Fonseca, Rafaël

Abstract Introduction Previous studies have documented substantial economic burden for multiple myeloma (MM) patients (pts). However, data on the economic burden of disease progression in the US are limited. In this study, we estimated effects of disease progression on healthcare resource utilization (HRU) and costs among pts with MM who have received at least one line of therapy (LOT) in the US. Methods Data from the Truven Analytics MedStat MarketScan® Commercial Claims and Encounters and Medicare and Coordination of Benefits databases were used. A retrospective incident user cohort of adult pts with a confirmed diagnosis (Dx), defined as ≥1 inpatient or ≥2 non-diagnostic outpatient claims 30-365 days apart with diagnosis, of MM who initiated a course of MM therapy during the study period (Jan 1, 2006 to Dec 31, 2016) was identified. The first date with Dx for MM was defined as the "Dx date" and LOT was identified based on a published algorithm. Pts were excluded if they had a gap in enrollment during the period beginning 6-month before the Dx date through 30-days after the first LOT (1L) initiation date, received MM therapy or unclassified antineoplastic medications before the Dx date or stem cell transplant (SCT) at any time during the study period, or had missing information required to identify LOT or assess baseline characteristics or study outcomes. The 12 months after initiation of each LOT was designated the "event identification period" for progression. Disease progression was defined as advancement to the next LOT, ICD-9/10 or CPT/HCPCS diagnosis or procedure codes indicative of bone metastasis, hypercalcemia, soft tissue plasmacytoma, skeletal related events, or acute kidney disease while off MM therapy, or death. The "event date" for progression was defined as date with evidence of progression. For each pt with progression, one pt without progression was randomly selected and assigned an index date to ensure that distribution of time from LOT initiation to event date for pts with progression was the same as that for pts without progression. For each LOT (L1-L4), annual HRU and costs from index date through disenrollment or the end of the study period were compared for pts with vs without progression using inverse probability of treatment weighting (IPTW) to adjust for differences between groups in baseline characteristics including year of index date, age, gender, region, plan type, Medicare status, comorbidities, and pre-index HRU and healthcare costs. All costs were adjusted to 2016 US dollars. In a subgroup analysis, HRU and costs were evaluated for LOTs initiated from 2013 to 2016 to reflect patterns of treatment in current era. Results Of the 28,184 adult MM pts who received one or more MM therapy during the study period, 11,179 qualified for the study, including 4468 and 6598 pts with and without progression during 1L, respectively. The corresponding numbers for 2L, 3L, and 4L were 1563 and 2207, 618 and 714, and 244 and 260, respectively. Mean age at index date was 68 years; 57% were male. After IPTW, all baseline characteristics were well balanced in all LOTs with standardized mean differences <0.1 for all characteristics. The mean number of hospitalizations per year was greater for patents with progression in all LOTs, with differences ranging from 0.46 (95%CI 0.40, 0.52) for 1L to 0.89 (95%CI 0.67, 1.11) for 3L. In all LOTs, annual costs of inpatient and outpatient services were greater for pts with progression while costs of outpatient prescriptions were greater among patient without progression. Total healthcare costs were greater for pts with vs without progression in all LOTs with hospitalizations and outpatient visit costs being key drivers. Total incremental annual costs in those who progressed were higher by $30,381 (1L), $33,064 (2L), $34,495 (3L), and $25,163 (4L). When the analysis was restricted to LOTs initiated between 2013 and 2016, the incremental costs in patients who progressed were greater in the most recent era: $52,739 (1L), $49,012 (2L), $25,329 (3L), and $65,400. Conclusions For MM pts receiving drug therapy, the economic burden of disease progression is substantial across all LOTs and this burden is greater in the most recent era (2013 to 2016). Treatments that prevent or delay progression are likely to yield important reductions in downstream disease management costs. These savings should be considered in frameworks assessing the value of innovative treatments for MM. Disclosures Hagiwara: Jazz Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Consultancy; Amgen: Research Funding; Amgen: Consultancy; Policy Analysis, Inc: Employment. Delea:Novartis: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy, Research Funding; Sanofi: Consultancy, Research Funding; Takeda: Research Funding; Seattle Genetics: Research Funding; Policy Analysis Inc.: Employment. Panjabi:Amgen: Employment, Equity Ownership. Yucel:Amgen: Employment, Equity Ownership. Fonseca:Mayo Clinic: Employment; Amgen: Consultancy.

