Overall Survival In Multiple Myeloma Research Articles

A large meta-analysis establishes the role of MRD negativity in long-term survival outcomes in patients with multiple myeloma

AbstractThe prognostic value of minimal residual disease (MRD) for progression-free survival (PFS) and overall survival (OS) was evaluated in a large cohort of patients with multiple myeloma (MM) using a systematic literature review and meta-analysis. Medline and EMBASE databases were searched for articles published up to 8 June 2019, with no date limit on the indexed database. Clinical end points stratified by MRD status (positive or negative) were extracted, including hazard ratios (HRs) on PFS and OS, P values, and confidence intervals (CIs). HRs were estimated based on reconstructed patient-level data from published Kaplan-Meier curves. Forty-four eligible studies with PFS data from 8098 patients, and 23 studies with OS data from 4297 patients were identified to assess the association between MRD status and survival outcomes. Compared with MRD positivity, achieving MRD negativity improved PFS (HR, 0.33; 95% CI, 0.29-0.37; P < .001) and OS (HR, 0.45; 95% CI, 0.39-0.51; P < .001). MRD negativity was associated with significantly improved survival outcomes regardless of disease setting (newly diagnosed or relapsed/refractory MM), MRD sensitivity thresholds, cytogenetic risk, method of MRD assessment, depth of clinical response at the time of MRD measurement, and MRD assessment premaintenance and 12 months after start of maintenance therapy. The strong prognostic value of MRD negativity and its association with favorable outcomes in various disease and treatment settings sets the stage to adopt MRD as a treatment end point, including development of therapeutic strategies. This large meta-analysis confirms the utility of MRD as a relevant surrogate for PFS and OS in MM.

Lnc NEAT1/miR-29b-3p/Sp1 form a positive feedback loop and modulate bortezomib resistance in human multiple myeloma cells

The overall survival of multiple myeloma (MM) patients significantly improved with the use of proteasome inhibitor such as bortezomib. However, resistance to sorafenib limits its use. Bortezomib-resistant MM cells were generated and their bortezomib-resistant properties were confirmed by cell viability and apoptosis assays. To explore functions and underlying mechanisms of long non-coding RNA nuclear paraspeckle assembly transcript 1 (NEAT1) on bortezomib resistance in MM, MTT assays, flow cytometry analyses, dual luciferase report gene assays, RNA pulldown assays and chromatin immunoprecipitation assays were carried out. NEAT1 and specific protein 1 (Sp1) was upregulated while miR-29b-3p was down regulated in bortezomib-resistant MM cells. NEAT1 promoted Sp1 expression by sponging miR-29b-3p and then enhanced the tolerance of MM cells to bortezomib. Sp1 targeted to NEAT1 promoter region promoting NEAT1 transcription and formed a positive feedback loop. NEAT1 and Sp1 levels were higher and miR-29b-3p was levels were lower in bortezomib-resistant MM patients. NEAT1/miR-29b-3p/Sp1 feedback loop enhanced the tolerance of MM cells to bortezomib. These results indicate potentially valuable targets for overcoming bortezomib resistance for MM.

Monoclonal Protein Response Trajectory and Survival in Newly Diagnosed Multiple Myeloma: A Retrospective Cohort Study

Background: Multiple myeloma is a heterogenous plasma cell cancer characterized by expression of a monoclonal protein (M-protein) or free light chains (FLC). Although survival has improved over the past 15 years, outcomes are variable and not fully predicted by conventional prognostic markers. Survival is associated with depth and duration of response to treatment but it is not known if the trajectory of response is associated with survival. We hypothesized that the trajectory of M-protein over the first six months of treatment in patients with newly diagnosed multiple myeloma can identify distinct clinical groups and is an independent predictor of overall survival (OS). The objectives of our study are to: 1) Identify groups of patients with different M-protein trajectories using trajectory analysis; 2) Evaluate patient and illness factors associated with different M-protein trajectories; and 3) Determine whether M-protein trajectory is an independent predictor of OS in newly diagnosed multiple myeloma. Methods: We conducted a retrospective cohort review of all patients with newly diagnosed multiple myeloma in Manitoba between 2012 and 2017 who had a measurable M-protein at presentation and who were initially treated with bortezomib-based chemotherapy. Baseline characteristics and monthly response assessments up to six months were collected and analyzed using trajectory analysis. We used latent class mixed models (LCMM) to produce trajectory groups of M-protein response over time. We used the Bayesian Information Criterion and clinical validity characteristics to select the optimal trajectory model. We developed a multinomial logistic model to evaluate the association of patient and illness characteristics with M-protein trajectories. We constructed a multivariable Cox proportional hazard model adjusted for trajectory group, ISS stage, transplant status, LDH, renal failure and platelet count to evaluate the association of M-protein trajectory on OS in multiple myeloma. Results: 266 patients were included in the trajectory analysis. 154 (57.9%) were male. Mean age was 66.4 years (SD 10.1). 29 (10.9%) were classified as ISS stage 1, 80 (30.1%) as ISS stage 2, and 109 (41.0%) as ISS stage 3. The best fit trajectory model identified three trajectory groups representing distinct M-protein trajectories over time (Figure 1). We plotted the trajectory of the absolute value for M-protein as the percentage change from baseline did not separate the population into distinct groups. Baseline bone marrow plasma percentage (p&amp;lt;0.01), albumin (p&amp;lt;0.01), and hemoglobin (p&amp;lt;0.01) were significantly associated with trajectory group membership. The median follow-up was 2.74 years for the OS analysis. The median OS was not reached for the low group, 4.3 years for the moderate group, and 5.4 years for the high group. In a multivariable Cox proportional hazard model, we found that trajectory group was not significantly associated with OS (moderate group HR 1.18, 95%CI 0.48-2.91, high group HR 1.10, 95%Cl 0.62-1.88). Variables significantly associated with OS included ISS stage (p&amp;lt;0.025), LDH (p&amp;lt;0.022), platelet count (p&amp;lt;0.001), and receipt of a stem cell transplant (p&amp;lt;0.001). Discussion and Conclusions: In this retrospective cohort study of patients with newly diagnosed multiple myeloma, we identified three distinct groups based on their M-protein trajectory over time. The identified groups have different mean baseline M-protein values and follow different evolutionary patterns over time. While M-protein trajectory group was not associated with differences in OS, the small sample size and short follow-up may limit interpretation of the results. Our analyses only looked at the M-protein trajectory over the first six months after treatment start, which indicates an early response to treatment. It is possible this early response does not play a large role in the OS of patients with myeloma given the mutliple lines of chemotherapy they may receive. Further studies are planned to assess the achievement of a complete remission at one year or at renal recovery for patients affected with renal involvement. Alternative uses for M-protein trajectory analysis include the trajectory of M-protein prior to relapse or in patients with smoldering myeloma to identify who may benefit from earlier treatment. Disclosures Kotb: Takeda: Honoraria; Merck: Honoraria, Research Funding; Sanofi: Research Funding; Celgene: Honoraria; Janssen: Honoraria; Amgen: Honoraria; Karyopharm: Current equity holder in publicly-traded company.

