patients exposed to, and putatively resistant to, lenalidomide had lower CRBN levels in paired samples before and after therapy. In summary, CRBN is an essential requirement for IMiD activity and a possible biomarker for the clinical assessment of antimyeloma efficacy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Primary central nervous system lymphoma (PCNSL) is an aggressive non-Hodgkin lymphoma confined to the central nervous system. Whether there is a PCNSL-specific genomic signature and, if so, how it ...differs from systemic diffuse large B-cell lymphoma (DLBCL) is uncertain.
We performed a comprehensive genomic study of tumor samples from 19 immunocompetent PCNSL patients. Testing comprised array-comparative genomic hybridization and whole exome sequencing.
Biallelic inactivation of TOX and PRKCD was recurrently found in PCNSL but not in systemic DLBCL, suggesting a specific role in PCNSL pathogenesis. In addition, we found a high prevalence of MYD88 mutations (79%) and CDKN2A biallelic loss (60%). Several genes recurrently affected in PCNSL were common with systemic DLBCL, including loss of TNFAIP3, PRDM1, GNA13, TMEM30A, TBL1XR1, B2M, CD58, activating mutations of CD79B, CARD11, and translocations IgH-BCL6. Overall, B-cell receptor/Toll-like receptor/NF-κB pathways were altered in >90% of PNCSL, highlighting its value for targeted therapeutic approaches. Furthermore, integrated analysis showed enrichment of pathways associated with immune response, proliferation, apoptosis, and lymphocyte differentiation.
In summary, genome-wide analysis uncovered novel recurrent alterations, including TOX and PRKCD, helping to differentiate PCNSL from systemic DLBCL and related lymphomas.
Fluorescence in situ hybridization (FISH) is more sensitive than conventional cytogenetics for recognizing chromosomal changes. Several FISH-detected abnormalities have been associated with inferior ...prognosis, including deletion of chromosomes 17 and 13 (Δ13) and t(4;14)(p16.3;q32). We analyzed the prognostic value of FISH testing in 238 patients who received high-dose therapy between January 1990 and September 2001. All patients had pretransplantation cytoplasmic immunoglobulin FISH done on cytospin slides from bone marrow aspirates for t(11;14), t(4;14), and -17(p13.1) (TP53). Time to progression and overall survival were significantly shorter for patients with t(4;14) and those with -17(p13.1) but were not affected by t(11;14). Overall survival was significantly shorter for patients with both t(4;14) and Δ13 abnormalities than for those with Δ13 alone (26.8 vs 18.8 months). In a multivariable analysis of the effect of Δ13 and t(4;14), the risk ratio for t(4;14) was greater than for Δ13 (2.6 vs 1.5). For high-dose therapy patients, -17(p13) and t(4;14) have clinical importance for estimating time to progression and overall survival. The presence of t(4;14) identifies a subset of patients whose time to progression is only 8.2 months. These patients receive minimal benefit from autologous stem cell transplantation and are candidates for novel therapeutic approaches. (Blood. 2005;106:2837-2840)
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Epidemiological data have suggested that African American (AA) persons are twice as likely to be diagnosed with multiple myeloma (MM) compared with European American (EA) persons. Here, we have ...analyzed a set of cytogenetic and genomic data derived from AA and EA MM patients. We have compared the frequency of IgH translocations in a series of data from 115 AA patients from 3 studies and 353 EA patients from the Eastern Cooperative Oncology Group (ECOG) studies E4A03 and E9487. We have also interrogated tumors from 45 AA and 196 EA MM patients for somatic copy number abnormalities associated with poor outcome. In addition, 35 AA and 178 EA patients were investigated for a transcriptional profile associated with high-risk disease. Overall, based on this cohort, genetic profiles were similar except for a significantly lower frequency of IgH translocations (40% vs 52%; P = .032) in AA patients. Frequency differences of somatic copy number aberrations were not significant after correction for multiple testing. There was also no significant difference in the frequency of high-risk disease based on gene expression profiling. Our study represents the first comprehensive comparisons of the frequency and distribution of molecular alterations in MM tumors between AA and EA patients. ECOG E4A03 is registered with ClinicalTrials.gov, number NCT00098475. ECOG E9487 is a companion validation set to the ECOG study E9486 and is registered with the National Institutes of Health, National Cancer Institute, Clinical Trials (PDQ), number EST-9486.
