Dispenzieri, Angela

Abstract Background: Clonal cytogenetic aberrations define multiple myeloma (MM) into unique subsets of the disease each one with unique clinical and biologic features, associations with laboratory and pathologic markers and presumed differential influence on disease progression. While it is widely accepted that translocations represent primordial events in the pathogenesis of MM, it is controversial whether all translocations can be associated with disease stability and non-malignant behavior (i.e. in MGUS/SMM). We have found the translocations in cases of MGUS using dual fusion, cIg enhanced, interphase FISH, while others have found this translocation at lower prevalence using single fusion interphase FISH or the RT-PCR for IgH/MMSET. We thus sought to clarify by expanding the study of the t(4;14) among patients with MGUS and SMM. Materials and methods: We studied 210 patients who had the diagnosis of MGUS and SMM and entered into the Mayo Clinic Dysproteinemia database. Patients were excluded if they had active MM, extramedullary disease or plasmacytoma. Patients with isolated lytic bone lesions could be included if they had no overt evidence of progression. All studied patients had provided written informed consent for the collection of a research bone marrow aliquot that was collected at the time of routine bone marrow procurement. All patients had cytospin slides that were studied for a t(4;14) using cIg-FISH as previously described by us and using a double fusion FISH strategy. The importance of this is that the strategy will detect unbalanced t(4;14) with loss of der(14). Results: Twenty patients (9.5%) had evidence of the chromosome translocation. Detailed demographic data was available in 19; 14 were women (74%), 13 of 19 (68%) had SMM and there was no bias for heavy chain IgA (26%). Patients with t(4;14) were slightly younger than those without the abnormality (52 vs. 61 years), had similar hemoglobin concentrations, had slightly higher concentration of the serum M spike (2.0 vs 1.75 g/dl) and had overall slightly higher bone marrow plasmacytosis (median 23% vs 10%). Patients were followed since diagnosis for a median of 33 months (range 2–162 months). Three patients progressed to active MM at 12, 12 and 26 months after original diagnosis (all three originally having indolent/SMM). Conclusion: The t(4;14) can occur in patients with MGUS and SMM and without evidence of progression to MM. The prevalence is similar to that observed in MM, albeit slightly lower (9.5% versus 14%). In most “benign” plasma cell neoplasms the translocation is associated with greater plasmacytosis and thus enriched for in the smoldering MM category. It is also likely that the t(4;14) confers a higher risk of progression to MM given; a) its enrichment in SMM, b) the slightly higher prevalence of the translocation in MM as opposed to MGUS/SMM, and c) the well documented aggressive clinical course of MM with t(4;14).

Abstract Activation of NFkB has been noted in late B-cell malignancies, but no genetic basis for this activation has been shown except for rare mutations of the NFkB pathway in lymphoma and none have been described in MM. Bortezomib, highly tumoricidal in a subset of MM patients, inhibits NFkB suggesting it’s role as a therapeutic target. Here we show for the first time the critical importance of mutations that dysregulate this potential survival pathway in human myeloma cell lines (HMCL) and new diagnosis MM patients. We performed high-density oligonucleotide array CGH (Agilent 44k) on CD138+ selected MM cells from 68 patients and 42 unique HMCL. Initially we focused on small loci, bi-allelically deleted, as markers for inactivation of potential tumor suppressor genes. We next developed FISH probes for the identified loci to confirm the bi-allelic deletions seen by aCGH. We next sequenced all samples with monoallelic deletions, and additional unselected patients, and identified additional inactivating mutations. Multiple novel tumor suppressor genes (TSG) were identified and validated, whose loss of function (both in patients and HMCL) leads to activation of the non-canonical NFkB pathway including: TRAF2 (9q34), TRAF3 (14q32), BIRC2/BIRC3 (11q22) and CYLD (16q12). Functional studies showed that HMCL with deletion or mutations in these genes have markedly increased NFkB2 p52/p100 ratios relative to other HMCL (and for BIRC2/BIRC3 relative to an isogenic line that retains one copy