Association between Spending in Oncology Care Model-Defined Episodes and Overall Survival in Multiple Myeloma Using 2012-2017 Medicare Data

Introduction: The Oncology Care Model (OCM) is an innovative payment model introduced by the Centers for Medicare &amp; Medicaid Services in 2016, which aims to improve quality and reduce the cost of cancer care. Under this framework, practices are incentivized to reduce spending in chemotherapy-centered episodes. Previous studies using data from pre-OCM periods (i.e. before July 1, 2016) suggested that reducing OCM episode costs, particularly disease-specific drug costs, may adversely affect overall survival (OS) in patients with multiple myeloma (MM). Using more recent data that covers 1.5 years after OCM implementation, the current study aimed to evaluate trends in OCM-defined episode costs and OS over time. Additionally, the association between OCM-defined MM episode costs and OS in MM, as well as changes in the association between the pre- and post-OCM periods, were evaluated. Methods: Patients with newly diagnosed MM (NDMM) and ≥ 1 qualifying OCM-defined MM episode between 2012 and 2017 were selected from the 100% Medicare data. OCM episodes were defined as the 6-month period following a triggering MM treatment claim. Each episode was linked to a practice and classified based on participation in the OCM and occurrence of pre- versus post-OCM implementation. Regression models were developed, based on the OCM algorithm, to adjust for case severity mix at the practice level. The models evaluated the impact of patient and episode characteristics on total episode costs, and episode subcomponents (e.g. MM-specific drugs, other medical treatment). Based on the regression outputs, standardized costs were calculated for each practice, adjusting for differences in patient and episode characteristics. All costs were inflated to 2017 US dollars (USD). From initial MM diagnosis, mean unadjusted episode costs, mean standardized episode costs, and 1-year OS rate were described over time by the year of first episode initiation. Two Cox proportional hazards models were constructed for OS with adjustment for key patient covariates (i.e. age, gender, comorbidity index, race, number of OCM episodes, and disability entitlement). Model 1 evaluated the association between OS and standardized total episode costs and the proportion of episode costs attributed to MM-specific drugs. Model 2 evaluated the effect on OS of the interaction between the time period (i.e. pre-OCM vs post-OCM) and total standardized episode costs. The analyses were repeated for key patient subgroups stratified by comorbidity status (i.e. low Charlson Comorbidity Index [CCI] vs high CCI) and practice type (i.e. OCM vs non-OCM). Results: A total of 17,363 patients with NDMM (51.0% male) were included in the analysis. Mean age at diagnosis was 74.8 years (30.0-102.0). Patient characteristics were comparable between pre-OCM and post-OCM periods. There were a total of 41,972 OCM episodes during the mean 2.2 years (standard deviation [SD] 1.4) of follow-up. Average (SD) MM-drug costs, other medical and drug costs, and total costs per OCM episode were USD 51,482 (USD 31,752), USD 22,625 (USD 28,452), and USD 74,107 (USD 38,606), respectively. From 2012 to 2017, average total episode costs, MM-drug costs, and survival all increased (Table). Model 1 indicated that a USD 10,000 increase in standardized total costs was associated with a 27.5% lower risk of death (hazard ratio [HR] 0.725; P &amp;lt; 0.05) and that MM-drug costs were the primary driver for the improved OS. The hazard of death decreased by 21.3% (HR 0.787; P &amp;lt; 0.05) for every 10% increase in the proportion of costs attributed to MM-drug costs versus other medical costs. Model 2 showed the association was similar during pre-OCM and post-OCM periods. Consistent results were observed between subgroups of high versus low CCI and OCM versus non-OCM practices. Conclusions: The analysis identified a positive correlation between average spending within OCM-defined episodes and OS among patients with NDMM, demonstrating observable clinical value for patients. This correlation remained consistent across pre-OCM and post-OCM periods. A closer evaluation of the cost subcomponents suggested that MM-specific drug costs are a primary driver for the observed OS benefit. Patient benefit from the innovative, albeit higher cost, therapies is noteworthy given the improved survival of MM. Careful evaluation is warranted for healthcare providers when attempting to reduce spending in response to new payment models. Disclosures Niesvizky: BMS: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Karyopharm: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Janssen: Consultancy, Honoraria. Clancy:BMS: Current Employment, Current equity holder in publicly-traded company. Copher:Bristol Myers Squibb: Current Employment. Thomas:BMS: Current Employment. Qi:BMS: Other: Employee of Analysis Group Inc., which received consulting fees; Astellas Pharma, Inc.: Research Funding. Zhou:BMS: Other: Employee of Analysis Group Inc., which received consulting fees. Zichlin:BMS: Other: Employee of Analysis Group Inc., which received consulting fees. Koenigsberg:BMS: Other: Employee of Analysis Group Inc., which received consulting fees. Signorovitch:BMS: Other: Employee of Analysis Group Inc., which received consulting fees.

Early Mortality in Patients with Multiple Myeloma Treated with Novel Agents - Analysis from Polish Myeloma Study Group

