Date Of Multiple Myeloma Diagnosis Research Articles

Real-World Pitfalls of Analyzing Real-World Data: A Cautionary Note and Path Forward.

Real-world data (RWD) are pervasive in oncology research and offer insights into clinical trends and patient outcomes. However, RWD have shortcomings, making them prone to pitfalls during survival analyses. The American Society of Clinical Oncology (ASCO) CancerLinQ Discovery (CLQD) multiple myeloma (MM) data set was used to demonstrate some common pitfalls when analyzing survival from RWD: using incorrect surrogate markers for missing data and/or classification errors, ignoring deaths at time zero, and failing to account for guarantee-time bias. The ASCO CLQD MM data set (July 19, 2021, release) was used to compare overall survival (OS) in patients with a known versus presumed date of MM diagnosis, in patients with secondary AML (sAML) with early deaths (ie, 0 months) included versus dropped, and in patients with second primary malignancies (SPMs) matched versus unmatched to control for time-related confounding factors (ie, guarantee-time bias). Analyses were conducted using STATA Version 17.0 (College Station, TX). In the CLQD MM data set, 28% of patients were missing a diagnosis date. Attempts to use the presumed diagnosis date (ie, first bortezomib or lenalidomide administration) as a surrogate marker for missing diagnosis dates were not successful as median OS was significantly different in patients with a recorded versus presumed diagnosis date (107 v 40 months, hazard ratio [HR], 2.5; 95% CI, 2.39 to 2.64; P < .001). Dropping deaths within 1 month of sAML diagnosis resulted in an exaggerated median OS (46 v 39 months). OS in patients with MM with SPMs differed substantially before and after incorporation of matching methods to account for guarantee-time bias (HR, 0.73; 95% CI, 0.67 to 0.78; P < .001 before matching, HR, 1.30; 95% CI, 1.18 to 1.43; P < .001 after matching). To fully maximize the benefits of RWD in oncology research, clinicians must be aware of analytic methods that can overcome pitfalls in survival analyses.

Pitfalls with analyses of real-world data: A look at ASCO’s CancerLinQ Discovery Multiple Myeloma dataset.

e20033 Background: Real world data (RWD) are increasingly used in oncology research. Yet, a big limitation of RWD is missing data, potentially generating misleading conclusions. Methods for handling missing data include excluding patients with missing variables, using machine-based or statistically-imputed values, or using proxies (surrogates). Another limitation deals with excluding deaths at time zero, which may lead to misleading conclusions when analyzing survival of patients with aggressive cancers. This work highlights the impacts data exclusion, variable surrogacy, and death at time zero have on survival analysis results. Methods: ASCO’s CancerLinQ Discovery Multiple Myeloma (MM) dataset was used to assess overall survival (OS) in patients with MM diagnosed from 2009-2021. Of the 34,234 patients included in the actual analyses, 3,582 (10%) were missing a recorded date of MM diagnosis. In these cases, dates of first anti-myeloma therapy were used as surrogates since most MMs are treated at diagnosis. OS was compared between MM patients with “known” vs. surrogate or “presumed” diagnosis dates. To assess how the inclusion of deaths at time zero may or may not affect OS, the data were first analyzed by excluding patients who died within 1 month of second primary malignancy (SPM) diagnosis, including secondary AML (sAML). A second analysis of the same sample added a constant (0.5) to all survival times, allowing for inclusion of patients who died within one month of diagnosis. Analyses were conducted with STATA Version 17.0 (College Station, TX). Results: Despite the strong, positive correlation between recorded MM diagnosis date and date of first anti-myeloma therapy, there was a statistically significant difference in survival of MM patients with a known vs. presumed date of diagnosis (median OS 115 vs. 45 months, HR 2.54, 95% CI 2.41-2.69, p &lt; 0.001). Dropping vs. including deaths within one month of diagnosis resulted in a marked difference (i.e., nearly 1 year) in median OS from the date of diagnosis of any SPM (113 vs. 103.5 months) as well as sAML (41 vs. 30.5 months). Conclusions: Although RWD hold promise, oncologists must be aware of common pitfalls in survival analyses: missing data, variable surrogates, and deaths at time zero being dropped. Patients with a recorded date of MM diagnosis appear to be fundamentally different from those who don’t have a date of diagnosis but do have a date of anti-myeloma therapy recorded. For aggressive malignancies, excluding patients who died at time zero can lead to over-estimation of survival. Adding a small constant (0.5) to the time variable can enable the inclusion of patients who die quickly after their cancer diagnosis. In conclusion, when utilizing RWD to guide clinical decision making, it is important to be aware of common threats to data validity, which can produce misleading results.