of BIRC2/BIRC3), indicating genetic activation of the non-canonical NFkB pathway. Reintroduction of deleted TSG into HMCL inhibited cell growth and resulted in cell death (see data on abstract by J. Keats et al). We next focused our analysis (of combined aCGH and GEP data) on positive regulators of this pathway. Rare IgH translocations of NIK have recently been identified in MM. By aCGH we identified amplification and rearrangements of NIK. We identified dysregulated expression of TNF family receptors that activate the non-canonical pathway: CD40 (translocation), TACI (amplification) and LTBR. All of the HMCL with these mutations also showed increased NFkB2 p52/p100 ratios, consistent with activation of the non-canonical NFkB. These mutations correlate with a gene expression profile of NFkB activation that is detected in one half of patients. In summary, we have determined for the first time the genetic basis for constitutive NFkB activation - present in 19/42 HMCL, and we estimate in at least one quarter of newly diagnosed patients (approximately one half of those with evidence of NFkB activation by GEP). We propose a mechanism in which positive (TACI, CD40, LTBR) and negative regulators (TRAF2, TRAF3, BIRC2/BIRC3, CYLD) of the pathway converge on NIK to mediate the processing of NFKB2 p100 to p52. The preponderance of genetic evidence suggests that drugs that target the non-canonical NFkB pathway, will be most effective in treating the 50% of MM patients with NFkB activation.

Abstract H-MM affects about 40–50% of patients, and a similar proportion of MGUS/SMM. The genetic evolution of the disease and the clinical implications of the co-existence of 13q- or t(14q32) are unknown. We conducted a global survey of genetic abnormalities in H-MM in order to describe genetic evolution pathways. H-MM cases from the Mitelman cancer genetic database were combined with cases from the Mayo Clinic MM genetic database. All abnormalities (regional/whole chromosome gains/losses, breakpoints and translocations) were plotted against a 344-chromosome band profile created in a matrix format, and the number of genetic abnormalities per tumor (NAPT) logged. The abnormalities present in more than 5% of tumors were considered recurrent and each karyotype was scored for the presence or absence of each of the recurrent abnormalities. To investigate the temporal pattern of acquisition of genetic abnormalities, all tumors with a given abnormality were selected and the distributions of NAPT plotted. The modes of these distributions were used as a value of ‘lateness’, referred to as time of occurrence (TO). The impact of co-existence of 13q- and t(14q32) on progression free survival (PFS) and overall survival (OS) in H-MM was determined for MM patients entered into an Eastern Cooperative Oncology Group chemotherapy trial. Four hundred and sixty-nine H-MM patients were included in the karyotypic analysis. The median chromosome number was 53 (range 48–74) and the median NAPT was 10 (range 1–25). The distribution of NAPT revealed a normal distribution, suggesting an obligatory acquisition of a given number of genetic abnormalities. The most common abnormalities were trisomies of chromosomes 3,5,7,9,11,15,19 and 21 affecting a third or more of the patients. Deletions and abnormalities of even-numbered chromosomes occur in 20% or less of patients. None of the more than 300 specific translocations detected were recurrent. However, 5 translocation breakpoints were recurrent including 14q32, 8q24 and 11q13. TO analysis suggest that for H-MM, the trisomies are early genetic events, translocations occur midway and deletions tend to be later events. Amongst the trisomies, correlation analysis does not suggest a particular order of acquisition. Clustering analysis using principal component analysis suggests that in H-MM, IgH translocations are secondary events associated with disease evolution rather than defining unique biological entities. Consistent with this, survival of H-MM patients is not affected by 13q- status but is negatively impacted by the presence of t(14q32) especially those with unknown partners (p<0.05). The data presented suggest that H-MM fit a proposed aneuploid model of cancer due to auto-catalytic chromosome reassortment (Duesberg et al Cell Cycle2003:2:202–210). The presence of tumor specific trisomies and the apparent similar phenotype induced by various combinations of trisomies are consistent with this model.