Background The precise molecular mechanism and targets of lenalidomide specific anti-Multiple Myeloma (MM) activity remain largely unknown, although, cereblon (CRBN) has been identified as a central mediator of activity with IRF-4 acting as a downstream molecule. Lenalidomide resistance in MM cells which, despite CRBN depletion, are able to restore their IRF-4 levels suggests the existence of alternative pathways. Methods To measure apoptosis and gene expression analysis 1x 106cells were incubated with 10μm to 50μm of lenalidomide for 24 to 96 hours before they were examined by annexin-PI and FACS analysis. Gene and protein expression were measured by RT-PCR, western blot, and immunohistochemistry. For lenalidomide followed bortezomib serial studies, cells were incubated with 10μm of lenalidomide for 48 hours and later treated with bortezomib for 24 to 48 hrs. CRBN and immunoglobulin light chain knock-down were performed by lentiviral mediated shRNA. Results We found lenalidomide induces Endoplasmic reticulum stress (ERS) via accumulation of intracellular immunoglobulin proteins, but only in the presence of CRBN in a panel of MM cell lines. This accumulation of intracellular proteins resulted in ERS as documented by western blot and RT-PCR in OPM2 and MMIS cell lines. We next utilized OPM2 cells knocked down for CRBN and control, non-target (NT), and treated with different doses of lenalidomide. After three days of treatment an ERS response was occurring in OPM2-NT cells but not in CRBN knockdown cells. Using Western blot we found decreased XBP-1u and increased XBP-1s, ERS marker proteins, in CRBN positive (NT) cells after 72 hours of lenalidomide treatment, but not in CRBN knock-down cells. Another ERS marker GRP78/BiP was also clearly accumulated after lenalidomide treatment in CRBN positive cells. Inactivation of the tumor suppressor p53 by degradation is a mechanism utilized by cells to adapt to ERS has been reported. We also found that p53 protein down regulated after lenalidomide treatment in CRBN positive OPM2 and MMIS cells. We have analyzed other isogenic cell lines MM1.S (lenalidomide-sensitive) and isogenic MM1.Sres (lenalidomide-resistant) HMCLs and found that lenalidomide induces ERS in MM1.S but not MM1.Sres cells. CRBN is important for lenalidomide to induce immunoglobulin protein accumulation and ERS was further proved by over-expressing CRBN in OCI-My5 MM cell line and subsequent lenalidomide treatment. To test the effect of light chain accumulation as ER stressors, we knocked down immunoglobulin light chain lambda in human MM cell line OPM2. Knock-down of lambda light chain in OPM2 cells resulted in lenalidomide resistance and it induced endoplasmic reticulum stress mediated anti-myeloma activity. Our preliminary data reveals that lenalidomide mediated progressive ERS can positively enhance bortezomib induced apoptosis in an in-vitro MM model. We pre-treated myeloma cell lines with lenalidomide and subsequently treated with bortezomib. MM cells pre-treated with lenalidomide for two days and there after treated with bortezomib clearly shown increased sensitivity to bortezomib induced apoptosis than non-pre-lenalidomide treated cells. Conclusion Here we show that lenalidomide causes accumulation of immunoglobulin light chains, inducing progressive ER stress, resulting in anti-myeloma activity and that effect depends on the presence of CRBN. Proteasome inhibitors such as bortezomib also sensitize MM cells to endoplasmic reticulum stress-mediated apoptosis. Our data demonstrated the synergistic effect of lenalidomide and proteasome inhibitors, likely due to the augmented protein stress. This data support the use of serial therapy utilizing pre-lenalidomide treatment followed by bortezomib or carfilzomib treatment. Disclosures: Fonseca: Medtronic: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; Genzyme: Consultancy; BMS: Consultancy; Lilly: Consultancy; Onyx: Consultancy, Research Funding; Binding Site: Consultancy; Millennium: Consultancy; AMGEN: Consultancy; Cylene: Research Funding; Prognostication of MM based on genetic categorization of the disease: Prognostication of MM based on genetic categorization of the disease, Prognostication of MM based on genetic categorization of the disease Patents & Royalties.

Abstract Abstract 3150 Introduction. Affordability of health care in the United States (US), and the impact of patient insurance coverage on it have been shown to be associated with the delivery and timeliness of access to care. With increasing costs of novel therapies in hematology and oncology, this concern has been raised in hematologic cancers. This analysis evaluates whether the health-related quality of life (HRQOL) of patients with active, symptomatic multiple myeloma (MM) patients in the US varies by their insurance coverage as they initiate treatment. Methods. Baseline data were collected in Connect MM®, a prospective observational registry initiated in September 2009 involving centers in the US. Data on patient demographics and clinical characteristics were provided by clinicians. HRQOL was reported by patients in the clinic at enrollment, within two months of diagnosis. Patients completed 3 psychometrically validated instruments: the Brief Pain Inventory (BPI), EQ-5D, and Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM). Standard analyses were conducted of each instrument given clinical characteristics at that time. Patients were characterized as to the main source of their insurance coverage: Medicare, Medicaid or Commercial. The Medicare cohort included those with supplemental commercial coverage, and the Medicaid cohort included those with dual Medicare-Medicaid coverage. Reported mean BPI, EQ-5D and FACT-MM scores were analyzed by patient insurance coverage. Statistical significance of score differences among sub-cohorts was ascertained by ANOVA using SAS 9.1. Results. HRQOL data and insurance status were reported by 863 patients, enrolled from 189 centers. Patients were predominantly male (57%) and white (82%) with mean age at 67.0 (standard deviation [SD] 11.3) yrs. HRQOL scores by insurance status are presented: Overall FACT-MM results indicate that Medicaid insurance status is associated with greater decrement in baseline HRQOL compared to the other groups. Statistically significant differences are noted in the FACT-G general cancer HRQOL score, and its physical, social/family and emotional component scores. BPI data (on a scale of 0 [no pain] to 10 [worst pain] indicate that average pain may be worse among Medicaid patients compared to either Medicare or commercially insured patients. There are no statistically significant differences on EQ-5D scores (on a scale of 1 [no problem] to 2 [some problems] to 3 [incapacity] between cohorts based on insurance status. Conclusions. Initial results from the Connect MM® Registry indicate that HRQOL at baseline prior to initiation of treatment is worse among Medicaid patients compared to those with either Medicare or commercial coverage. This should be investigated to determine whether Medicaid patients are accessing care later in disease progression than others covered by Medicare or commercial insurance. Furthermore, future analyses should be conducted of patients by insurance coverage to determine whether status may be associated with access to medical care, subsequent clinical outcomes, and HRQOL over time. Results reported here should serve as a baseline reference. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Membership on an entity's Board of Directors or advisory committees. Fonseca:Celgene: Membership on an entity's Board of Directors or advisory committees. Narang:Celgene: Membership on an entity's Board of Directors or advisory committees. Shah:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Khan:Celgene: Employment, Equity Ownership.