Background Although the introduction of novel agents improved the survival outcomes in patients with multiple myeloma (MM), some patients died within one year (early mortality, EM) following diagnosis. In this study, we evaluated the EM rate, and investigated the risk factors associated with EM in MM patients. Aims In this study we investigated risk factors associated with EM in MM patients initially treated with novel-agent containing regimen. Methods We conducted a multicenter (15 Polish sites) retrospective study a cohort of symptomatic MM pts diagnosed between October 2006 and November 2019 and living &amp;lt; 365 days (d) after diagnosis. All pts were dead at the time of the analysis. Data were collected from medical registries and databases. Mortality rate and cause at 2, 6, and 12 months following diagnosis was evaluated. Clinical staging was performed using the International Staging System (ISS). Response to treatment was evaluated according to the International Myeloma Working Group (IMWG) consensus criteria (2016). Statistical analysis was performed using R-studio v.1.3.959. and significant levels were set at p&amp;lt;0.05. Results Of the 197 pts were included in the study, 112 (57%) male and the median age at diagnosis was 69 y (41-91). The MM type of 100 patients (52%) was Immunoglobulin (Ig) G, 24% of patients was IgA, 15% of patients had light chain disease, and 3% of patients IgM or IgD. At diagnosis, renal impairment (RI) was present in 43%, extramedullary disease (EMD) in 15% of the pts; 15% were in stage I, 10% in stage II, 60% in stage III (ISS) and 15% not done. Fluorescent in situ hybridization analysis was performed in 59 pts, 69% presenting high-risk cytogenetic abnormalities (HRC) [t(4;14), t(14;16), t(14;20) or del17p]. 54% pts were &amp;gt;2 comorbidities at diagnosis. Heart disease was presented at diagnosis in 57% pts and diabetes in 22% pts. First-line treatment (1stL), 41% of the pts patients were bortezomib-based (Bor) regimens, 25% Bor with thalidomide (VT)-based, 22% IMiD-based and 13% others. Response evaluation showed an overall response rate (ORR) of 44% (3% CR; 14% VGPR; 27% PR). 46% pts survived &amp;lt; 2 months, 29%; 2-6 months and 25%: 6-12 month. Median time until death was 2.5 month; 31% of pts died directly from progression disease (PD), and 69% from other causes [infection in 66%, cardiovascular complications in 27%, RI in 8%]. In our study, age &amp;gt; 65 y (HR 1.67; 95% CI 1.24-2.26; p=0.0007), and &amp;gt;75 y (HR 1.5; 95% CI 1.10-2.03; p=0.0087), &amp;gt;2 comorbidities (p=0.002), heart disease (HR 2.12; 95% CI 1.57-2.85; p &amp;lt; 0.0001), RI (HR 0.7; 95% CI 0.53-0.95; p=0.029), dependence of dialysis (HR 1.50; 95% CI 1.05-2.14; p=0.029) were associated with increased risk of death. Mortality predictive value showed HRC (p=0.05), lactate dehydrogenase levels (HR 0.65; 95% CI 0.38-1.1; p=0.002), and &amp;gt;PR (HR 0.30; 95% CI 0.21-0.43; p&amp;lt;0.0001). Moreover, sex, hypertension, diabetes, type of MM, extramedullary disease, ISS stage, hemoglobin level, count of platelets didn't show a mortality predictive value. Conclusions IMWG response criteria are not adequate to predict short-term outcome in the era of novel agents. Infections and refractory disease were the leading contributors to early death in our pts cohort. These data may provide new opportunities to define patient-adapted treatment strategies in order to decrease EM and improve overall survival in MM. Disclosures Wrobel: BMS/Celgene: Membership on an entity's Board of Directors or advisory committees; Novartis: Honoraria; Roche: Research Funding; Janssen: Honoraria. Robak:Abbvie, Pharmacyclics, Gilead, GlaxoSmithKline, Novartis, Janssen, F. Hoffmann-La Roche, Acerta, AstraZeneca, BioGene, UCB: Research Funding; F. Hoffmann-La Roche, Abbvie, Pharmacyclics, Novartis, Janssen, Acerta, AstraZeneca, BioGene, UCB, Sandoz: Honoraria. Robak:Bristol Meyers Squibb: Research Funding; Roche: Consultancy, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Novartis: Honoraria, Research Funding; Takeda: Consultancy; GSK: Research Funding; UTX-TGR: Research Funding; Acerta: Research Funding; BioGene: Honoraria, Research Funding; Morphosys: Research Funding; Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Octapharma: Honoraria; AbbVie: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES (paid by any for-profit health care company), Research Funding; Medical University of Lodz: Current Employment; UCB: Honoraria, Research Funding; Pfizer: Research Funding; Momenta: Consultancy; Sandoz: Consultancy, Honoraria; Pharmacyclics LLC, an AbbVie Company: Honoraria, Research Funding; AstraZeneca: Honoraria, Research Funding.

Impact of the Availability of Novel Drugs on Overall Survival of Multiple Myeloma Patients: A Real-World Study

Introduction: Multiple myeloma is an incurable hematologic malignancy. However, many novel drugs (lenalidomide, carfilzomib, daratumumab, elotuzumab and ixazomib) have recently been approved in Brazil for this disease. Proving that the availability of these drugs increases survival is not straightforward, since pivotal trials with these drugs were designed to show benefit in progression-free survival and not in overall survival. Hypothesis: We have hypothesized that the availability of novel drugs would reduce the risk of death. Methods: This is a real-world, unicenter analysis that included patients with multiple myeloma treated between 1993 and 2017. The availability of novel drugs (lenalidomide, carfilzomib, daratumumab, elotuzumab and ixazomib) was treated as a time-dependent covariate and analyzed by Cox model. The analysis was controlled for the International Staging System (ISS) and for age. Results: With a median follow-up of 6 years, we included 151 patients with multiple myeloma. Fourty percent had ISS-I, 34% ISS-II and 26% ISS-III. Mean age was 60.5 y/o (SD: 12.2). There has been 51 deaths, and 5-y overall survival was 90% for ISS-I, 80% for ISS-II and 54% for ISS-III (p=0.0004). In multivariable analysis, age (HR=1.06, p&amp;lt;0.0001) and ISS-III (HR=4.51, p&amp;lt;0.0001) were risk factors for death, while the availability of two or more novel drugs was protective (HR=0.31, p=0.006). The availability of a single novel drug was also protective (HR=0.58), although it did not reach statistical significance (p=0.13). Adjusted Simon-Makuch survival plot is in figure 1 (adjusted for ISS III and 60 y/o). Discussion: Our results show that the availability of two or more novel drugs increases overall survival in multiple myeloma. This is an important finding, since the pivotal trials were designed to show advantages in progression-free survival and, once achieved, the experimental drug was offered to the control group, hampering overall survival analyses. Overall survival benefit, therefore, are more likely to be seen in real-world studies. We included the availability of novel drugs as a time-dependent, and the interpretation of our results is that patients alive when two novel drugs became available had benefit in overall survival. Our study has two weaknesses. Two or more novel drugs were more likely to be available for patients from a more recent time. This difference could be due to changes in supportive care, but there has been no major change in supportive care for multiple myeloma patients. Another weakness is that patient alive in the more recent years may have not received novel drug-based treatment. Considering that multiple myeloma is an incurable disease, this is unlikely for the majority of patients. In conclusion, the availability of two or more novel drugs for multiple myeloma improves survival. Figure Disclosures No relevant conflicts of interest to declare.

The Prognostic Significance of Acquired 1q22 Gain in Multiple Myeloma

The Prognostic Significance of Acquired 1q22 Gain in Multiple Myeloma

Impact of autologous stem cell transplantation on long term renal function and associated progression-free and overall survival in multiple myeloma

The long-term impact of Autologous hematopietic stem cell transplantation (ASCT) on renal function, and the impact of renal function on progression-free survival (PFS) and overall survival (OS) in patients with multiple myeloma are not known. We retrospectively reviewed the records of 885 patients at our institution. We used linear mixed effect models to study the change in estimated glomerular filtration rate (eGFR) and a joint model approach to assess associations between the eGFR, PFS and OS. Sensitivity analyses were conducted at days 0, 100, 180, and 365 post-SCT. eGFR post-ASCT was significantly lower than at day 0 but stabilized at approximately 80 mL/min/1.73 m2. There was no association between eGFR and PFS or OS.; However, relapsed disease and ISS stage were associated with shorter PFS and OS. This data suggests that although there is a modest decline in eGFR post-ASCT, it is not associated with an adverse impact on PFS or OS. KEY POINTS Advanced MM stage at diagnosis was associated with reduced eGFR at all stages of chronic kidney disease. eGFR was not associated with PFS or OS in any of the analyses, but disease-related factors prior to ASCT were all associated with reduced eGFR, PFS and OS. ASCT did not adversely impact kidney function and mitigated the risk of CKD on outcomes in MM.