Abstract Background: Abnormally increased tumor associated neovasculature plays an important role in tumor progression in solid tumors and hematological malignancies. In multiple myeloma (MM) bone marrow angiogenesis, measured in terms of microvessel density (MVD), has prognostic value, and appear to increase with disease progression from monoclonal gammopathy of undetermined significance to relapsed MM. We have shown that MVD has prognostic value in patients with newly diagnosed MM including patients undergoing upfront high dose therapy and stem cell transplantation, but comparison with other known prognostic factors has been limited by sample size. It is also not known whether the MVD adds prognostic value once the recently described International Staging System (ISS) is applied. The goal of this study was to determine the prognostic effect of bone marrow MVD in newly diagnosed MM relative to the ISS and other known prognostic factors. Methods: We studied 400 patients with newly diagnosed MM seen at the Mayo Clinic between March of 1988 and December 2001. Sections from bone marrow biopsy blocks from the time of initial diagnosis were studied by immunohistochemistry using antibodies against CD34 antigen to high light the endothelial cells. Under low power (100X); three areas with maximum number of microvessels (hotspots) were identified. Each of these areas was further studied at 400X magnification and the number of microvessels per high power field counted. The average of the three readings was taken as the MVD for the sample. In addition, the samples were graded as low, intermediate or high by using a visual estimate as previously described. Additional clinical data was extracted from medical records. Some of the patients have been included in previous studies related to angiogenesis. Results: A total of 400 patients in whom a bone marrow biopsy from within 30 days of diagnosis was available were studied. The pts were followed for a median of 37 months (Range: 1 month to 16.5 years) and 318 pts (80%) had died at the time of this analysis. The median MVD for the entire group was 14.7 (Range 0–168). The median overall survival for the three groups according to the MVD grade was lower for the high grade group (31.9 months) compared to the intermediate grade group (37.2 months) and the low grade group (not reached); P <0.029, log rank test. We examined this group of patients for other factors prognostic for overall survival. Factors significant on univariate analysis included ISS stage, platelet count (<150 vs. >= 150 X 106/L), and plasma cell labeling index (<1 vs >=1). In a multivariate analysis using these variables and MVD as a continuous variable, high MVD and the ISS staging system were significantly associated with poorer survival (Table). Conclusion: In this large group of pts with newly diagnosed MM, we confirm the prognostic value of increased bone marrow angiogenesis. We examined the MVD as a continuous variable in the multivariate analysis for a closer evaluation of this measure in this comparison. More importantly, the prognostic value appears to be independent of the ISS and other major prognostic factors. The resultsof this study reinforces the biological relevance of this finding in MM. HR 95% CI P value MVD 1.006 (1.001, 1.011) 0.0279 ISS Stage I 0.37 (0.25, 0.56) <0.001 ISS Stage II 0.58 (0.41, 0.83) 0.0025

Abstract We previously have reported that autograft absolute lymphocyte count (A-ALC) is a possible prognostic factor for survival after autologous peripheral blood stem cell transplant (ASCT) for myeloma (MM). Factors affecting A-ALC in MM are unknown. We hypothesize that method of stem cell mobilization, hematopoietic growth factor (HGF) vs. HGF+Cytoxan chemotherapy (C+HGF), directly affects A-ALC collection. 