A US National View of Prevalent and Newly Diagnosed Multiple Myeloma in 2021: A Retrospective Analysis of National All-Payer Claims Database

Introduction: Multiple myeloma (MM) is a rare and heterogeneous cancer with steadily improving patient survival in recent years due to advancement in therapies. Updates to the prevalence and incidence of MM using the latest nationally representative data are needed to support population health management, resource planning, and health economic assessments. Furthermore, disparities in disease burden, access to care, treatment patterns, and outcomes could exist across patient subpopulations with MM, prompting a need for comprehensive data to understand the population. Currently, there is a gap in such data due to the highly fragmented health care system in the US in which real-world evidence is often siloed and represents only a portion of the population. This study aims to provide a national view of MM by estimating the prevalence and incidence in US adults overall and by state/territory, payer type, race, and ethnicity in 2021. Methods: This is a retrospective study using the All-Payer Real-World Multiple Myeloma Research-Ready Data built using the US national all-payer claims database (APCD), which covers ~87% of the nationally insured population from 1/1/2014 to 1/31/2022. Data included adults with ≥2 claims with MM diagnosis (ICD-9-CM: 203.0x and ICD-10-CM: C90.0x) who had continuous capture with medical and pharmacy benefits for ≥12 months prior to and 30 days after the first MM diagnosis date. To be included in this study, patients also had to have ≥1 claim in 2021. The latest claim date in 2021 was defined as the index date. A subcohort of patients with newly diagnosed MM (NDMM; incident MM cases) were additionally required to have their first MM diagnosis date (the index date for the NDMM cohort) in 2021. Prevalence and incidence of MM were estimated using the number of patients in MM and NDMM cohorts, divided by the total APCD adult population with similar continuous capture eligibility. Prevalence and incidence were calculated for the overall population and stratified by state/territory, payer type, race, and ethnicity. Patient characteristics were captured at the index date and during the baseline period. The proportion of patients with NDMM who initiated their first treatment in 2021 and the time from diagnosis to their first treatment were captured. Results: A total of 63,281 MM and 9,674 NDMM patients met the study criteria. Mean age was 71.1 and 70.0 years, 51.4% and 52.9% were male, and 68.7% and 72.0% were covered by Medicare, respectively. Overall, about two-thirds of the patients had available race (74%), ethnicity (69%), and income data (76%), while 46% had education status. Among those with data, 15.6% of MM and 14.7% of NDMM cohorts were Black, 12.2% and 11.9% were Hispanic, 65.1% and 64.5% had an annual income ≤$50,000, and 67.5% and 67.2% had high school as their highest level of education. The overall prevalence of MM was 73.8 per 100,000 adults in 2021, with the prevalence being the highest among those who were Black (124.8), non-Hispanic (101.3), covered by Medicare (245.2), and residing in the US Virgin Islands (243.6) and Arkansas (126.5). The overall incidence of NDMM was 11.3 per 100,000 adults in 2021, and the incidence was highest among those who were Black (17.8), non-Hispanic (15.3), covered by Medicare (39.3), and those residing in Puerto Rico (24.5), the US Virgin Islands (22.8), and Washington (20.7; Tables 1 and 2). The mean Quan-Charlson comorbidity index (excluding MM diagnosis) was 2.8 for the MM cohort and 2.4 for the NDMM cohort. Commonly observed comorbidities for both cohorts included anemia (44.8% and 47.4%), diabetes with chronic complications (23.9% and 22.4%), peripheral neuropathy (24.8% and 15.2%), renal impairment (22.7% and 20.1%), and infections (21.9% and 14.4%). There were 3,377 (35%) patients with NDMM who initiated their first treatment in 2021, with a mean and median time to treatment of 50.8 (standard deviation = 67.5) and 27 days. Conclusions: While the prevalence and incidence of MM in 2021 estimated in this study were consistent with projected estimates from the literature, variations in rates of MM were observed across race, ethnicity, payer type, and state/territory, indicating potential disparities in the burden of MM. Such a comprehensive view of rates of MM could serve as a foundation for future health policy decisions, quality improvement, resource deployment, and initiatives to address health disparities across subpopulations. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