Abstract Abstract 2838 The combination of novel agents and chemo-immunotherapy (CIT) has led to a significant increase in both overall and complete response rates for chronic lymphocytic leukemia (CLL). There is, however, significant clinical heterogeneity in the overall effectiveness of CIT. Specifically, some patients are long-term responders who experience durable clinical remission while others, even though responding well initially, have less durable remissions. It is unclear if this heterogeneity is a reflection of an incomplete cytotoxic effect or whether certain leukemia sub-populations (i.e. subclones) are resistant to the effects of CIT. Comprehensive analysis of tumor cells has provided, in some malignancies, evidence of extraordinary genomic complexity and intraclonal genetic diversity. Conversely, little is known of the genetic architecture of the leukemic clone in CLL patients and the extent to which CLL tumor cells differentiate genetically at the subclonal level. In order to gain insight into the genetic architecture and clonal evolution underlying disease progression/relapse, we performed a sequential, longitudinal whole genome analysis by array-based comparative genomic hybridization (aCGH) in 22 CLL cases with evidence of clinical progression and/or clinical relapse post therapy. These patients received standard purine analogue, cyclophosphamide and rituximab (PCR) for progressive disease. For the purposes of this study, we classified samples as; time point 1 (TP1) collected >6 months before starting first-line CIT for disease progression; time point 2 (TP2) consisting of tumor samples at the time of initial progression requiring treatment; and time point 3 (TP3) consisting of tumor samples collected >6 months after initial treatment but prior to subsequent treatments. Overall, aCGH assay was performed in 54 samples from 22 cases (2 to 4 time points analyzed per patient): 6 cases were analyzed at TP1 and TP2, 8 at TP2 and TP3, 2 at TP1 and TP3, and the remaining 6 cases were analyzed at TP1, TP2 and TP3. In cases showing genetic changes between time points, FISH analyses were performed in 32 additional samples to assess intra-clonal diversity and provide a quantification of the clone size. There was a small increase in genomic complexity in later time points with a mean of 4 (median 4, range 0–12) CNAs detected at the first time point for each patient, increasing to a mean of 5.3 (median 4.5, range 0–21) CNAs at the last time point analyzed. Diverse patterns of changes in genetic architecture were observed. The simplest change in genetic architectures was the linear sequence, found in 2 cases (9%) and characterized by the maintenance of the initial abnormalities and the subsequent acquisition of additional CNAs in the same subclone. The pattern of changes in genetic architecture in another 4 patients (18%) demonstrated marked heterogeneity including multiple genetic subclones evolving either in succession or in parallel. In all 4 cases with multiple subclones, a marked shift in the dominant subclone was observed at the time of disease relapse, with the minor subclones at TP1 and TP2 becoming the dominant subclones at TP3. In addition, the subclonal evolution continued following secondary therapies, and in all 4 cases the emerging subclone showed resistance to multiple treatments. This argues strongly in favor of subclones with specific genetic structures becoming dominant with the selective evolutionary pressure imposed by therapy. In summary, this sequential genetic study reveals that CLL leukemic B cells exhibit an unanticipated level of heterogeneity including a variable number of genetically distinct subclones, which display dynamic behavior in disease progression. The characterization of this intraclonal architecture is of critical importance to better understand the mechanisms of disease progression and relapse as well as to ultimately inform us of individualized treatment strategies. Disclosures: Fonseca: Consulting :Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, Lilly Research Support: Cylene, Onyz, Celgene: Consultancy, Research Funding.