191 consecutive MM patients between 1994 and 2004 were analyzed retrospectively. Patients generally were mobilized with C+HGF prior to 2003. Thereafter, C+HGF was reserved largely for those with ≥4% circulating peripheral blood plasma cells (PC), a negative prognostic indicator. No patients were transplanted in disease relapse or refractory disease. Patients also were matched for age, sex, β2-microglobulin, conventional cytogenetics, LDH, c-reactive protein, number of prior therapies, plasma cell labeling index (PCLI), pre-mobilization ALC, and % bone marrow (BM) PC. The groups HGF (n=80) and C+HGF (n=111) differed with respect to the conditioning regimen (p < 0.0001), and presence of (≥4%) circulating peripheral blood PC (p<0.005). The primary end-point of the study was to assess the correlation between HGF vs C+HGF, and A-ALC. The secondary endpoint was to determine if HGF vs C+HGF affected survival post-ASCT. Patients mobilized with HGF had a higher A-ALC compared to those mobilized with C+HGF [0.764 x 109 lymphocytes/kg (range: 0.146–1.803) vs. 0.212 (range: 0.016–1.26), p<0.0001]. No association was identified between A-ALC and conditioning regimens (p = 0.19) and PC (p = 0.31). Median overall survival (OS) and progression-free survival (PFS) were longer in those mobilized with HGF vs. C+HGF (not reached vs. 48 months, p<0.0150; not reached vs. 21 months, p<0.007, respectively). Multivariate analysis demonstrated that age ≥50 vs age ≤50 (p<0.05) and A-ALC ≥0.5 vs <0.5x109 lymphocytes/kg (p<0.0397) were independent predictors of OS. Factors influencing PFS in the multivariate analysis included circulating PC ≥4% vs <4% (p<0.0157), PCLI ≥ 1% vs PCLI ≤ 1% (p<0.0107), and A-ALC ≥0.5 vs <0.5x109 lymphocytes/kg (p<0.0042). On multivariate analysis, the method of stem cell mobilization and the conditioning regimen did not have a statistically significant effect on either OS or PFS. We hypothesize that the differences in PFS and OS seen between the HGF vs C+HGF mobilization groups are mediated through the A-ALC. These data suggest that mobilization regimens should not only collect CD34+ stem cells, but also be optimized to collect an A-ALC target which may impact on PFS and OS post-ASCT.

Abstract Background: The presence of circulating myeloma cells (CMC) detected by flow cytometry at the time of diagnosis of multiple myeloma is associated with a shortened response to therapy and reduced overall survival (OS). We hypothesized that the presence of CMC at the time of stem cell collection prior to high dose therapy (HDT) and autologous stem cell transplantation (ASCT) would identifies a cohort of patients with a high risk of rapid progression. Methods: The Mayo Clinic myeloma transplant database was queried for patients who were mobilized using cyclophosphamide and hematopoietic growth factors. CMC was determined using flow cytometry by gating on a population of CD38 bright and CD45 negative cells. The impact of CMC on OS and time to progression (TTP) and its role in the context of established prognostic parameters was evaluated. Results: Of 246 patients with MM undergoing ASCT, 95 had CMC. Patients with CMC had significantly higher plasma cell labeling index, adverse cytogenetics, B2-M and resistant disease. Complete response (CR) rates post transplant were 32% and 36% for patients with and without CMC (p=0.5034). OS was 33.2 and 58.6 months (p=0.0052) while TTP was 14.1 and 22 months respectively (p=0.0005). Figure Figure On multivariate analysis, CMC remained an independent prognostic factor in a model that included cytogenetics and disease status at time of transplant (p=0.0314). A prognostic system based on the presence or absence of CMC and karyotype abnormalities was developed. Patients with neither, one or both parameters had a median, OS of 55, 48 and 21.5 months respectively (p<0.0001) while TTP was 22, 15.4 and 6.5 months for the same groups (p<0.0001). Conclusion: The presence of CMC at the time of HDT and ASCT is an independent prognostic factor. The combination of CMC and cytogenetics provides a simple yet powerful scoring system that stratifies patients and guides their management.