African American Race Is a Potential Favorable Biologic Factor That Impacts Clinical Outcome for Patients with Multiple Myeloma

Multiple myeloma (MM) remains an incurable malignancy characterized by plasma cells that are nurtured and proliferate within the permissive bone marrow milieu. It has a greater incidence in African Americans (AA) compared to whites (13.8 vs. 6.5/100,000). The five-year age adjusted mortality rate, according to SEER database, is greater in AA compared to white Pts (5.8 vs. 2.9/100,000), which is likely explained by a greater incidence in the AA population. However, recent reports have also shown that AAs with equal access to care have an even better survival than their white counterparts [Fiala et al. Cancer. 2017]. Conversely, results from the CoMMpass registry database showed that OS was shorter for AA compared with Whites (age-adjusted hazard ratio (HR) 1.7, 95% confidence interval 1.2-2.4, P = 0.003) [Derman et al. Blood Cancer J. 2020]. Here, we report the interplay of race and other dimensions of MM care using the National Cancer Database (NCDB). Methods: NCDB is the largest cancer database in the US including >70% of all newly diagnosed cancer patients. The International Classification of Diseases for Oncology (ICD-O) code of 9732 was used. OS was calculated from the date of MM diagnosis. Given that Smoldering MM (SMM) does not have specific ICD code, we defined patients who did not receive any treatment within 3 months after the diagnosis as SMM, similar to other authors (Ravindran et al. Blood Cancer J. 2016). Initiation of systemic treatment was considered as a surrogate of progression to symptomatic MM. Overall survival (OS) of SMM patients was calculated from initiation of systemic treatment after they progressed to MM, estimated by the Kaplan-Meier method, and compared with the log-rank test. Cumulative incidence of progression from SM to MM was calculated with death as a competing risk and compared with the Gray's test. Multivariable Cox and logistic regression analysis were performed to identify independent predictors of OS and progression to MM, respectively. Results: We identified 56,021 patients with MM and 11,485 with SMM between 2010 to 2014 in this database. Among MM patients, 42,836 (76%) were white and 11,255 (20%) self-identified as AA. For AA patients, there was a lower proportion of Medicare (46 vs. 56%), and private insurance (35 vs. 36%) and a higher percentage of Medicaid (11 vs. 5%) and uninsured Pts (6 vs. 3%) compared to Pts that self-identified as white. A larger proportion of AAs had a Charlson score ≥1 (30 vs. 24%, p<0.001). The percentage of Pts who underwent radiation was higher among whites compared to AA (23 vs 8%). However, unadjusted OS was greater for AA compared to white Pts, 55 vs. 48 months, respectively (P < 0.0001). Among SMM patients, 8,324 (72%) were white and 2,756 (24%) were AA. SMM was diagnosed in AA patients at a median of 3.7 years younger than in white patients. Similar socioeconomic disparities were observed in SMM as in MM cohort. The time from diagnosis of SMM to first therapy which is indicative of progression from SMM to MM is the same among AA and white (median time in days 136 vs 135 days, p=0.672) with comparable OS. Multivariable Cox and logistic regression analysis showed that lower age, AA race, Female gender, ASCT, living in a higher income area and having Medicare or Private insurance compared to no insurance were independent predictors for better OS in MM. Although other predictive factors persisted for patients with SMM, race did not reach statistical significance. Conclusion: Taken together, our results utilizing one of the largest available datasets in the US, reflect a similar outcome for AA and white patients with MM despite a clear disparity in healthcare access and SES. This finding might suggest a more favorable biology of the disease among AA Pts. The lower rate of radiation among AA is also an indirect measure of bone complications. AA enjoy less bone loss and fractures under physiologic and pathologic conditions. Further studies to elucidate the role of bony compartment of the MM microenvironment at the cellular and molecular levels might be able to explain this disparity and help advance a more personalized treatment options to improve outcomes. Figure 1View largeDownload PPTFigure 1View largeDownload PPT Close modal

