ALBERT

Description: Introduction: Gene expression profiling (GEP)-defined high-risk de novo multiple myeloma (HI-MM) has a dismal prognosis with median PFS and OS stagnating at 2 and 3 years, respectively, despite the incorporation of novel agents into our Total Therapy (TT) trials. Having seen encouraging results in relapsed-refractory MM with an extended 16-day metronomic therapy (Papanikolaou, Haematologica 2014), we tested this approach in a small cohort of untreated patients with HI-MM. METRO emphasizes targeting neo-angiogenesis and other components of the bone marrow micro-environment while avoiding cytokine surges with recovering hematopoiesis following myelotoxic therapy. Patients and Methods: 10 previously untreated patients with HI-MM, who were either ineligible or unwilling for our Total Therapy protocols received a single cycle of METRO. Therapy comprised of SC bortezomib 1.0mg/m2 (0.8mg/m2 in case of grade 〉2 peripheral neuropathy) on days 1, 4, 7, 10, 13, 16, 19, 22, 25 and 28 schedule, PO dexamethasone 12mg (8mg in case of prior intolerance of higher dose or diabetes mellitus) on days 1 to 4, 7 to 10, 13 to 16, 19 to 22 and 25 to 28, PO Thalidomide 100mg (50mg in case of peripheral neuropathy grade 〉2) and continuous IV infusions of doxorubicin and cisplatin at 1.0mg/m2 daily for 28 days. Cisplatin was dose-reduced for Cr 〉2mg/dL and omitted for Cr 〉3mg/dL. Arsenic tri-oxide was given at a fixed dose of 0.01mg/kg on the days after bortezomib. Laboratory monitoring for response and toxicities were done on a Monday-Wednesday-Friday schedule. Maximal responses, based on current IMWG definitions, were measured within 30 days of completion of cycle 1, and at least monthly thereafter. KM curves were current as of 07/31/14. The Institutional Review Board granted permission for our retrospective data review, the results of which are presented here. Results: Patient characteristics included age 〉=65 in 8, 5 male, 5 female with ISS III in 5 patients. Metaphase cytogenetic abnormalities (CA) were detected in 7 patients. GEP70 based high risk MM was present in all 10 patients, and GEP proliferation (PR) subgroup was dominant in 8 out of 10 patients. All 10 patients achieved at least PR, including 3 qualifying for VGPR and 4 for CR. Bone Marrow responses were equally encouraging in that 8 of 10 patients qualified for complete morphologic negativity including 4 with no minimal residual disease (MRD) by 8-color flow cytometry. Of 8 patients with FDG-avid PET-CT focal lesions, 6 achieved PET-CT CR; all patients showed decreases in SUV-max and SUV-diff (background SUV). Number and/or apparent diffusion coefficient (ADC) mapping of focal lesions and background marrow on diffusion-weighted MRI improved in all 7 evaluable patients. GEP70 risk morphed from high risk to low risk in 3/4 evaluable patients. Pre and post serologic, urinary and radiologic responses are shown in Figure 1. The median follow-up time for the population was 3.2 months (98 days). All 10 patients are alive from 1 to 7 months, and 1 suffered progression (Figure 2). Overall tolerance was good. Non-hematologic grade 3/4 SEs included fatigue, electrolyte abnormalities (20%), dyspnea, hypotension, LE edema and transaminitis (10%). Conclusion: Primary 28-day metronomic therapy is highly effective and well-tolerated in patients with previously untreated HI-MM. Further prospective studies with longer follow-up are currently being devised in an attempt to improve outcomes in this population. Figure 1: Individual responses Figure 1:. Individual responses Figure 2 Figure 2. Figure 3 Figure 3. Disclosures van Rhee: Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees; Millenium: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees. Zangari:Norvartis: Membership on an entity's Board of Directors or advisory committees; Onyx: Research Funding; Millennium: Research Funding.