Abstract Background: Solitary plasmacytoma of bone (SBP) is a localized collection of monoclonal plasma cells that is potentially curable with local radiation therapy but associated with a high risk of progression to multiple myeloma. We hypothesized that an abnormal immunoglobulin free light (FLC) ratio at diagnosis may be a prognostic indicator of transformation risk. Methods: We identified a cohort of 133 patients with SBP for whom stored serum taken at the time of diagnosis was available. The diagnosis was ascertained and serum FLC determined in 126 patients. Results: From this cohort, 48 patients have progressed to myeloma and the median time to progression among those who progressed was 1.9 years. On univariate analysis, age (p<0.001), gender (p=0.035), abnormal FLC ratio at diagnosis (p=0.009) and persistence of serum or urine M-protein after therapy (p=0.0070 were all associated with a shorter overall survival (OS) and time to progression to multiple myeloma. Progression by Normal FLC(0.26–1.65) Progression by Normal FLC(0.26–1.65) On multivariate analysis, an abnormal FLC ratio retained its independence in a model that includes age at diagnosis but lost its significance when combined with persistence of the serum or urine M-protein. However, serum or urine M-proteins are not detectable in a significant number of patients with SBP and therefore not informative. Conclusion: The FLC ratio at the time of diagnosis of SBP is a powerful predictor of risk and a useful aid to management of patients with this condition.

Abstract Introduction: We previously reported that serum cardiac biomarkers are among the most powerful predictors of overall survival. This observation was based on outcomes of more than 300 patients with primary systemic amyloidosis (AL) receiving either low dose chemotherapy or high dose chemotherapy with peripheral blood stem cell transplant (PBSCT). Not all institutions use the N-terminal pro-brain natriuretic peptide (NTproBNP) assay, but rather the B-type natriuretic peptide (BNP) assay. We therefore determined the relative utility of BNP in patients with AL undergoing PBSCT and up-dated our results using our NTproBNP-troponin T staging system. Methods: Between 4/10/96 and 2/24/05, 164 patients with AL undergoing PBSCT had measurements of serum cardiac biomarkers. All BNP measurements were done on fresh serum (Biosite Inc., San Diego). The NTproBNP (Roche Diagnostics, Indianapolis, IN) and troponin T (TnT) (Roche Diagnostics, Indianapolis, IN) measurements were done on either stored serum or on fresh samples as previously reported. Follow-up for patients was through March 2005. Results: Between 5/1/03 and 2/15/05, 72 patients had BNP measurements pre-transplant. The median value was 167 pg/ml (range 5 to 7739). Forty-two of these patients also had an NTproBNP measured. There was good agreement between the two tests in the 42 patients that had both measurements (rho 0.823, p<0.0001). To further test the relationship between the two tests, we evaluated the correlation between BNP and NTproBNP using 204 simultaneous measurements from 106 patients (rho=0.89, p<0.0001). Next, we tested the prognostic utility of BNP. Using a cut-off point of 120 pg/L (the upper limit of normal for women over the age of 70 and the 50th percentile of all measurements in our data set), we found that BNP was prognostic for survival post-transplant. It was independent of TnT values, and patients could be divided into 3 risk categories using these two measurements (low risk if both values were low, high-risk if both were high, and intermediate if either was high). This system was highly predictive of overall survival (Figure A). We next compared the BNP-TnT staging system to our previously reported NTproBNP-TnT staging system in the 42 patients that had all 3 values pre-transplant. The correlation between the two staging systems was excellent (rho=0.91, p<0.0001). Follow-up for the 100 patients who had been reported previously is now 26.9 months. As shown in Figure B, the NTproBNP-TnT system predicts for overall survival post transplant. Conclusions: Serum levels of cardiac biomarkers are invaluable prognostic markers in patients with AL. Preliminary data would suggest that a BNP-TnT system is as useful as the NTproBNP-TnT system. Risk thresholds: BNP <120 pg/ml; TnT <0.035 ng/ml; NT-proBNP < 332 pg/ml BNP-TnT statisfaction: low risk, both low; high risk, both high; intermediate, either high. NT-proBNP-TnT satisfaction: low risk, both low; high risk, both high; intermediate, either high. Risk thresholds: BNP <120 pg/ml; TnT <0.035 ng/ml; NT-proBNP < 332 pg/ml BNP-TnT statisfaction: low risk, both low; high risk, both high; intermediate, either high. NT-proBNP-TnT satisfaction: low risk, both low; high risk, both high; intermediate, either high.