Association of elevated red cell distribution width and overall survival in multiple myeloma.

8534 Background: The most widely used multiple myeloma (MM) staging system, the Revised International Staging System (R-ISS), is based on lactate dehydrogenase, albumin, cytogenetics, and beta-2 microglobulin (B2M). B2M has limited clinical utility, is often only obtained to compute R-ISS, and is often a send-out test. Prior studies have shown that elevated red cell distribution width (RDW), a common test that is part of the routine complete blood count, is associated with reduced overall survival (OS) in MM. We hypothesized that a MM staging system could be constructed replacing B2M with RDW. Methods: Patients treated at Vanderbilt University Medical Center from 2000 to 2018 with cancer registry-confirmed MM diagnoses were included. OS was computed by registry-curated death and diagnosis dates; living patients were censored at date last known alive or of last follow up. A Cox proportional hazards model determining the independent effects of R-ISS, age, and RDW on OS was built. An alternate staging system (RDW-SS) was developed, replacing the B2M cutoffs in R-ISS with RDW (stage 1: RDW &lt; 14.0% stage 2: RDW 14.0-15.5%; stage 3: RDW &gt; 15.5%). Cox models comparing RDW-SS and R-ISS after adjustment for age and category of induction therapy (proteasome inhibitor [PI] and immunomodulatory drug [IMiD]), PI only, IMiD only, other) were built. Results: In 604 MM patients with available data, RDW was independently associated with OS after adjustment (HR = 1.069 per 1% RDW increase, p &lt; 0.001). RDW-SS stages were associated with reduced OS (RDW-SS 2 HR 1.52, 95% CI 1.09 – 2.11, p = 0.01; RDW-SS 3 HR 2.13, 95% CI 1.37 – 3.28, p &lt; 0.001) after adjustment; R-ISS stages were not (Table). Conclusions: RDW at MM diagnosis was independently associated with reduced OS, after adjustment for the clinical factors of age and treatment exposure; notably, R-ISS was not. The RDW-SS is simpler to obtain than R-ISS and may have improved prognostic value pending independent validation. If confirmed, mechanistic study of the etiology of this relationship is warranted. [Table: see text]

Lenalidomide maintenance after second autologous stem cell transplant improves overall survival in multiple myeloma

Maintenance therapy after first autologous transplant (autoSCT) improves progression-free survival (PFS) and overall survival (OS) in multiple myeloma (MM). However, efficacy of maintenance therapy after second autoSCT is unknown. We retrospectively evaluated outcomes of 111 adult MM patients who underwent second autoSCT between January 2000 and December 2018. Lenalidomide up to 15 mg daily or subcutaneous bortezomib 1.3 mg/m2 every 2 weeks was considered maintenance therapy. Outcomes were compared among three groups: no-maintenance (n = 73), lenalidomide (n = 23), and bortezomib maintenance (n = 15). At a median follow-up of 58 months from second autoSCT for survival, 3-year PFS and OS for no-maintenance, lenalidomide, and bortezomib maintenance were 11.2%, 29.9%, and 0%, respectively; and 58.5%, 83.3%, and 67.5% respectively. Lenalidomide maintenance was associated with improved PFS (HR 0.46, p = 0.009) and OS (HR 0.25, p = 0.009) compared to no-maintenance. Lenalidomide maintenance therapy after second autoSCT appears to prolong PFS and OS.

Bortezomib Treatment Modulates Autophagy in Multiple Myeloma.

Although the introduction of bortezomib as a therapeutic strategy has improved the overall survival of multiple myeloma (MM) patients, 15–20% of high-risk patients do not respond to bortezomib over time or become resistant to treatment. Therefore, the development of new therapeutic strategies, such as combination therapies, is urgently needed. Methods: Given that bortezomib resistance may be mediated by activation of the autophagy pathway as an alternative mechanism of protein degradation, and that an enormous amounts of misfolded protein is generated in myeloma plasma cells (PCs), we investigated the effect of the simultaneous inhibition of proteasome by bortezomib and autophagy by hydroxychloroquine (HCQ) treatment on PCs and endothelial cells (ECs) isolated from patients with monoclonal gammopathy of undetermined significance (MGUS) and MM. Results: We found that bortezomib combined with HCQ induces synergistic cytotoxicity in myeloma PCs whereas this effect is lost on ECs. Levels of microtubule-associated protein light chain beta (LC3B) and p62 are differentially modulated in PCs and ECs, with effects on cell viability and proliferation. Conclusions: Our results suggest that treatment with bortezomib and HCQ should be associated with an anti-angiogenic drug to prevent the pro-angiogenic effect of bortezomib, the proliferation of a small residual tumor PC clone, and thus the relapse.

A Discrete Event Simulation Model to Evaluate the Impact of Treatment Sequences on Long-Term Patient Outcomes in Multiple Myeloma (MM)