Abstract Massively parallel sequencing analyses have revealed a common mutation within the MYD88 gene (MYD88L265P) occurring at high frequencies in many non-Hodgkin lymphomas (NHL) including the rare lymphoplasmacytic lymphoma, Waldenström’s macroglobulinemia (WM). Using whole exome sequencing, Sanger sequencing and allele-specific PCR, we validate the initial studies and detect the MYD88L265P mutation in the tumor genome of 97% of WM patients analyzed (n=39). MYD88L265P was detected at lower frequencies in other indolent lymphomas including LPL (0%), MALT (4%), nodal MZL (5%) and splenic MZL (8%); all but one MYD88L265P was heterozygous. Due to the high frequency of MYD88 mutation in WM and other NHL, and its known effects on malignant B cell survival, therapeutic targeting of MYD88 signaling pathways may be useful clinically. However, while the effects of MYD88L265P on the activity of IRAK1/4 and NF-κB are have been studied previously, we are lacking a thorough characterization of the role of intermediary signaling proteins such as TRAF6 and TAK1 on the biology of MYD88L265P-expressing B cells. A better understanding of the proteins involved in MYD88L265P signaling may lead to the development of more targeted and effective therapeutic approaches. In an attempt to identify MYD88L265P –specific therapeutic targets we first wanted to characterize the role of intermediary signaling proteins that facilitate the downstream activation of NF-κB. Upon activation of TLRs or IL-1b receptors, MYD88 forms a homodimer and recruits IRAK1/4 and TRAF6 into a complex resulting in association and phosphorylation of TAK1 followed by activation of NF-κB. We monitored the formation of a complex comprised of MYD88, IRAK1, IRAK4 and TRAF6 and immunoprecipitation of either endogenous IRAK4 or IRAK1 revealed constitutive association of IRAK with TRAF6 and MYD88L265P. To assess if the formation of a MYD88L265P/IRAK/TRAF6 complex results in downstream activation of TAK1, constitutive TAK1 phosphorylation was measured and detected in all three cell lines that express MYD88L265P. An association between TAK1 and TRAF6, another measure of TAK1 activation, was also detectable. When a similar analysis of TAK1 was performed in DLBCL cells expressing wild-type MYD88, no phosphorylation of TAK1 was detected, nor was TAK1 associated with TRAF6. IRAK1, IRAK4, TAK1, TRAF6, and MYD88 were expressed at similar levels in all cell lines studied and therefore did not contribute the differences in MYD88 complex formation observed between cell lines. These studies were further confirmed using HEK 293T cells that were transduced with either a vector control plasmid or HA-tagged MYD88WT or MYD88L265P expression plasmids. Together, these studies suggest that MYD88L265P forms a complex with IRAK and TRAF6 resulting in constitutive activation of TAK1 and NF-κB. To confirm the significance of TAK1-mediated MYD88L265P signaling on lymphoma cell growth, the effect of the selective TAK1 inhibitor, (5Z)-7-Oxozeaenol, on cell proliferation was tested. All MYD88L265P-expressing cell lines were sensitive to TAK1 inhibition in a dose-dependent manner (0-10 μM). In contrast, NHL cells expressing MYD88WT were found to be insensitive to TAK1 inhibition. We next tested the impact of the TAK1 inhibitor on a MYD88L265P positive WM patient sample. Similar to what was seen in the WM cell lines, the TAK1 inhibitor inhibited WM cell growth and survival in a dose dependent manner. Additionally, the TAK1 inhibitor significantly reduced the level of IL-10 secreted by each of the cell lines. Together, these data suggest that MYD88L265P drives cell proliferation and cytokine secretion through a TAK1-dependent mechanism. In conclusion, we are the first to validate by NGS in a large patient cohort the high prevalence and specificity of MYD88L265P in WM. Cells harboring the L265P mutation but not wild-type MYD88 exhibit constitutive signaling leading to the hyperactivation of NF-κB. We have established the role of TAK1 as an integral component of MYD88L265P signaling in both WM and DLBCL cell. Our data suggest that targeting TAK1 clinically may be an effective strategy for the treatment of WM and other lymphomas driven by MYD88L265P signaling. Disclosures: Fonseca: millennium: Consultancy; amgen: Consultancy; Binding site: Consultancy; onyx: Consultancy; medtronic: Consultancy; Genzyme: Consultancy; Otsuka: Consultancy; Celgene: Consultancy; lilly: Consultancy; Onyx: Research Funding; cylene: Research Funding.