Abstract Title: Primary Therapy with Bortezomib—The Role of Induction, Maintenance, and Re-Induction in Patients with High Risk Myeloma. Update of Results from E2A02. Angela Dispenzieri, MD1, Susanna Jacobus, PhD2, David Vesole, MD3 and Philip R. Greipp, MD1. 1Hematology, Mayo Clinic, Rochester, MN, United States, 55905 and 2Biostatistics, Eastern Cooperative Oncology Group, Boston, MA, United States, 02115. 3Saint Vincent’s Hospital, New York, NY 10010 Background: Single agent bortezomib as upfront therapy in patients with multiple myeloma (MM) results in response rates of 38% and the drug has been touted to be especially effective in patients with high risk disease. We sought to explore response rate, the role of maintenance and reinduction in a cohort of patients with high-risk MM. Methods: Patients with newly diagnosed high-risk myeloma (beta-2 microglobulin [B2M] >= 5.5., plasma cell labeling index [PCLI] >= 1, or deletion 13q) and adequate organ and functional status were eligible. Patients were treated with bortezomib 1.3 mg/m2 day 1, 4, 8, and 11 every 21 days for 8 cycles as induction. After induction, patients were scheduled to receive bortezomib 1.3 mg/m2 every other week indefinitely. Elective peripheral stem cell mobilization (growth factor alone) was allowed after 4 cycles of bortezomib. Patients relapsing on maintenance schedule had full induction schedule resumed. Responses as defined by the EBMT criteria were determined after each cycle and needed to be confirmed after at least 6 weeks. Results: Between March 15, 2004 and March 10, 2005, 44 patients enrolled on study. Among the 42 eligible treated patients, median age was 63; 51% were male. All patients had high risk disease: deletion 13q (6/41); PCLI >=1% (17/33); t(4:14) (4/27) and B2M >= 5.5 (34/43). Nineteen patients completed induction, i.e. 8 cycles of bortezomib. The most common causes for discontinuing therapy were: progressive disease (n=17), AE (n=7), alternate therapy (n=4), death (n=1), and other (n=11). Forty-eight percent of patients achieved a partial response (PR) or better with induction (0 complete responses, 2 very good PR, 17 PR, 3 minimal responses, 5 no response, 9 progressive disease, and 6 inevaluable or missing). Response rates across risk groups did not differ with a PR or better for patients with deletion 13q (2/6); PCLI >=1% (8/17); t(4:14) (2/4) and B2M >= 5.5 (15/33). One patient’s response was upgraded to CR during maintenance. The rate of painful peripheral neuropathy during all courses of therapy was: grade 1, n=25; grade 2, n=2; and grade 3, n=2. With a median follow-up of 41.6 months (95%CI 36.6–43), 43% of patients have died. Median overall survival (OS) has not been reached (Figure), and the 1- and 2-year OS rates were 88.1% (95%CI 73.7–94.9%) and 76.2% (95%CI 60.3–86.4%) respectively. The median progression free survival (PFS) was 16.3 months (95%CI 6.2–26.6) and the 1- and 2-PFS were 76.7% (95%CI 58.8–87.6%) and 38.3% (95%CI 20.6–55.9%), respectively. Fifteen patients went on to maintenance. The distribution by risk group for patients entering maintenance was not different across groups: deletion 13q, 3/6; high PCLI, 6/17; high B2M, 11/33; t(4;14), 1/4; and p53, 0/2. For those entering maintenance, the median PFS was 19.8 months (Figure), and the 1 year PFS rate was 75% (95%CI 40.8–91.2%). Of the 7 patients progressing on maintenance who received reinduction with bortezomib, no patient responded. Only 2 remain on therapy. Figure Figure Conclusions: In high risk patients, upfront bortezomib results in response rates comparable to those reported for unselected cohorts of newly diagnosed myeloma patients. For patients responding to therapy, maintenance therapy is feasible. Reinduction was unsuccessful in high risk patients failing maintenance.