Purpose: Many new therapies have been approved for the treatment of multiple myeloma (MM) in recent years. In June 2019, daratumumab (Darzalex®), a CD38-directed monoclonal antibody, in combination with lenalidomide and dexamethasone (DRd), received FDA approval for the treatment of newly diagnosed MM (NDMM) patients ineligible for stem cell transplantation. This approval provides NDMM patients with a new option as first-line therapy, however, with many options for MM treatment available, identification of the optimal sequence of treatments becomes of critical importance to healthcare providers and payers. Objective: To develop a treatment sequencing discrete event simulation (DES) model that compares unique treatment sequences and estimates the impact of first-line DRd on longer-term outcomes (i.e. survival through multiple lines of therapy) in a general population of MM patients. Methods: A DES model of MM treatment sequences was developed. FDA approved and NCCN recommended non-transplant therapies were included. Treatment efficacy was estimated by digitizing and extrapolating progression-free and overall survival (OS) Kaplan-Meier (KM) data, using established methods (Guyot et al., 2012). Five common parametric functions were fit, and the curve-of-best-fit was determined by standard statistics (i.e., Akaike &amp; Bayesian information criterion) and visual inspection. The model was developed to allow patients to go through up to 6 lines of treatment. The time of progression and death events were randomly assigned based on the estimated parametric functions. All-cause mortality data (US Census 2016) were considered in the simulation of survival. Where data were not available, previous therapies were assumed not to impact the efficacy of subsequent therapies. Model survival predictions were validated against published real-world estimates of survival from: 1) a retrospective analysis of a large American electronic medical record database, Humedica (Hari et al., 2018) and 2) a retrospective analysis of the Dutch PHAROS registry (Verelst et al., 2017). The Humedica and PHAROS datasets reported on the effects of three and four lines of treatment, respectively, starting with newly diagnosed patients. From the Humedica dataset, first-line therapy consisted of proteasome inhibitor- (PI), immunomodulatory- (IMiD), and PI + IMiD-based regimens in 42%, 34% and 18% of patients, respectively, with other regimens used in 7% of cases. Treatment was primarily doublets (63%) rather than triplets (37%). From the PHAROS registry, first-line therapy was primarily thalidomide-based (66%), bortezomib-based (15%), or lenalidomide-based (7%). Statistically, validation was quantified through the calculation of the mean absolute percent error (MAPE), a commonly used statistic to assess the accuracy of forecasts. To estimate the impact of first-line DRd, a hypothetical analysis was simulated wherein all first-line treatments described within both the Humedica and PHAROS datasets were replaced with DRd. Following DRd, patients received subsequent treatment as described within those datasets. Results: Restriction of the modeled treatment algorithm to treatment patterns described within the Humedica database and PHAROS registry led to valid simulated OS estimates that were in line with the published data (MAPE values of 9% and 19% for Humedica and PHAROS, respectively). Utilization of DRd as first-line treatment was estimated to increase OS in scenario analyses (Table 1). The DES model estimated 5-year survival rates for frontline DRd with subsequent therapy based upon the Humedica and PHAROS datasets were 62% and 57%, respectively. In contrast, the estimated 5-year survival for the Humedica and PHAROS datasets without DRd frontline was 40% and 26% respectively, highlighting a 22-31% incremental survival benefit due to DRd at 5-years. Conclusions: The MM DES model validated well to the published estimates of real-world OS. Preliminary results indicate that first-line treatment with DRd may improve OS in MM compared with historical treatment sequences, that include PI+IMiD based triplets as first-line treatment. The model is being further developed to describe the impact of sequencing other MM treatment regimens to estimate the optimal treatment pathways. Disclosures Liu: Janssen Scientific Affairs, LLC: Employment, Equity Ownership. Moldaver:Janssen Scientific Affairs, LLC: Consultancy. Zhu:Janssen Scientific Affairs, LLC: Other: contractor for Janssen. Zhou:Janssen Scientific Affairs, LLC: Consultancy. Maiese:Janssen: Employment, Equity Ownership. Hollmann:Janssen Scientific Affairs, LLC: Consultancy.

Interactome Analysis of APOBEC3B in Multiple Myeloma

Apolipoprotein B mRNA-editing enzyme catalytic polypeptide-like (APOBEC) family proteins restrict retroviruses and retrotransposons by inducing hypermutation or degradation of the replication intermediates through their DNA cytidine deaminase activity. APOBECs can also act as endogenous sources of DNA damage that mutate many human cancers. Accumulation of APOBEC signature mutations is associated with disease progression and poor overall survival in multiple myeloma (Walker et al. Nat Commun, 2015). Among APOBEC3 enzymes, APOBEC3B (A3B) is the only family member that is predominantly located in the nucleus throughout the cell cycle. We previously reported that A3B knockdown decreased cytidine deaminase activity in myeloma cells, suggesting that among APOBECs, A3B plays a major role in cytidine deamination-related mutagenesis in myeloma cells (Yamazaki et al., Sci Rep, 2019). Recent studies showed that cofactors of A3B could affect the functions of A3B: heterogeneous nuclear ribonucleoproteins (hnRNPs) interact with surface hydrophobic residues of the N-terminal domain in order to bind to A3B (Xiao et al., Nuc. Acids Res, 2017; Zhang al., Cell Microbiol, 2008); BORF2, an Epstein-Barr viral protein, interacts with the A3B catalytic domain and inhibits A3B DNA cytidine deaminase activity (Cheng et al., Nat Microbiol, 2018). However, the biological mechanisms of how endogenous A3B induces mutations in genomic DNA are still unclear. In this study, we aim to ascertain the cofactors for nucleic acid binding and elucidate the regulatory mechanisms that prevent APOBEC-mediated genomic mutagenesis. Because of the high homology between APOBEC3 proteins, a specific antibody against A3B is not available, and it is difficult to analyze A3B-interaction at the endogenous expression level. To overcome this technical impediment, we used a lentiCRISPR system to insert a FLAG-tag sequence at the C-terminus of the A3B gene in A3B highly expressing myeloma cell lines (AMO1 and RPMI8226). We then conducted A3B-immunoprecipitation with the anti-FLAG M2 antibody, followed by mass spectrometry (MS) analysis to identify potential A3B interacting proteins. MS analysis identified 40 putative interacting proteins and these proteins were clustered largely into two interaction networks: ribonucleoprotein complex and ribosomal-associated proteins. We also performed Gene Ontology (GO) enrichment analysis and revealed that spliceosome, ribosome, and RNA transport were significantly enriched terms. We confirmed the binding between A3B and selected A3B interacting proteins: hnRNPs, interleukin enhancer-binding factor 2 and 3 (ILF2, ILF3) in myeloma cell lines by co-immunoprecipitation assays. Next, we tested the intracellular colocalization of overexpressed A3B and interacting proteins in Hela cells by immunofluorescence microscopy. We found that ILF2 presents strong colocalization with A3B in the nuclei of cells. We also employed density-gradient sedimentation analysis to test if these proteins form high molecular mass (HMM) complexes with A3B in the nucleus using HEK293T cells expressing FLAG-tagged A3B. We detected that ILF2 is one of the components of HMM A3B complexes. To check whether these putative interacting proteins affect A3B cytidine deaminase activity, we next performed an in vitro luminescence-based screening assay (AlphaScreen)using a FLAG-GST protein library which was produced by the wheat cell-free protein production system. We found that hnRNP A1 and ILF2 decreased A3B cytidine deaminase activity. This study provides for the first time a proteomic characterization of A3B interactome in a myeloma cell context. Our findings reveal putative A3B cofactors in myeloma cell lines which may regulate the catalytic activity of A3B. We discuss how these proteins bind A3B and affect its activity in myeloma cells. Disclosures Takaori-Kondo: Pfizer: Honoraria; Janssen: Honoraria; Novartis: Honoraria; Celgene: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Ono: Research Funding; Takeda: Research Funding; Chugai: Research Funding; Kyowa Kirin: Research Funding.