Description: Abstract 1850 The use of the word cure when discussing MM therapy remains taboo. Albeit most investigators applaud the enormous improvement in clinical outcomes ushered in initially by autotransplant-supported high-dose melphalan. Additionally, the introduction of novel agents inaugurated with thalidomide and followed by bortezomib and lenalidomide have continued a course towards a cure status. Overall survival (OS) and progression-free survival (PFS) are particularly poor with GEP-defined high-risk MM. Here we have examined whether, due to much earlier data maturation in high-risk MM, a fraction of long-term progression-free survivors can be discerned. This fraction of patients not susceptible to progression is consistent with the concept of cure. Here, we use a logistic/Weibull mixture model to estimate the proportion of long-term progression-free survivors. TT2 and TT3 results have been reported previously. We estimated 4-yr rates of OS, PFS and continuous CR (CCR) in TT2's control arm (TT2-), TT2's thalidomide arm (TT2+), TT3A (with VTD maintenance) and TT3B (with VRD maintenance) (Table 1). Progressive improvement in all 3 endpoints were noted with transition from TT2- to TT2+ and further to TT3A/B among the “any high risk feature” cohort and especially for GEP-70-defined high risk. Next we applied the logistic/Weilbull mixture model revealing progressive increments in predicted fractions of long-term PFS (Table 2). These data are depicted graphically with p-values in Figure 1. We also examined relative survival rates for patients who remain PFS after 3yr in the context of age and gender matched survival for the general population (Figure 2). These observations are compatible with a finite cure rate in high-risk myeloma. Data will be presented on gene probes of plasma cells and whole bone marrow biopsies, which may define at a baseline status, candidates with high cure potential. Table 1. Estimated OS, PFS and CCR at 4-years from Enrollment by High Risk Features A. TT2 Risk Factor TT2 - Thal TT2 + Thal N OS PFS CCR N OS PFS CCR Any High Risk Feature 143 53.85% 34.97% 15.38% 134 59.70% 49.25% 35.82% B2M 〉 5.5 mg/L 63 52.38% 31.75% 22.22% 59 55.93% 45.76% 30.51% Any CA 104 50.96% 32.69% 10.58% 93 59.14% 47.31% 32.26% CA13 42 40.48% 26.19% 14.29% 58 50.00% 39.66% 24.14% CA13/Hypodiploid 59 45.76% 32.20% 15.25% 64 51.56% 40.63% 26.56% GEP-70 High Risk 20 25.00% 10.00% 10.00% 26 34.62% 23.08% 19.23% LDH 〉 300 U/L 15 53.33% 26.67% 20.00% 13 38.46% 38.46% 38.46% B. TT3 Risk Factor TT3a TT3b N OS PFS CCR N OS PFS CCR Any High Risk Feature 139 64.75% 58.27% 43.88% 97 63.27% 57.12% 42.27% B2M 〉 5.5 mg/L 65 53.85% 46.15% 29.23% 50 58.82% 52.94% 30.00% Any CA 100 62.00% 56.00% 47.00% 69 62.86% 58.54% 46.38% CA13 53 60.38% 50.94% 43.40% 38 60.53% 55.26% 47.37% CA13/Hypodiploid 65 61.54% 52.31% 46.15% 49 59.18% 55.10% 44.90% GEP-70 High Risk 40 42.50% 35.00% 30.00% 37 37.84% 35.14% 24.32% LDH 〉 300 U/L 7 42.86% 42.86% 0.00% 10 20.00% 20.00% 20.00% Table 2. Model Estimates for Proportions of Long-term Progression Free Survivors in High Risk Subgroups. (These estimates were derived from a logistic/Weibull mixture model for progression-free survival. Based on observed survival trends, these models predict a fraction of patients that is not susceptible to the event of interest). Protocol Predicted Fraction of Long-term Progression-Free Survivors with 95% CI Any High Risk Feature B2M 〉 5.5 mg/dL Any CA CA13 CA13/Hypodiploid GEP-70 HR TT2 - Thal 0.07 (0.00, 0.14) 0.07 (−0.04, 0.18) 0.08 (0.02, 0.15) 0.09 (0.00, 0.19) 0.11 (0.02, 0.19) 0.04 (−0.06, 0.15) TT2 + Thal 0.17 (0.04, 0.30) 0.12 (−0.02, 0.27) 0.19 (0.07, 0.31) 0.20 (0.08, 0.32) 0.18 (0.05, 0.31) 0.15 (0.01, 0.30) TT3a 0.29 (0.09, 0.49) 0.21 (0.04, 0.37) 0.35 (0.20, 0.50) 0.30 (0.10, 0.49) 0.31 (0.12, 0.51) 0.17 (0.03, 0.32) TT3b 0.46 (0.28, 0.65) 0.41 (0.16, 0.67) 0.54 (0.40, 0.68) 0.51 (0.34, 0.69) 0.52 (0.37, 0.67) 0.34 (0.18, 0.51) Figure 1: Model Estimates for Proportions of Long-term Progression Free Survivors in High Risk Subgroups. With the exception of TT2- in high B2M and GEP-70 and of TT2+ in high B2M settings, all other subsets were significant (solid symbols). Highest success rates were observed for TT3B reaching 40% to 50%. Figure 1:. Model Estimates for Proportions