Abstract Multiple myeloma (MM) is characterized by clonal proliferation of a neoplastic plasma cell and its production of a monoclonal immunoglobulin; evolving from an asymptomatic pre-malignant stage named monoclonal gammopathy of undetermined significance (MGUS). At the time of diagnosis with MM, lytic lesions are present in approximately 70-80% of patients. Lytic lesions increase the risk for skeletal related events as well as treatment costs, while lowering quality of life and overall survival. Metastatic bone surveys underestimate bone disease since plain radiographs demonstrate abnormalities until at least 30% of trabecular bone has been lost and cannot provide information about ongoing bone remodeling. Bone scintigraphy lacks usefulness in following bone disease due to decreased osteoblast activity in MM, while Dual-energy X-ray absorptiometry scans produce heterogeneous local bone mineral density changes and are not recommended to evaluate bone disease in these patients. Biomarkers (eg, N- and C-terminal telopeptides of type I collagen) have been used to assess bone metabolism balance (BMB; ie, the difference between bone formation and resorption) in MM prior and subsequent to specific therapies, however, consensus is still lacking and their clinical utility is uncertain. Calcium in nature consists of six isotopes, and the relative abundance of the isotopes varies measurably. The strength of molecular bonds depends on atomic weight of the participating atoms. Calcium (Ca) containing compounds react at different rates depending on atomic mass. Bone formation favors lighter isotopes of Ca, depleting soft tissue of light Ca isotopes, while bone resorption releases this isotopically light Ca back into soft tissue with little or no selectivity. As a result of this difference in isotope fractionation, Ca isotopic composition in soft tissue should shift to heavier Ca isotope values in positive BMB and lighter values in negative BMB. In order to identify whether Ca isotopic composition can be used as a marker of myeloma-induced bone disease, we first set out to determine its association with MM disease activity. Using multiple collector inductively coupled plasma mass spectrometry, we determined the Ca isotopic composition in 108 peripheral blood samples from 54 patients with monoclonal gammopathies. Ca isotopic composition was determined as the ratio between the naturally occurring 44Ca and 42Ca isotopes (δ44/42Ca) relative to a standard in parts per ten thousand units, as previously described by Morgan et al. Disease activity was determined at the time of δ44/42Ca determination by assessing disease status and response to treatment, as described by the International Myeloma Working Group uniform response criteria, defining progressive or relapsed disease as active disease, and stable or responsive disease as non-active. Categorical variables were analyzed using chi squared or Fisher’s exact test, interval variables were analyzed using a one-tailed t-test. A repeated measures logistic regression model was developed using a cross-sectional time-series generalized estimating equation. All statistical analysis was done using Stata/SE 12.0. Fifty-four adult patients (61% male) diagnosed with monoclonal gammopathy, ranging from MGUS (n=1) to SMM (n=4) to MM (n=49), were assessed at different time points, with 7 patients being assessed once, 41 were assessed twice, 5 were assessed 3 times, while 1 patient was assessed 4 times. Mean age at the time of first assessment was 66, ranging from 45 to 84. Mean δ44/42Ca was statistically lower in the active disease group as compared to the non-active group (-0.7536 vs -0.6564, p=0.0466). In a statistically significant repeated measurement logistic regression model (p= 0.0239), δ44/42Ca is associated with active disease (OR=0. 054, p=0.031, 95% CI=0.004-0.765) after adjusting for age, gender, presence of anemia, serum creatinine, free light chain ratio, current bisphosphonate and current anti-myeloma therapy. A lower δ44/42Ca in the active disease group might suggest a link between a more intense level of bone resorption and myeloma activity. Ca isotopic composition can become part of the clinician’s arsenal to determine disease status in a patient with MM. In order to further characterize δ44/42Ca to specifically infer myeloma-induced bone disease activity, further studies that include serum biomarkers and dynamic imaging should be performed. Disclosures: Gordon: Arizona State University: “Application of Ca isotope analysis to the early detection of metastatic cancer” (AzTE reference number M13-117) Patents & Royalties; Arizona State University: “Isotopic biomarkers for rapid assessment of bone mineral balance in biomedical applications” (US Application #PCT/US2011/039780; AzTE reference number M10-102L), “Isotopic biomarkers for rapid assessment of bone mineral balance in biomedical applications” (US Application #PCT/US2011/039780; AzTE reference number M10-102L) Patents & Royalties. Skulan:AZTE: “Application of Ca isotope analysis to the early detection of metastatic cancer” (AzTE reference number M13-117) Patents & Royalties; AZTE: “Isotopic biomarkers for rapid assessment of bone mineral balance in biomedical applications” (US Application #PCT/US2011/039780; AzTE reference number M10-102L), “Isotopic biomarkers for rapid assessment of bone mineral balance in biomedical applications” (US Application #PCT/US2011/039780; AzTE reference number M10-102L) Patents & Royalties. Anbar:Arizona State University: “Isotopic biomarkers for rapid assessment of bone mineral balance in biomedical applications” (US Application #PCT/US2011/039780; AzTE reference number M10-102L), “Isotopic biomarkers for rapid assessment of bone mineral balance in biomedical applications” (US Application #PCT/US2011/039780; AzTE reference number M10-102L) Patents & Royalties; Arizona State University: “Application of Ca isotope analysis to the early detection of metastatic cancer” (AzTE reference number M13-117) Patents & Royalties. Fonseca:AMGEN: Consultancy; Millennium: Consultancy; Binding Site: Consultancy; Onyx: Consultancy, Research Funding; Lilly: Consultancy; BMS: Consultancy; Genzyme: Consultancy; Celgene: Consultancy; Medtronic: Consultancy; Otsuka: Consultancy; Cylene: Research Funding; Prognostication of MM based on genetic categorization of the disease: Patents & Royalties.