Combined Inhibition of HDAC and AKT As a Strategy to Overcome Multi-Drug Resistance in Patients with Multiple Myeloma

Nowadays, patients with multiple myeloma (MM) have multiple choices of therapy including monoclonal antibodies, proteasome inhibitors, and immunomodulatory drugs (IMiDs), whereas some patients still develop resistance to these drugs and require novel therapeutic modalities. Here, we focused on inhibition of HDAC and AKT to overcome drug resistance. Lenalidomide (Len) selectively binds to cereblon (CRBN), which mediates recruitment of specific substrates like IKZF1 to E3 ubiquitin ligase and subsequent degradation, resulting in downregulation of IRF-4 and c-Myc. Then, we developed Len-resistant myeloma cells by RNAi-mediated downregulation of CRBN. Treatment of these cells with HDAC inhibitors reduced IKZF1 mRNA, suggesting potential efficacy of HDAC inhibitors against CRBN-low expressing or mutated MM. According to the integrated database for expression profile and disease prognosis (GenomicScape, http://www.genomicscape.com), higher expression of MICA was significantly associated with better overall survival in MM. MICA is an NK cell-activating ligand and plays an important role in ADCC. We observed that ADCC activity of both daratumumab and elotuzumab against MM cells was enhanced in the presence of HDAC inhibitors, which was compatible with our previous data that HDAC inhibitors upregulated MICA mRNA expression via inhibition of IKZF1 (ASH2018 abstract #4435). We also observed that HDAC inhibitors upregulated MICA mRNA in CRBN-deficient cells, suggesting promise of the combination of HDAC inhibitors and monoclonal antibodies against Len-resistant MM. Len-resistance is also affected by phosphorylation status of GSK-3. PI3K/AKT pathway is frequently activated in MM cells, and AKT inactivates GSK-3 by direct phosphorylation, resulting in c-Myc stabilization. Enhanced phosphorylation of GSK-3 was observed in CRBN-deficient H929 cells after long-term culture with Len, and such a phosphorylation status of GSK-3 was correlated with less CRBN amount and higher Len concentration (Figure 1). Afuresertib, an AKT inhibitor, suppressed GSK-3 phosphorylation (p-GSK-3) with or without ACY-1215, an HDAC inhibitor, leading to a substantial decrease of c-Myc (Figure 2). On the other hand, CHIR 99021, a GSK-3 inhibitor, partially counteracted to cytotoxic effect of afuresertib on H929 cells (Figure 3). These results suggest that increased p-GSK-3 is involved in acquired Len-resistance, and that combined inhibition of HDAC and AKT can overcome Len-resistance through decreased p-GSK-3. Furthermore, we examined the efficacy of CUDC-907, a dual HDAC and PI3K inhibitor. CUDC-907 had a cytotoxic effect on the MM cell lines including those had low CRBN expression. Bortezomib, doxorubicin, and dexamethasone resistant MM cell lines were also sensitive to CUDC-907. CUDC-907 upregulated MICA mRNA expression, but downregulated IKZF1 mRNA expression. Treatment of RPMI-8226 cells with CUDC-907 enhanced the ADCC activity of daratumumab (Figure 4). Furthermore, CUDC-907 was effective on primary MM cells which were resistant to bortezomib and Len (Figure 5). Thus, dual inhibition of HDAC and AKT with or without monoclonal antibodies is a promising therapeutic approach to multi-drug resistant MM. Disclosures Imai: Celgene: Honoraria, Research Funding; Janssen Parmaceutical K.K.: Honoraria, Research Funding; Bristol-Myers Squibb: Research Funding. Futami:Torii Pharmaceutical: Research Funding. Ri:Janssen Pharmaceutical: Honoraria, Research Funding; Takeda Pharmaceutical: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Daiichi Sankyo: Research Funding; Ono Pharmaceutical: Honoraria, Research Funding; Kyowa Kirin: Research Funding; Chugai Pharmaceutical: Research Funding; Sanofi: Honoraria, Research Funding; Abbvie: Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; MSD: Research Funding; Novartis Pharma: Research Funding; Gilead Sciences: Research Funding; Astellas Pharma: Research Funding; Teijin Pharma: Research Funding. Yasui:TokioTHERA Holdings, Inc.: Equity Ownership. Iida:Teijin Pharma: Research Funding; Celgene: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Astellas: Research Funding; Gilead: Research Funding; Sanofi: Research Funding; MSD: Research Funding; Abbvie: Research Funding; Kyowa Kirin: Research Funding; Chugai: Research Funding; Novartis: Honoraria, Research Funding; Bristol-Myers Squibb: Honoraria, Research Funding; Daichi Sankyo: Honoraria, Research Funding. Tojo:Torii Pharmaceutical: Research Funding; AMED: Research Funding.

Moffitt Cancer Center 2-Year Single-Institution Experience with Next-Generation Sequencing Minimal Residual Disease Detection: Clinical Utility, Application, and Correlation with Outcomes in Plasma Cell and Lymphoid Malignancies

Moffitt Cancer Center 2-Year Single-Institution Experience with Next-Generation Sequencing Minimal Residual Disease Detection: Clinical Utility, Application, and Correlation with Outcomes in Plasma Cell and Lymphoid Malignancies

Phase 2 Trial of LDE225 and Lenalidomide Maintenance Post Autologous Stem Cell Transplant for Multiple Myeloma