MM-531 Case Control Study of Outcomes of Autologous Stem Cell Transplantation in Jehovah's Witness Multiple Myeloma Patients

Jehovah's Witnesses (JW) persons do not accept blood transfusions. Autologous stem cell transplantation (ASCT) after using high-dose chemotherapy is the standard of care in treatment of multiple myeloma (MM). Patients usually require blood transfusions during ASCT. We sought to analyze safety outcomes of single or tandem ASCT in JW MM patients. We performed a case control study at the University of Arkansas for Medical Sciences for JW and non-JW MM patients who underwent single or tandem ASCT from 1990-2021. Matching (1:2) was done based on age, date of MM diagnosis, race/ethnicity, performance status, stage indicated by International Staging System (ISS), and number of ASCT. Wilcoxon Rank-Sum test was used to test continuous variables, while Fisher's exact test was used for categorical variables. A total of 13 JW MM patients received ASCT in the study period (8 single, 5 tandem) compared to 26 non-JW MM patients (16 single, 10 tandem). For JW patients who received single ASCT, median age was 66 (range:65.8-67.5 years), 50% were female, 62.5% were black. Average CD34 stem cells collected/infused were 23/5.8 million cells in JW compared to 30.1/5.1 million cells in non-JW, respectively. For JW patients who received tandem ASCT, median age was 49 (range:46-52 years), 50% were female, 62.5% were black. Average CD34 stem cells collected/infused were 34/10.8 million in JW compared to 21.3/8.8 million in non-JW, respectively. Lowest hemoglobin and platelets level in JW were 6.6 g/dl and 3000 k/uL, respectively. 100-days mortality for all patients was 0%. Multivariable analysis showed no significant difference in 30 days/100 days re-hospitalization, major and/or minor bleeding adverse events, response to treatment (very good partial response or better). Bloodless single/tandem ASCT can be done safely for selected JW MM patients with no significant difference in safety/outcomes.

Characteristics and Treatment of Patients with Multiple Myeloma Who Received Daratumumab in a Large Claims Database in the United States