Abstract The treatment and natural history of smoldering myeloma has been an area of intense preclinical and clinical study. Historical attempts to treat these patients have not demonstrated benefit, likely as a consequence of lack of attention to the vast heterogeneity contained within the diagnosis. More recent risk criteria from both US and Spanish investigators have identified a cohort of smoldering myeloma patients at high risk for progression in a short time, using different methodology. Recently the PETHEMA group published a randomized clinical trial testing lenalidomide/dexamethasone vs observation among high risk smoldering patients, and demonstrated a clear benefit in terms of progression free and overall survival favoring early intervention. However, the risk criteria utilized a highly sensitive method of flow cytometry, a test not routinely available in the US. It is not clear that the group of patients defined in the PETHEMA study share similar outcomes with those defined as high risk using the ECOG/Mayo criteria. A recent publication demonstrated only 25% overlap for the highest risk smoldering patients when using either the PETHEMA or the ECOG criteria. To further evaluate the potential benefit of early intervention in a high risk smoldering cohort, the ECOG myeloma group designed a phase II/III trial testing the safety and efficacy of single agent lenalidomide. We report here on the safety and efficacy of the phase II portion of the trial. The phase II group of patients received lenalidomide alone at a dose of 25 mg days 1-21 every 28 days. The primary endpoint for the safety study was the rate of any treatment-related grade 4-5 non-hematologic toxicity plus grade 3 non-hematologic toxicity that affects vital organ function (such as cardiac, hepatic, or thromboembolic events) observed within 6 cycles of treatment. Patients were to be diagnosed with high-risk smoldering multiple myeloma (SMM) within the past 12 months, as confirmed by both of the following: bone marrow plasmacytosis with >= 10% plasma cells or sheets of plasma cells and an abnormal serum free light chain ratio (<0.125 or >8.0) by serum FLC assay. Patients must have had measurable levels of monoclonal protein. Patients must have had no lytic lesions on skeletal surveys and no hypercalcemia (i.e. >= 11 mg/dL). Among the final phase II cohort (n=44 patients), 55% were female, and 43% were 65 years and older. Enrollment began in January 2011 and lasted 2 years with the last patient completing 6 cycles of treatment in August 2013. The median treatment duration of the entire cohort is 13.5 cycles (range 1-30 cycles). Mean percentage lenalidomide dose over the first 6 cycles was 94, 89, 82, 79, 76, 72. With a median follow up of 17 months, 2 patients had progression on therapy. Fifteen patients are off treatment for the following reasons: disease progression (n=2), AE/complication (n=5), death (n=2), patient withdrawal/refusal (n=5), other (n=1); 6 of the 15 patients ended treatment before completing 6 cycles. Of 44 patients assessed for toxicity, 11 patients [25.0%, 95% CI: (13.2%-40.3%)] experienced worst grade treatment-related non-hematologic toxicity of grade 3 or higher based on CTCAE v4, with neutropenia and fatigue being the most frequent. This includes 2 fatal deaths (MI and TE). Two patients [4.6%, 95% CI: (0.1%-15.5%)] experienced a serious adverse event as defined for the purposes of the phase II toxicity analysis that included treatment-related grade 4-5 non-hematologic toxicity or any grade 3 toxicity affecting vital organ function (such as cardiac, hepatic, or thromboembolic events) during the first 6 cycles of treatment. Twelve patients achieved partial response or better [33.3%, 95% CI: (15.0%-42.8%)] along with 25 patients reporting stable disease. Lenalidomide has shown promise in the treatment of high-risk smoldering myeloma and based on this analysis, accrual to the phase III portion is ongoing. In the context of the encouraging data from the PETHEMA group, completion of the phase III portion of this study is needed to validate their findings using a different criteria, and using a steroid sparing approach. This study was coordinated by the Eastern Cooperative Oncology Group (Robert L. Comis, M.D., Chair) and supported in part by Public Health Service Grants CA23318, CA66636, CA21115, CA13650, CA32102 and from the National Cancer Institute, National Institutes of Health and the Department of Health and Human Services. Disclosures: Lonial: Millennium: Consultancy; Celgene: Consultancy; Novartis: Consultancy; BMS: Consultancy; Sanofi: Consultancy; Onyx: Consultancy.