Background: Lenalidomide maintenance therapy post-autologous stem cell transplantation (ASCT) is associated with improved progression-free survival (PFS) and possibly overall survival in multiple myeloma (MM). However, almost all patients do relapse as a result of residual multiple myeloma cells that remain after the high-dose chemotherapy. In the myeloma setting it has been found that the hedgehog (Hh) pathway is essential for maintaining a subset of tumor causing stem cells. LDE 225 (Sonidegib) is a potent selective oral bioavailable antagonist of Smoothened (SMO), a component of the Hh signaling pathway. In in vitro experiments, LDE225 treatment of myeloma cell lines resulted in a modest inhibition of cell proliferation at increasing doses. When LDE225 was combined with lenalidomide, a more than additive effect was observed in terms of cell proliferation, an effect that was more pronounced in the context of myeloma cell lines growing in co-culture with marrow derived stromal cells. These findings form the basis of evaluation of LDE 225 as a strategy to enhance the activity of lenalidomide in the post-transplant maintenance setting. The minimal residual state post SCT provides the most optimal situation for evaluation of a drug that is likely to work by inhibiting the tumor cells that escaped high dose therapy. Methods: Multiple myeloma patients without evidence of progression, who were 60 - 120 days after a single autologous stem cell transplant (SCT), performed within 1 year of diagnosis were eligible for the study. Maintenance therapy was started approximately 3 months after SCT. Treatment consisted of lenalidomide 10 mg days 1-21 and LDE225 400 mg days 1-28 in 28-day cycles for a total of 18 cycles. The goal of the study was to assess toxicity of this combination, complete response rate (CR) progression free survival (PFS) at 1 and 2 year and overall survival (OS). CR and PFS were estimated using an exact binomial distribution and Kaplan Meier curves respectively. Results: A total of 28 patients were accrued from Jan 2014 to Aug 2016, 1 patient canceled prior to treatment and 1 patient was deemed ineligible resulting in 26 evaluable pts for CR and PFS. The median age of all pts (n=26) was 60 years (range 43-69) and 50% were males. Seventy-three percent of patients reported one treatment regimen prior to SCT, while 27% reported 2 or more prior regimens. The other characteristics of the patient are summarized in Table 1. Twenty seven pts received at least one cycle of treatment and are evaluable for toxicities (AE). Patients were treated for a median of 12.5 (range 1-18) cycles. While 10 pts (38.5%) completed protocol treatment (18 cycles), the remaining 16 pts went off treatment due to AEs (6, 23%), disease progression (3, 11.5%), refusal of further treatment (3, 11.5%) and other reasons (4, 15.4%). A grade 3 or higher AE at least possibly attributed to either drug was seen in 63%. Grade 3+ hematologic toxicities were noted in 30%, with 7% neutropenia and 4% thrombocytopenia. Notable grade 2+ non-hematologic toxicities with more than 5% incidence were dysgeusia 22%, alopecia 11%, and anorexia 7%. Grade 3+ non-hematologic toxicities were fatigue, myalgia and arthralgia each at 7%. The CR rate in evaluable patients was 46% (5 CRs and 7 sCRs) with a 95% CI of 27% - 66%. CR rate improved from 31% to 46%. VGPR or better improved from 42% to 85%. The 24-month PFS (time from SCT to progression or death due to any cause) was 73% (95% CI: 57.9 - 92.3%) with a median time to censoring of 38 months. Conclusion: Lenalidomide in combination with LDE225 as posttransplant maintenance therapy was associated with some toxicity but manageable. The combination improved the depth of response after autologous stem cell transplant. Long-term follow-up is needed to determine overall survival. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Celgene: Research Funding; Takeda: Research Funding; Pfizer: Research Funding; Janssen: Consultancy; Intellia: Consultancy; Akcea: Consultancy; Alnylam: Research Funding. Gertz:Ionis: Honoraria; Alnylam: Honoraria; Prothena: Honoraria; Celgene: Honoraria; Spectrum: Honoraria, Research Funding; Janssen: Honoraria. Kapoor:Glaxo Smith Kline: Research Funding; Amgen: Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Celgene: Honoraria; Sanofi: Consultancy, Research Funding. Dingli:alexion: Consultancy; Janssen: Consultancy; Millenium: Consultancy; Rigel: Consultancy; Karyopharm: Research Funding. Russell:Imanis: Equity Ownership. Kumar:Janssen: Consultancy, Research Funding; Takeda: Research Funding; Celgene: Consultancy, Research Funding. OffLabel Disclosure: Sonidegib (LDE 225) is a selective oral bioavailable antagonist of Smoothened (SMO), a component of the hedgehog signaling pathway.

Metaphase Cytogenetics for Risk Stratification in Newly Diagnosed Multiple Myeloma

Introduction: Abnormal metaphase cytogenetics are associated with inferior survival in newly diagnosed multiple myeloma (MM). These abnormalities are only detected in one third of cases due to the low proliferative rate of plasma cells. It is unknown if metaphase cytogenetics improve risk stratification when using contemporary prognostic models such as the revised international staging system (R-ISS), which incorporates interphase fluorescence in situ hybridization (FISH). Aims: The aims of this study were to 1) characterize the association between abnormalities on metaphase cytogenetics and overall survival (OS) in newly diagnosed MM treated with novel agents and 2) evaluate whether the addition of metaphase cytogenetics to R-ISS, age, and plasma cell labeling index (PCLI) improves model discrimination with respect to OS. Methods: We analyzed a retrospective cohort of 483 newly diagnosed MM patients treated with proteasome inhibitors (PI) and/or immunomodulators (IMID) who had metaphase cytogenetics performed prior to initiation of therapy. Abnormal metaphase cytogenetics were defined as MM specific abnormalities, while normal metaphase cytogenetics included constitutional cytogenetic variants, age-related Y chromosome loss, and normal metaphase karyotypes. Multivariable adjusted proportional hazards regression models were fit for the association between known prognostic factors and OS. Covariates associated with inferior OS on multivariable analysis included R-ISS stage, age ≥ 70, PCLI ≥ 2, and abnormal metaphase cytogenetics. We devised a risk scoring system weighted by their respective hazard ratios (R-ISS II +1, R-ISS III + 2, age ≥ 70 +2, PCLI ≥ 2 +1, metaphase cytogenetic abnormalities + 1). Low (LR), intermediate (IR), and high risk (HR) groups were established based on risk scores of 0-1, 2-3, and 4-5 in modeling without metaphase cytogenetics, and scores of 0-1, 2-3, and 4-6 in modeling incorporating metaphase cytogenetics, respectively. Survival estimates were calculated using the Kaplan-Meier method. Survival analysis was stratified by LR, IR, and HR groups in models 1) excluding metaphase cytogenetics 2) including metaphase cytogenetics and 3) including metaphase cytogenetics, with IR stratified by presence and absence of metaphase cytogenetic abnormalities. Survival estimates were compared between groups using the log-rank test. Harrell's C was used to compare the predictive power of risk modeling with and without metaphase cytogenetics. Results: Median age at diagnosis was 66 (31-95), 281 patients (58%) were men, median follow up was 5.5 years (0.04-14.4), and median OS was 6.4 years (95% CI 5.7-6.8). Ninety-seven patients (20%) were R-ISS stage I, 318 (66%) stage II, and 68 (14%) stage III. One-hundred and fourteen patients (24%) had high-risk abnormalities by FISH, and 115 (24%) had abnormal metaphase cytogenetics. Three-hundred and thirteen patients (65%) received an IMID, 119 (25%) a PI, 51 (10%) received IMID and PI, and 137 (28%) underwent upfront autologous hematopoietic stem cell transplantation (ASCT). On multivariable analysis, R-ISS (HR 1.59, 95% CI 1.29-1.97, p &lt; 0.001), age ≥ 70 (HR 2.32, 95% CI 1.83-2.93, p &lt; 0.001), PCLI ≥ 2, (HR 1.52, 95% CI 1.16-2.00, p=0.002) and abnormalities on metaphase cytogenetics (HR 1.35, 95% CI 1.05-1.75, p=0.019) were associated with inferior OS. IR and HR groups experienced significantly worse survival compared to LR groups in models excluding (Figure 1A) and including (Figure 1B) the effect of metaphase cytogenetics (p &lt; 0.001 for all comparisons). However, the inclusion of metaphase cytogenetics did not improve discrimination. Likewise, subgroup analysis of IR patients by the presence or absence of metaphase cytogenetic abnormalities did not improve risk stratification (Figure 1C) (p &lt; 0.001). The addition of metaphase cytogenetics to risk modeling with R-ISS stage, age ≥ 70, and PCLI ≥ 2 did not improve prognostic performance when evaluated by Harrell's C (c=0.636 without cytogenetics, c=0.642 with cytogenetics, absolute difference 0.005, 95% CI 0.002-0.012, p=0.142). Conclusions: Abnormalities on metaphase cytogenetics at diagnosis are associated with inferior OS in MM when accounting for the effects of R-ISS, age, and PCLI. However, the addition of metaphase cytogenetics to prognostic modeling incorporating these covariates did not significantly improve risk stratification. Disclosures Lacy: Celgene: Research Funding. Dispenzieri:Akcea: Consultancy; Intellia: Consultancy; Alnylam: Research Funding; Celgene: Research Funding; Janssen: Consultancy; Pfizer: Research Funding; Takeda: Research Funding. Kapoor:Celgene: Honoraria; Sanofi: Consultancy, Research Funding; Janssen: Research Funding; Cellectar: Consultancy; Takeda: Honoraria, Research Funding; Amgen: Research Funding; Glaxo Smith Kline: Research Funding. Leung:Prothena: Membership on an entity's Board of Directors or advisory committees; Takeda: Research Funding; Omeros: Research Funding; Aduro: Membership on an entity's Board of Directors or advisory committees. Kumar:Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Association between a Polygenic Risk Score for Multiple Myeloma Risk and Overall Survival