Introduction: Daratumumab (DARA) is a human IgGk monoclonal antibody targeting CD38 with a direct on-tumor and immunomodulatory mechanism of action. Since its approval for relapsed or refractory multiple myeloma (MM) in 2015 and newly diagnosed MM (NDMM) in 2018, DARA has become the foundation of treatment for MM. However, there is limited real-world evidence describing patients (pts) with MM treated with DARA-containing regimens in the US, especially for NDMM pts. Thus, using a large US claims database, we evaluated pt and treatment characteristics among MM pts who received DARA-containing regimens as first-line (1L) or second-line (2L) therapy, and separately for the subset who received DARA plus lenalidomide/dexamethasone (D-Rd) given its more recent approval in NDMM.Methods: This retrospective, observational cohort study evaluated pts aged ≥18 years at the index date (first observed treatment date with ≥1 medical or pharmacy claim for DARA) from the Optum Clinformatics Data Mart database between January 1, 2013 and December 31, 2020, with ≥1 diagnosis code for MM before the index date, and who were continuously enrolled in a medical benefit plan and pharmacy plan from ≥6 months before the initial MM diagnosis date to the index date. Pts with a hematopoietic stem cell transplant from 6 months before the observed initial MM diagnosis date to the index date were excluded. Eligible pts were categorized into 4 cohorts: pts with (1) a DARA-containing regimen as 1L (1L DARA-based cohort), (2) a DARA-containing regimen as 2L (2L DARA-based cohort), (3) D-Rd as 1L (1L D-Rd cohort), and (4) D-Rd as 2L (2L D-Rd cohort) after the observed initial MM diagnosis. Demographics were assessed on the index date; clinical characteristics, all-cause healthcare resource utilization (HCRU), and total all-cause healthcare costs (medical + pharmacy costs) were measured during the 6-month baseline period before the index date.Results: Among the 1L DARA-based cohort (n=235), 48 (20.4%) pts received D-Rd (1L D-Rd cohort). Overall, the most common 1L DARA-based regimens (with or without dexamethasone or prednisone) were D-R (28.5%), DARA plus bortezomib (V)/R (D-VR; 23.8%), D-V (18.7%), and D (14.9%). Among the 2L DARA-based cohort (n=310), 44 (14.2%) pts received D-Rd (2L D-Rd cohort). In the 1L DARA-based and 1L D-Rd cohorts, the mean (SD) age on the index date was 72.4 (9.0) and 76.1 (7.9) years, respectively. In the 2L DARA-based and 2L D-Rd cohorts, the mean (SD) age on the index date was 72.7 (9.3) and 70.5 (11.5) years, respectively. Mean baseline Quan-Charlson Comorbidity index was higher in the 2L cohorts versus 1L cohorts (1L DARA-based: 3.1; 1L D-Rd: 2.8; 2L DARA-based: 3.5; 2L D-Rd: 3.6). Hypercalcemia, renal impairment, anemia, and/or bone lesions (CRAB symptoms) were identified in about 50% of pts in all cohorts. Renal impairment was identified in 32.3%, 22.9%, 32.9%, and 34.1% of pts in the 1L DARA-based, 1L D-Rd, 2L DARA-based, and 2L D-Rd cohorts, respectively. Cardiovascular conditions (myocardial infarction, angina, peripheral vascular disease, and/or congestive heart failure) were found in 26.4% of pts in the 1L DARA-based cohort, 29.2% in the 1L D-Rd cohort, 34.5% in the 2L DARA-based cohort, and 47.7% in the 2L D-Rd cohort. The most common (>5% of pts) 1L regimens for pts in the 2L D-Rd cohort were VRd (17 [38.6%] pts), Vd (6 [13.6%]), V/cyclophosphamide (C)/d (4 [9.1%]), Rd (4 [9.1%]), and VC (3 [6.8%]). In the 1L DARA-based, 1L D-Rd, 2L DARA-based, and 2L D-Rd cohorts, 47.7%, 41.7%, 47.7%, and 54.5% of pts, respectively, had ≥1 hospitalization, and mean numbers of outpatient encounters were 26.4, 25.1, 50.6, and 52.8 within the 6-month baseline period. Mean 6-month baseline total healthcare cost (in 2020 USD) was $53,874 (medical: $51,837; pharmacy: $2,038) in the 1L DARA-based cohort, $39,695 ($35,896; $3,799) in the 1L D-Rd cohort, $131,832 ($96,737; $35,095) in the 2L DARA-based cohort, and $136,218 ($97,380; $38,838) in the 2L D-Rd cohort.Conclusions: In this real-world assessment using claims data, pts with MM receiving DARA-based therapy in 1L or 2L had median age ≥70 years, with high clinical burden as observed by their comorbidities, HCRU, and costs. Understanding the characteristics of real-world pts with MM treated with DARA-based therapy can further aid in the understanding of effective use of DARA in the real world. DisclosuresFeng: Janssen: Current Employment. Fu: Janssen: Current Employment. Khare: Janssen: Current Employment. Ogbonnaya: Janssen: Current Employment. Kaila: Janssen Scientific Affairs, LLC: Current Employment.