of Long-term Progression Free Survivors in High Risk Subgroups. With the exception of TT2- in high B2M and GEP-70 and of TT2+ in high B2M settings, all other subsets were significant (solid symbols). Highest success rates were observed for TT3B reaching 40% to 50%. Figure 2: Relative survival by protocol restricted to patients remaining progression-free after 3 years. For several scenarios (A, B, C), normal-like values are reached progressively earlier with transition from TT2- to TT2+ to TT3A to TT3B. Figure 2:. Relative survival by protocol restricted to patients remaining progression-free after 3 years. For several scenarios (A, B, C), normal-like values are reached progressively earlier with transition from TT2- to TT2+ to TT3A to TT3B. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 2925 Background: Multiple myeloma (MM) patients can present with neurologic manifestation either as part of the disease process or as a therapeutic complication, such as due to metabolic disorders such as hypercalcemia, uremia and hyperviscosity; due to peripheral neuropathy, spinal cord compression and cranial nerve infiltration. Invasion of the central nervous system (CNS) in MM disease is an extremely rare occurrence and is associated with advanced disease with poor prognosis. Herein, we are presenting the UARK experience of CNS involvement in MM. Patients and Methods: The UARK MM database was used to conduct a retrospective analysis identifying CNS MM cases presenting between January 1996 and March 2012. Cases were identified from a review of the cytology laboratory archive material; data were also retrieved from the cytogenetic laboratory database, and magnetic resonance imaging (MRI). Descriptive analyses were performed on available data on patient characteristics, disease course and outcomes. Results: 35 patients were identified with mean age at diagnosis being 55.4 years (range: 32–80 years) presenting with neurologic symptoms enlisted in Table 1. All patients had received prior systemic chemotherapy (SC) alone (n=11), or combination of SC and autologous stem cell transplant (ASCT, n=21), or combination of ASCT and allogeneic stem cell transplant (n=3). Eight (23.5%) patients had elevated B2M 〉5.5 mg/L, twenty four (71%) patients had elevated LDH (〉 2 times upper limit of normal) and 5 (14%) had secondary plasma cell leukemia. The mean interval from diagnosis of MM to diagnosis of CNS MM was 23.5 months (range: 3–121 months). At the time of diagnosis of CNS MM, 3 (8.6%) patients were in complete remission (CR) by standard criteria and 15 (42.9%) patients were in progressive disease (PD). Magnetic resonance imaging (MRI) was performed in 34 patients, showing diffuse or localized leptomeningeal disease in 20 (58.8%) patients, 3 (8.8%) patients had a combination of both leptomeningeal disease with adjacent breakout MM focal lesion, and 2 (6%) patients had MM focal lesions adjacent to the meninges and sinuses without leptomeningeal disease. All 35 patients had malignant plasma cells in CSF analysis. 31 patients received chemotherapy to include intrathecal chemotherapy (IT) as a part of their treatment. IT consisted of cytarabine, methotrexate and hydrocortisone +/− thiotepa. 28 patients were treated with both IT and SC together: alone (n=8), or in combination of ASCT (n=13), or combination of ASCT and cranial irradiation (CI) (n=4), or combination with CI (n=1), or combination with both CI and Allogeneic SCT (n=1), or with Allogeneic SCT (n=1). Conclusion: In our experience, CNS MM is an aggressive terminal disease feature associated with other poor prognostic disease features such as high B2M, LDH and secondary plasma cell leukemia. The present review suggests that the patterns for CNS involvement are variable, such as hematogenous spread of plasma cells seen in PCL, or direct continuous spread from the eroded lytic lesions of the skull. The available novel agents do not provide therapeutic concentrations of drug in the CSF as they do not cross the blood-brain barrier. The study highlights an unmet need in this subset of high risk, relapsed/refractory MM patients. Adequate CNS penetration needs to be considered in MM novel drug development. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 4526 Introduction: Prolonged and persistent neutropenia (white blood cell (WBC) ≤1000/μL) after chemotherapy is associated with increased risk for infection in cancer patients and is often an indication for a diagnostic bone marrow aspirate and biopsy. A test that predicts WBC recovery ≥ 1000/μL and that obviates the need for marrow sampling would be of clinical value. The immature reticulocyte fraction (IRF) reflects erythroid production and hence a recovering marrow. Materials and Methods: We identified 17 myeloma patients with prolonged pancytopenia after either myeloablative or non-myeloablative chemotherapy between March 2010 and February 2011, and compared the time of occurrence of IRF doubling (IRF-D) to the findings on bone marrow examination. Results: The time to IRF doubling preceded increase of WBC ≥ 1000/μL in 15 of 17 patients by a mean of 4.5 days (range 0–18 days). In two patients, the IRF-D coincided with WBC ≥ 1000/μL. The IRF doubled 2–4 days before the bone marrow examination in four patients and at a mean of 3.7 days (range 1–13 days) after the marrow examination in the remaining 13. Conclusion: We conclude that the IRF-D is a simple, inexpensive and widely available test that can precede marrow recovery by several days and may therefore obviate the need for a diagnostic bone marrow aspirate and biopsy in patients with prolonged and persistent neutropenia. Disclosures: No relevant conflicts of interest to declare.

Description: Abstract 324 Background: There has been recent evidence that lenalidomide, while used in the treatment of myelodysplastic syndromes (MDS), also has been associated with an enhanced risk of secondary malignancies including MDS. Here we are examining the impact of maintenance on the development of metaphase-based MDS-associated cytogenetic abnormalities (MDS-CA), and subsequent development of therapy related MDS (t-MDS) and acute leukemia (t-AL) in the two arms of Total Therapy 2 (TT2) and two successive Total Therapy 3 trials (TT3A, TT3B). Methods: The details of TT2/TT3A/TT3B trials and patient outcomes have been reported previously. TT2 (median follow-up 118 months) patients were then randomized to receive thalidomide maintenance (TT2+Thal) for 3 years versus no thalidomide (TT2-Thal). Maintenance in TT3A (median follow-up 78 moths) consisted of VTD in the first year and TD for years 2 and 3 in TT3A, while TT3B (median follow-up 48 months) employed VRD for all 3 years. The patient populations were as follows: TT2-Thal arm (n=283), TT2+Thal arm (n=270), TT3A (n=279) and TT3B (n=162). Bone marrow examination with conventional cytogenetics was performed at baseline, post-induction, post-transplant and then at least semi-annually from maintenance in all patients prospectively. Chi-square and Fisher's exact tests were used to compare baseline characteristics between protocols. Univariate and multivariate Cox proportional hazard regression were used to model associations between baseline covariates and onset of MDS-CA and t-MDS/t-AL. Kaplan and Meier method was used to model cumulative incidence of MDS-CA and t-MDS/t-AL. Results: Baseline characteristics were fairly comparable between the two arms of TT2 and the two TT3 studies, except a higher proportion of GEP70 high risk patients in TT3B. Cumulative incidence of MDS-CA was significantly higher in TT3B protocol from time of first transplant (Figure 1), with the most common cytogenetic abnormality being deletion of chromosome 20 (del20, 35%), followed by monosomy/deletion 7 (27%) and monosomy/deletion 5 (17%) across all protocols. Of the 71 patients with an MDS-CA, 29 were also diagnosed with clinical MDS or AML; for these 29 patients, the median time to this diagnosis from first transplant was 58 months. The cumulative incidence of MDS-CA was higher and achieved more statistical significance (Figure 2) in TT3B compared to TT3A when landmarked from the start of maintenance. In univariate analysis for all patients, TT3B emerged as a significant variable in the univariate Cox regression model for MDS-CA, and in both the univariate and multivariate models for del20. Univariate and multivariate modeling within TT3B patient population did not reveal significance with cumulative dosing of different maintenance drugs. Discussion: Three randomized phase III trials (IFM-2005-02, CALGB 101104 and