Abstract Background: The free light chain (FLC) assay allows a nephelometric measurement of this free kappa and lambda light chains that circulate as monomers or dimers, not bound to the immunoglobulin heavy chain. Estimation of the free light chain levels and their ratio has utility in screening, prognostication and treatment response assessment in multiple myeloma, and is particularly useful in light chain myeloma. Previous studies have suggested that absence of a functional rearrangement on at least one of the IgH allele is the basis of light chain myeloma. Translocations involving the immunoglobulin heavy chain (IgH) locus on chromosome 14 can be detected using FISH in over half of the patients with myeloma. We hypothesized that presence of an IgH translocation may be associated with compromised production of heavy chains and leads to unbalanced, excess production of clonal light chain. Methods: From February 1988 to May 1992, 653 patients with previously untreated multiple myeloma were enrolled on the phase III clinical trial E9486. Serum free light chains were run on stored sera obtained at baseline in 495 patients as part of a previous study. Among these patients, 314 patients were previously studied using FISH for presence or absence of IgH translocations, p53 abnormalities and deletion 13 and were included in the current analysis. Results: The median difference between the involved and uninvolved FLC (FLCdiff) was higher among the group of patients with any IgH translocation abnormality compared to those with none (Figure 1). This was particularly evident among the patients with a t(14;16) who had the highest FLCdiff. In a multivariate analysis, we examined if the prognostic value seen with FLCdiff was independent of the presence of IgH translocations t(4:14) and t(14;16), which are associated with a worse outcome. The presence of t(4;14) or t(14;16) was associated with FLCdiff groups using a cutoff point of 185, with 13% of those with FLCd ≤185 and 27% of those with FLCd > 185 having the translocations (P= 0.008). At the cutoff value of 185, the prognostic value of the FLC-diff on progression free and overall survival appears to be independent of these high risk IgH translocations (P-value=0.03 and 0.003, respectively for PFS and OS) We then examined the prognostic value of the FLC-diff in the group of patients without these two high risk abnormalities and were able to confirm that they remained prognostic for PFS (P=0.009) and OS (p=0.005). However, among the group of patients with either of the two high risk IgH abnormalities, FLCdiff estimate added little to assessment of their outcome (P=0.97 and 0.20, respectively for PFS and OS). Conclusion: Elevated free light chain levels are associated with presence of IgH translocations and these patients are more likely to harbor the high risk genetic abnormalities. Routine FISH testing for patients with newly diagnosed myeloma will allow us to confirm these and allow better risk stratification of the patients. Additional work needs to be done to help us better understand the molecular basis for unbalanced light chain excretion by myeloma cells and the current finding of the association with IgH translocation abnormalities should form the basis for this work. Figure 1. Distribution of FLC ratio (inv vs. uninv) and FLC difference (inv − uninv) among patients. Solid squares represent patients with t(4;14) or t(14;16) or t(11;14) or other 14q32 translocation; open circles represent patients without t(4;14), t(14;16), t(11;14) and any other 14q32 translocations. The horizontal dashed lines refer to FLC ratio original values of 100 and 1000, and vertical dashed lines refer to FLC difference original values of 10 and 100. Solid line indicates significant association (P<=0.05) between the dichotomized FLC groups and translocation status. Figure 1. Distribution of FLC ratio (inv vs. uninv) and FLC difference (inv − uninv) among patients. Solid squares represent patients with t(4;14) or t(14;16) or t(11;14) or other 14q32 translocation; open circles represent patients without t(4;14), t(14;16), t(11;14) and any other 14q32 translocations. The horizontal dashed lines refer to FLC ratio original values of 100 and 1000, and vertical dashed lines refer to FLC difference original values of 10 and 100. Solid line indicates significant association (P<=0.05) between the dichotomized FLC groups and translocation status.