Abstract Abstract 5070 Introduction. Studies in the United States (US) have identified variation in incidence and survival of multiple myeloma (MM) patients of different races, and noted that MM is the most common hematologic cancer among African Americans. This analysis was conducted to evaluate whether the health-related quality of life (HRQOL) of patients in the US as they initiate treatment with active, symptomatic MM varies by race. Methods. Data were collected in Connect MM®, a prospective observational registry begun in September 2009 involving centers in the US. Data on patient demographics and clinical characteristics were provided by clinicians. HRQOL was reported by patients in the clinic at enrollment, within two months of diagnosis. Patients completed 3 psychometrically validated instruments: the Brief Pain Inventory (BPI), EQ-5D, and Functional Assessment of Cancer Therapy-Multiple Myeloma (FACT-MM). Standard analyses were conducted of each instrument. Reported mean BPI, EQ-5D and FACT-MM scores were analyzed by patient race. Statistical significance of score differences was ascertained by ANOVA using SAS 9.1 in two ways: (1) among three different racial categories (White, Black and Other), and (2) between Blacks and non-Blacks. Hispanic/Latino patients and Asian patients comprise most of the Other cohort. Results. HRQOL data at baseline were reported by 916 pts, enrolled from 189 centers. Of these patients, 82% were White, 12% were Black, and 5% were of another race (Other). Among evaluable patients, the different race groups did not differ statistically by ECOG status or multiple myeloma stage (measured by either the International Staging System or the Durie and Salmon system). The three racial groups differed by age, with the mean (SD) age of Blacks (63 (11)) and Others (63 (13)) being less than that of Whites (68 (11), p<0.0001). Gender was trending, but not statistically significantly different, between races, with males comprising 58% of Whites, 52% of Blacks, and 46% of Others (p=0.1803). HRQOL scores by race are presented here: Overall FACT-MM results indicate that baseline HRQOL does not vary between races, as the main summary scores do not differ statistically, although the FACT-MM Total scores of Blacks and Whites are trending higher than those of Others. Only the emotional and social/family domain scores of the FACT-MM vary statistically, as Blacks show a worse mean score in the social/family domain and a better score in the emotional domain. BPI data (on a scale of 0 [no pain] to 10 [worst pain] do not show a statistically significant difference between races, and the same is true of the five EQ-5D domains (measured on a scale of 1 [no problem] to 2 [some problems] to 3 [incapacity]. Conclusions. Initial results from the Connect MM® Registry indicate that HRQOL at baseline prior to initiation of treatment does not vary by patient race. As such, these results may serve as a baseline reference for future analyses. In particular, as patients proceed through therapy, analyses should be conducted of patients by race, among other factors, to determine whether it may be associated with subsequent clinical outcomes and HRQOL over time. Disclosures: Pashos: Celgene: Membership on an entity's Board of Directors or advisory committees. Durie:Celgene: Membership on an entity's Board of Directors or advisory committees. Rifkin:Celgene: Membership on an entity's Board of Directors or advisory committees. Terebelo:Celgene: Membership on an entity's Board of Directors or advisory committees. Gasparetto:Celgene: Membership on an entity's Board of Directors or advisory committees. Mehta:Celgene: Membership on an entity's Board of Directors or advisory committees. Toomey:Celgene: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Membership on an entity's Board of Directors or advisory committees. Fonseca:Celgene: Membership on an entity's Board of Directors or advisory committees. Narang:Celgene: Membership on an entity's Board of Directors or advisory committees. Shah:Celgene: Membership on an entity's Board of Directors or advisory committees. Swern:Celgene Corporation: Employment, Equity Ownership. Sullivan:Celgene: Employment, Equity Ownership. Street:Celgene: Employment, Equity Ownership. Khan:Celgene: Employment, Equity Ownership.

Abstract Abstract 5060 Introduction In multiple myeloma, cytogenetics is informative in only about a third of patients. Despite this limitation, it remains a commonly available laboratory investigation that has prognostic utility and allows detection of global changes including ploidy. While cytogenetics abnormalities in myeloma have been well documented, a direct comparison between Western and Asian patients has not been performed. Methods Retrospective analysis of 190 newly diagnosed multiple myeloma patients presenting to the National University Hospital Singapore (NUH) between 2000–2009, and 494 newly diagnosed multiple myeloma patients from the Mayo Clinic myeloma database from 2000 to 2005 were analyzed. All abnormalities were logged onto an excel spreadsheet where all cytobands were represented. Gains, losses and structural abnormalities including specific translocations were documented separately. Abnormalities present in 5% or more samples with cytogenetic abnormalities were further analysed and compared between the 2 cohorts using chi-square test. Bonferroni correction is used when multiple comparisons were made. Results 80/190 (42%) of NUH patients had an abnormal karyotype compared with 180/494 (36%) in the Mayo clinic cohort (not statistically significant p=0.17). Distribution of ploidy status was very similar between the NUH and Mayo cohort with 35% and 27% being hyperdiploid in the NUH and Mayo cohort respectively (p=0.57). In both