MM-015) have demonstrated an increase incidence of second malignancies in patients receiving lenalidomide maintenance after having been exposed to alkylating agent melphalan. In our present study, we are reporting an increased incidence of MDS-CA in the TT3B trial that employed VRD maintenance when compared with predecessor TT3A and TT2 trials. The data suggests that the risk is associated with lenalidomide exposure rather than its cumulative dosing in patients with prior exposure to therapy with alkylating agents. Pairwise log-rank comparisons: Disclosures: Sawyer: University of Arkansas for Medical Sciences: Employment, under panding process, under panding process Patents & Royalties.

Description: Key Points MDS-CAs were observed in 11% of 1080 patients and often preceded clinical MDS/acute leukemia. Risk factors for MDS-type cytogenetic abnormalities included immuno-modulatory drugs, older age, male gender, and low CD34 dose (

Description: Abstract 195 GEP analysis is a robust method to distinguish low- and high-risk multiple myeloma (MM), pertaining to 85% and 15% of newly diagnosed patients, respectively (Shaughnessy et al., Blood, 2007; 109:2276–84). As developed in TT2 and validated in TT3A and TT3B, we are now examining, similar to previous work in high-risk MM, whether we can define outliers among low-risk MM, i.e., patients not living up to the low-risk prediction model. Toward this end, we scrutinized early relapses in TT3A and TT3B within three years of protocol entry. Using logistic regression analysis, we identified baseline parameters including GEP, en route for distinguishing this high-risk subset among low-risk MM. Also examined was whether a new model could be built within low-risk disease that allowed for the identification of a high-risk subset. Our database was interrogated for patients known to have GEP-defined low-risk in the GEP-70 model. Table 1 summarizes the 3-year events among GEP-70 low-risk subjects per protocol. An optimal cut-point at +0.146 distinguished, among the combined TT2 and TT3 patients, inferior progression-free survival (PFS) and overall survival (OS) (Figure 1a). Next, we examined outcomes among all TT2 and TT3 patients with GEP data, including those with traditionally-defined high-risk (〉=0.66). Here, we were able to distinguish three subgroups with distinctly different PFS and OS (Figure 1b). Utilizing logistic regression analysis, limited to traditionally-defined GEP-70 low-risk MM (=0.146 (HR=2.61, p=0.0005), the presence of cytogenetic abnormalities (CA) (HR=1.93, p=0.018), B2M 〉5.5mg/L (HR=1.95, p=0.04) and LDH 〉190U/L (HR=1.93, 0.02). These are all reported in Table 2. In conclusion, we have identified, within GEP-70 low-risk patients, a new cut-point. This allows a better categorization of patients having truly low risk disease. Also, above which a prognosis intermediate to the traditional high-risk prognostic group (〉=0.66) could be identified. GEP 〉0.146 dominated a multivariate logistic regression model. Further efforts will be presented on unique genes characterizing this intermediate risk group in relationship to low and high-risk subsets. Table 1. Three-year Events Among GEP-70 Subjects Per Protocol Protocol Total with GEP GEP-70 low-risk GEP-70 low-risk, event within first 3 years TT2 - thalidomide 176 156 55 TT2 + thalidomide 175 149 36 TT3A 275 235 39 TT3B 166 129 23 Table 2. Logistic Regression for 3-year Event Factors, TT2+3 GEP-70 Low-Risk ( 5.5 mg/L 666 24/69 (35%) 59/328 (18%) 1.95 (1.03, 3.69) 0.0401 LDH 〉= 190 U/L 668 33/99 (33%) 50/298 (17%) 1.93 (1.10, 3.40) 0.0229 Cytogenetic abnormalities 665 35/116 (30%) 48/281 (17%) 1.93 (1.12, 3.32) 0.0182 GEP-70 score 〉 0.146 669 37/104 (36%) 46/293 (16%) 2.61 (1.52, 4.47) 0.0005 OR - Odds Ratio, 95% CI - 95% Confidence Interval, P - value from Wald Chi - Square Test in Logistic Regression. NS2 - Multivariate results not statistically significant at 0.05 level. Univariate p - values reported regardless of significance. Multivariate model uses stepwise selection with entry level 0.1 and variable remains if meets the 0.05 level. A multivariate p - value greater than 0.05 indicates variable forced into model with significant variables chosen using stepwise selection. Disclosures: No relevant conflicts of interest to declare.