•In this study, African American MM patients have a significantly lower frequency of IgH translocations than European American patients.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The International Myeloma Working Group has proposed the Revised International Staging System (R-ISS) for risk stratification of multiple myeloma (MM) patients. There are a limited number of studies ...that have validated this risk model in the autologous stem cell transplant (ASCT) setting. In this retrospective study, we evaluated the applicability and value for predicting survival of the R-ISS model in 134 MM patients treated with new agents and ASCT at the Mayo Clinic in Arizona and the University Hospital of Salamanca in Spain. The patients were reclassified at diagnosis according to the R-ISS: 44 patients (33%) had stage I, 75 (56%) had stage II, and 15 (11%) had stage III. After a median follow-up of 60 months, R-ISS assessed at diagnosis was an independent predictor for overall survival (OS) after ASCT, with median OS not reached, 111 and 37 months for R-ISS I, II and III, respectively (
P
< 0.001). We also found that patients belonging to R-ISS II and having high-risk chromosomal abnormalities (CA) had a significant shorter median OS than those with R-ISS II without CA: 70 vs. 111 months, respectively. Therefore, this study lends further support for the R-ISS as a reliable prognostic tool for estimating survival in transplant myeloma patients and suggests the importance of high-risk CA in the R-ISS II group.
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EMUNI, FIS, FZAB, GEOZS, GIS, IJS, IMTLJ, KILJ, KISLJ, MFDPS, NLZOH, NUK, OBVAL, OILJ, PNG, SAZU, SBCE, SBJE, SBMB, SBNM, UKNU, UL, UM, UPUK, VKSCE, ZAGLJ
Detection of specific chromosomal abnormalities by FISH and metaphase cytogenetics allows risk stratification in multiple myeloma; however, gene expression profiling (GEP) based signatures may enable ...more specific risk categorization. We examined the utility of 2 GEP-based risk stratification systems among patients undergoing initial therapy with lenalidomide in the context of a phase 3 trial. Among 45 patients studied at baseline, 7 (16%) and 10 (22%), respectively, were high-risk using the GEP70 and GEP15 signatures. The median overall survival for the GEP70 high-risk group was 19 months versus not reached for the rest (hazard ratio = 14.1). Although the medians were not reached, the GEP15 also predicted a poor outcome among the high-risk patients. The C-statistic for the GEP70, GEP15, and FISH based risk stratification systems was 0.74, 0.7, and 0.7, respectively. Here we demonstrate the prognostic value for GEP risk stratification in a group of patients primarily treated with novel agents. This trial was registered at www.clinicaltrials.gov as #NCT00098475.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Multiple myeloma can be categorized into hyperdiploid or non-hyperdiploid myeloma based on the number of chromosomes found in the tumor clone. Among the non-hyperdiploid myelomas, the hypodiploid ...subtype has the most aggressive clinical phenotype, but the genetic differences between groups are not completely defined. In order to understand the genetic background of hypodiploid multiple myeloma better, we compared the genomic (array-based comparative genomic hybridization) and transcriptomic (gene expression profiling) background of 49 patients with hypodiploid myeloma with 50 other non-hyperdiploid and 125 hyperdiploid myeloma patients. There were significant chromosomal and gene expression differences between hyperdiploid patients and non-hyperdiploid and hypodiploid patients. Non-hyperdiploid and hypodiploid patients shared most of the chromosomal abnormalities; nevertheless a subset of these abnormalities, such as monosomies 13, 14 and 22, was markedly increased in hypodiploid patients. Furthermore, deletions of 1p, 12p, 16q and 17p, all associated with poor outcome or progression in multiple myeloma, were significantly enriched in hypodiploid patients. Molecular risk-stratification indices reinforce the worse prognosis associated with hypodiploid multiple myeloma compared with non-hyperdiploid multiple myeloma. Gene expression profiling clustered hypodiploid and non-hyperdiploid subgroups closer than hyperdiploid myeloma but also highlighted the up-regulation of CCND2, WHSC1/MMSET and FGFR3 in the hypodiploid subtype. In summary, hypodiploid multiple myeloma is genetically similar to non-hyperdiploid multiple myeloma but characterized by a higher prevalence of genetic alterations associated with poor outcome and disease progression. It is provocative to hypothesize that hypodiploid multiple myeloma is an advanced stage of non-hyperdiploid multiple myeloma.
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