Background Genome-wide association studies (GWAS) conducted in populations of European ancestry (EA) have identified and confirmed 23 germline susceptibility loci for multiple myeloma (MM). The effect sizes of single nucleotide polymorphisms (SNPs) at these loci are small, therefore combining them into a single summary measure, known as a polygenic risk score (PRS), may provide a more meaningful risk factor. We have previously shown a PRS comprised of the 23 SNPs for MM contributes to increased risk of MM, with a 2.7-fold increase for highest vs. lowest PRS quintiles. Whether the MM-PRS is also associated with overall survival (OS) in MM cases has not been evaluated. We examined the association between MM-PRS and OS in two EA studies. Methods The first study consisted of 2,179 EA MM cases from ten studies included in the Multiple Myeloma Working Group within the International Lymphoma Consortium (InterLymph). Cases were diagnosed between 1970 and 2015 and genotyped using multiple platforms (Oncoarray, Affymetrix, Human660W-quad Beadchip, and Illumina arrays); 885 cases also had stage [based on International Staging System (ISS)] available. Each of the GWAS was subjected to rigorous standard quality control independently (prior to imputation via the Michigan imputation server based on the Haplotype Reference Consortium (HRC). The second study consisted of 515 newly diagnosed EA MM cases from CoMMpass (Relating Clinical Outcomes in Multiple Myeloma to Personal Assessment of Genetic Profile), diagnosed from 2011-2013, who had whole genome sequencing (WGS) performed on germline DNA. The WGS data was used to call common germline genetic variants through the Mayo Clinic bioinformatics pipeline. Briefly, genetic variants were detected with GenomeGPS, aligned to the hg19 reference genome, called using the GATK (V3.6) Haplotype Caller, and merged for multiple-sample joint calling. To reduce the false positive variants, variant quality score recalibration (VQSR) was applied for both SNPs and INDELs. After quality control, 458 EA samples remained. Follow-up was available for both studies and consisted of time from MM diagnosis date until death or date of last known follow-up. The PRS was constructed from the 23 MM SNPs using the published per allele odds ratio associated with MM risk. The published log odds ratios for each SNP were multiplied by the number of risk alleles (0, 1, 2) for the corresponding SNP, and summed, resulting in a unique score per person. Kaplan-Meier curves and Cox proportional hazard models were used to assess the association between PRS with MM OS considering two models: 1) adjusted for age, sex, study and 2) additional adjustment by stage (ISS). Hazard ratios (OR) and 95% confidence intervals (CI) were estimated. The PRS was evaluated both as a continuous variable, per standard deviation (SD), and as a categorical variable (quintiles). Results MM cases (N=2,179) in the InterLymph study were 59% male and 41% female and the median age was 61.0 years (26-90 years). Median follow-up time was 57.2 months (1.0-509.0 months) with 868 reported deaths. MM cases with stage information available consisted of 20% stage I (n=178), 53% stage II (n=466), and 27% stage III (n=241). No association was observed between PRS and OS in MM patients regardless of adjustment for stage (continuous PRS (HR: 1.03, 95% CI: 0.83-1.28, P=0.80) or by quintile PRS (p&gt;0.05)) (Table). The CoMMpass EA MM cases (n=458) had similar distributions for sex (61% male and 39% females) but were slightly older 65 years (27-93 years) and had shorter follow-up time (median=39.75 months (0.13-77.2)) with 117 deaths. Stage was available for 96% of CoMMpass cases including 36% stage I (n=159), 33% stage II (n=146), and 31% stage III (n=134). We also observed no association of PRS and OS in the CoMMpass study (HR=1.02, 95% CI: 0.72 -1.46, P= 0.89), adjusted for age, sex, and stage (Table). Discussion A PRS score for MM risk is not associated with OS for MM cases in two EA populations. Given that prior studies have shown association of genetic variation with MM survival, efforts to identify additional loci associated with OS or MM specific survival are warranted. Future studies should also consider germline variants impact on molecular subtypes, specific therapies, and outcomes. Disclosures Kumar: Celgene: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Takeda: Research Funding.

Association Between Costs of Care in Oncology Care Model (OCM)-Defined Episodes and Overall Survival in Multiple Myeloma

The OCM was introduced in 2016 with the goal of improving quality and reducing costs associated with cancer care. Under this framework, practices are incentivized to reduce spending on chemotherapy-centered episodes. A previous study using SEER-Medicare data (2007–2013) suggested that reducing OCM episode costs in multiple myeloma (MM) may adversely affect patient survival. The present study aimed to evaluate the association between OCM-defined episode costs as well as MM-specific drug costs and overall survival (OS) in MM patients, using more recent data (2010–2015) and included 100% Medicare patients.

Development of a prognostic model for overall survival in multiple myeloma using the Connect® MM Patient Registry.

SummaryMedian overall survival (OS) has improved for patients with newly diagnosed multiple myeloma (NDMM), but prognosis varies depending on baseline patient characteristics. Current models use data from selected clinical trial populations, which prevent application to patients in an unselected community setting that reflects routine clinical practice. Using data from the Connect® MM Registry, a large, US, multicentre, prospective observational cohort study (Cohort 1: 2009–2011; Cohort 2: 2012–2016) of 3011 patients with NDMM, we identified prognostic variables for OS via the multivariable analysis of baseline patient characteristics in Cohort 1 (n = 1493) and developed a tool to examine individual outcomes. Factors associated with OS (n = 1450 treated patients; P < 0·05) were age, del(17p), triplet therapy use, EQ‐5D mobility, International Staging System stage, solitary plasmacytoma, history of diabetes, platelet count, Eastern Cooperative Oncology Group performance status and serum creatinine, which were used to create survival matrices for 3‐ and 5‐year OS. The model was internally and externally validated using Connect MM Cohort 2 (Harrell's concordance index, 0·698), MM‐015 (0·649), and the phase 3 FIRST (0·647) clinical trials. This novel prognostic tool may help inform outcomes for NDMM in the era of triplet therapy use with novel agents.