cohorts, the most common gains are whole chromosome gains involving chromosomes that are commonly trisomic in hyperdiploid myeloma. However, the pattern of trisomies is different between the NUH and Mayo cohort, with trisomies of chromosome 5, 7, and 19 more common in NUH (p-values <0.0001 for all three comparisons). Loss of 1p21was more common in NUH compared with Mayo (9% vs 2%, p=0.01) although loss of chromosome 7 was more common in Mayo compared to NUH (15% vs 0%, p=0.0002). t(11;14) is the most common translocations for both cohorts. Translocations involving chromosome 1 with different partners are also common in both cohorts. However, there are also interesting differences. Rearrangements involving the IgH (14q32) [10% NUH vs 4% in Mayo] and MYC (8q24) [6% in NUH vs 1% in mayo] loci are more common in the NUH cohort. In fact, when MYC translocations with IgH or IgL are included, 9 (11%) cases in the NUH cohort were affected versus 4 (in the Mayo Clinic cohort (p=0.0002). Recurrent rearrangement of 3q27 was observed in 5% of the NUH cohort while no cases were noted in the Mayo cohort. A search of the Mitelman Database of Chromosome Aberrations and Gene Fusion in Cancer (http://cgap.nci.nih.gov/Chromosomes/Mitelman) showed that only 4 out of 1643 Caucasian myeloma karyotype recorded had this abnormality (p<0.0001). 1q21 deletion and MYC rearrangements are associated with poorer prognosis. Conclusion From this comparison, the general patterns of cytogenetic abnormalities are similar between Asian and Western patients. The most important difference between Asian patients and western patients was the higher incidence of poor prognostic cytogenetic abnormalities in Asian patients including 1p21 deletion and gene rearrangements involving the MYC gene locus. 3q27 was predominantly seen in the Asian patient cohort and rarely in western patients. This could be a unique feature of Asian myeloma patients and more studies will have to be done to confirm this. These differences may have important implication on outcome of patients in Asian and Western Countries, and also unique biology that could potentially be exploited therapeutically. Disclosures: Fonseca: Consulting:Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, Lilly Research Support: Cylene, Onyz, Celgene: Consultancy, Research Funding.

Abstract Abstract 2881 Multiple myeloma (MM) is characterized by a remarkable heterogeneity in outcome following standard and high-dose therapies. Significant efforts have been made to identify genetic changes and signatures that can predict clinical outcome and include them in the routine clinical care. Gene expression profiling (GEP) studies have achieved a central role in the study of multiple myeloma (MM), as they become a critical component in the risk-based stratification of the disease. To molecularly stratify disease-risk groups, we performed GEP on purified plasma cells (obtained from the immunobead selection of CD138+ cells) from 489 MM samples in different stages of the disease using the Affymetrix U133Plus2.0 array. A total of 162 probes were analyzed using an in house automated script to generate a GEP report with the most used risk stratification indices and signatures, including the UAMS 70-gene, UAMS class, TC classification, proliferation and centrosome signature, and NFKB activation indices. In a subset of 57 samples, IgH translocations were analyzed using FISH and results were correlated with GEP data. A macrophage index was calculated and used as a surrogate measurement of non-plasma cell contamination. A total of 49 samples (10%) were excluded from subsequent analysis as the macrophage index indicated a significant contamination with no plasma cells, hence potentially compromising the results. The percent of high-risk disease patients identified from different signatures ranged from 26.4% by using high proliferation index to 28.8% with high centrosome signature and 31.3% with high 70-gene index. This percent of high-risk cases based on the 70-gene index is similar to what was found in Total therapy 2 (TT2) and TT3 cohorts. A third of patients (33.2%) were classified as D1 in the TC class, followed by 11q13 (19.3%), D2 (16.4%), 4p16 (13.8%), MAF (6.1%), None (4.7%), D1+D2 (4.5%) and 6p21 (1.8%). The NF-kB pathway was likely activated in 45.5% to 59.5% of cases, depending on the index used for its calculation. High proliferation index and high centrosome signature significantly correlates with 70-gene high-risk group (p<0.0001). Conversely, the activation of NF-kB pathway was not significantly different between high- and low- risk subgroups. TC subgroups D1 (p<0.0001) and 11q13 (p=0.01) were significantly more common in the 70-gene low-risk group. Similarly, TC subgroups 4p16 (p=0.0004), Maf (p=0.02) and D2 (p=0.05) were enriched in the high-risk group. Translocations t(4;14)(p16;q32), t(11;14)(q13;q32) and t(14;16)(q32;q23) were precisely predicted by the TC classification (100% correspondence). Cases with IgH translocations with unknown partner were classified in subgroups D1 (33%), D2 (25%), 6p21 (25%) and Maf (16%). Here we summarized the associations between the most significant gene expression indices and signatures relevant to MM risk-stratification. The multiple variables simultaneously analyzed in an automated way, provide a powerful and fast tool for risk-stratification, helping in the therapeutic decision-making. Disclosures: Stewart: Celgene: Consultancy, Research Funding; Millennium: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; BMS: Consultancy, Research Funding; Onyx Pharmaceuticals: Consultancy, Research Funding. Fonseca:Consulting :Genzyme, Medtronic, BMS, Amgen, Otsuka, Celgene, Intellikine, Lilly Research Support: Cylene, Onyz, Celgene: Consultancy, Research Funding.