Description: Intra-tumoral heterogeneity (ITH) is increasingly viewed as the Achilles heel of treatment failure in malignant disease including multiple myeloma (MM). Most MM patients harbor focal lesions (FL) that are recognized on MRI long before bone destruction is detectable by conventional X-ray examination. Serial MRI examinations show that eventually 60% of patients will achieve resolution of FL (MRI-CR). However, this will lag behind the onset of a clinical CR by 18 to 24 months, thus attesting to the biological differences between FL and diffuse MM growth patterns. Consequently, we performed concurrent gene expression profiling (GEP) analyses of plasma cells (PC) from both random bone marrow (RBM) via iliac crest and FL. Our primary aims were to first compare the molecular profiles of FL vs. RBM, second to determine if ITH existed (as defined molecular subgroup and risk), and finally to investigate if the bone marrow micro-environment (ME) contained a biologically interesting signature. A total of 176 patients were available for this study with a breakdown of: TT3 (n=23), TT4 for low-risk (n=131) and TT5 for high-risk MM (n=22). Regarding the molecular analyses of PCs, GEP-based risk (GEP-70, GEP-5) and molecular subgroup correspondence were examined for commonalties and differences between RBM and FL. A “filtering” approach for ME genes was also developed and bone marrow biopsy (BMBx) GEP data derived from this method is under analysis. PC risk correspondence between FL and RBM was 86% for GEP70 and 88% for the GEP5 model. Additionally, 82% had a molecular subgroup concordance, however, they did differ among subgroups (p=0.020) by Fisher's Exact Test. A lower concordance was noted in the CD2, LB, and PR subgroups (67%, 69%, 73%, respectively). GEP70 and GEP5 risk concordance between RBM and FL samples by molecular subgroup was also examined. The overall correlation coefficients were 0.619 (GEP70) and 0.597 (GEP5). The best correspondence was noted for CD1, MF and PR subgroups especially for the GEP5 model. HY, LB and MS showed intermediate correlations, while CD2 fared worst with values of only 0.322 for GEP70 and 0.267 for GEP5 model. Figure 1 portrays these data in more detail for the GEP70 and GEP5 models. Good correlations were noted between RBM and FL based risk scores in case of molecular subgroup concordance (left panels) in both GEP5 and GEP70 risk models, whereas considerable scatter existed in case of subgroup discordance (right panels). The clinical implications in TT4 regarding RBM and FL derived risk and molecular subgroup information, viewed in the context of standard prognostic baseline variables are portrayed in Table 1. High B2M levels at both cut-points imparted inferior OS and PFS as did low hemoglobin. Although present in 42% of patients, cytogenetic abnormalities (CA) did not affect outcomes. FL-based GEP5-defined high-risk designation conferred poor OS and PFS. B2M〉5.5mg/L and FL-derived GEP5 high-risk MM, pertaining to 29% and 11% of patients, survived the multivariate model for both OS and PFS. Next, in examining PC-GEP differences among RBM and FL sites, 199 gene probes were identified with a false discovery rate (FDR) of 1x10-6. Additionally, 55 of the 199 belong to four molecular networks of inter related genes associated with: lipid metabolism, cellular movement, growth and proliferation, and cell-to-cell interactions. Multivariate analysis identified the GEP5 high risk designation of focal lesion PCs to be significantly prognostic with a HR=3.73 (p=0.023).Table 1Cox regression analysis of variables linked to overall and progression-free survival in TT4.Overall SurvivalProgression-Free SurvivalVariablen/N (%)HR (95% CI)P-valueHR (95% CI)P-valueMultivariateB2M 〉 5.5 mg/L38/130 (29%)3.71 (1.49, 9.22)0.0053.84 (1.58, 9.31)0.003FL GEP5 High Risk14/130 (11%)3.68 (1.19, 11.41)0.0243.73 (1.20, 11.62)0.023HR- Hazard Ratio, 95% CI- 95% Confidence Interval, P-value from Wald Chi-Square Test in Cox RegressionNS2- Multivariate results not statistically significant at 0.05 level. All univariate p-values reported regardless of significance.Multivariate model uses stepwise selection with entry level 0.1 and variable remains if meets the 0.05 level.A multivariate p-value greater than 0.05 indicates variable forced into model with significant variables chosen using stepwise selection. Disclosures: No relevant conflicts of interest to declare.

Description: Introduction Multiple Myeloma (MM) is considered a malignancy of post germinal center long-lived plasma cells. Nevertheless T-cell independent antigen stimulation before the exposure of the B-cell to the germinal center can happen and results to IgM secreting short lived plasma cells and lymphoplasmacytes representing thus a potential alternative normal counterpart for IgM plasma cell dyscrasias. IgM myeloma is an infrequent subtytpe of MM with an estimated prevalence of 0.5%. Due to its rarity little is known about its characteristics and prognosis in comparison with Waldestrom’s macroglobulinemia (WM) and the other MM subtypes. Purpose To identify the characteristics and the prognosis of IgM MM, and compare it predominantly with WM and subsequently with the rest of the MM subtypes. Methods We interogatted our Multiple Myeloma Data Base for cases of IgM MM and their respective Overall Survival (OS), Progression Free Survival (PFS), bone disease as defined by x-Rays, PET-CT and MRI, Gene Expression Profile (GEP), and common disease characteristics (anemia,calcium, creatinine) and compare it to the prognosis of WM and non-IgM MM. Diagnosis was based on the morphological and immunophenotypical findings of pathologically examined biopsy specimens along with the presence or not of typical clinical characteristics of MM (lytic bone lesions, hypercalcemia, renal failure) or typical clinical characteristics of WM (organomegaly, lymphadenopathy). Results There were 22 confirmed IgM MM cases. 14 of them presented at MIRT at initial diagnosis while 8 had previously been treated elsewhere. Osteolytic bone lesions and/or pathological fractures by x-ray and CT examination were evident in 16 cases. For the remaining 6 cases active bone focal lesions by either MRI or PET were identified in three. There was no organomegaly evident in cases with an available PET/CT at baseline, while only one had evidence of hilar and mediastinal lymphadenopathy along with calcified lung nodules. Elevated creatinine levels (〉2.0 mg/dl) were evident in 4 cases at initial diagnosis. Their disease characteristics are depicted in the table 1. Median OS for IgM MM was 4.9 years while PFS could not be accurately estimated due to lack of data on patients treated elsewhere. Median OS for a historical control of 158 WM cases in MIRT was 9.2 years (Clin Lymphoma Myeloma Leuk. 11(1):139-42). Median OS of the WM group remained largely unaffected, even when the subgroup of the WM cases requiring treatment was analyzed (9.0 years).To further clarify if the IgM MM differs in terms of OS from the other isotypes of MM, we compared the IgM group to a group of 61 non-IgM MM cases which were matched by important prognostic clinical factors (age, creatinine〉 2mg/dl, LDH〉190u/L, b-2M 〉5.5mg/dl and Albumin

Description: Abstract 1962 Older age and higher serum creatinine levels have long been considered adverse features for overall survival (OS) and progression-free survival (PFS) in MM. Here we are reporting on these variables and their impact on clinical outcomes with the evolution of TT protocols. Among patients