Real-World Treatment Outcomes in Patients with Newly Diagnosed Multiple Myeloma Treated with Triplet Therapy without Stem Cell Transplant: An Enhanced Electronic Health Records Database

Real-World Treatment Outcomes in Patients with Newly Diagnosed Multiple Myeloma Treated with Triplet Therapy without Stem Cell Transplant: An Enhanced Electronic Health Records Database

Acute Myeloid Leukemia (AML) and Myelodysplastic Syndromes (MDS) after Multiple Myeloma: Assessment of Risk Factors

Risk factors for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in patients with multiple myeloma (MM) are not well understood. We have previously shown that monoclonal gammopathy of undetermined significance (MGUS) is associated with an excess risk of AML/MDS, indicating an inherent excess risk of AML/MDS in plasma cell disorders. In addition, randomized studies have shown that lenalidomide maintenance is associated with increased relative risk of AML/MDS. The excess risk of AML/MDS in lenalidomide treated patients has been found to be most prominent in patients that also receive alkylating agents. A recent randomized clinical study shows that delayed autologous transplant has the same overall survival as upfront autologous transplant with high dose melphalan at 3 years of follow-up; also emerging data shows that minimal residual disease (MRD) negativity has very similar progression free survival independent of therapy. Thus, patients treated with modern combination therapy who obtain MRD negativity might not have additional benefit from upfront autologous transplant. We were motivated to better define the role of alkylating therapy in relation to subsequent risk of secondary malignancies.All patients diagnosed with MM from January 1, 1958 to December 31, 2011 were identified from the Swedish Cancer Registry. Information was obtained regarding all subsequent hematologic malignancies among patients in the MM cohort. Each patient with MM and a subsequent AML/MDS diagnosis (i.e., cases) was matched to another MM patient without AML/MDS for year of birth, sex, and date of MM diagnosis (i.e., control group). Detailed information on baseline characteristics at diagnosis and treatment was collected from medical records. Patients with MM and AML/MDS were also compared to MM patients that developed lymphoproliferative malignancies. Characteristics at MM diagnosis, radiation therapy, and ASCT were compared between groups with Kruskal-Wallis and Chi-square tests. Cumulative chemotherapy doses were analyzed with one way ANOVA. Post hoc analysis with Fisher´s LSD was performed.A total of 26,627 patients were diagnosed with MM in Sweden during the study period. Of these, 224 patients developed hematological malignancies. Data was found for 89 MM and subsequent AML/MDS patients and they were matched to 89 controls. Preliminary results from the first 12 controls were available for analysis, number of controls will be updated as more data has been reviewed. A total of 100 patients had lymphoproliferative malignancies and 1/3 of them were randomly selected. The demographic and clinical characteristics for all groups are listed in Table. The median age at MM diagnosis was 67 years (39 females and 50 males) for cases, 72 years (7 females and 5 males) for controls and 70 years (10 females and 23 males) for patients with lymphoproliferative malignancies. The median time from MM diagnosis to AML/MDS diagnosis was 3.8 (range 0.4-17.1) years and 3.4 (range 0.4-29.4) years for patients who developed lymphoproliferative malignancies. The mean cumulative melphalan dose was 1,318 mg (SD ± 1,159 mg) for cases, 704 mg (SD ± 588 mg) for the controls and 967 mg (SD ± 978 mg) for patients who developed lymphoproliferative malignancies. There was a statistically significant difference of mean cumulative melphalan dose between groups (F (2,123) = 3.14, p= 0.047). Post hoc analysis confirmed that cases had a statistically significant higher mean cumulative melphalan dose compared to controls, p <0.05.The preliminary results from this large nationwide population based study including almost 27,000 MM patients in Sweden over >50 years shows that the mean cumulative dose of melphalan was higher in MM patients who developed AML/MDS compared to MM patients who did not. With the average myeloma patient living over 10-15 years from diagnosis, strategies to avoid secondary complications is becoming more important. Our results showing that melphalan is associated with an increased risk of AML/MDS, call for studies using response driven (i.e. MRD based) therapy in myeloma; were high dose melphalan is rather offered to patients who are MRD positive. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Cumulative exposure to melphalan chemotherapy and subsequent risk of developing acute myeloid leukemia and myelodysplastic syndromes in patients with multiple myeloma.

The aim of this study was to determine risk factors for development of acute myeloid leukemia/myelodysplastic syndromes (AML/MDS) in patients with multiple myeloma (MM). We identified all patients diagnosed with MM in Sweden from January 1st, 1958 to December 31, 2011. A total of 26627 patients were diagnosed with MM with during the study period. Of these, 124 patients (0.5%) developed subsequent AML/MDS. For each patient with MM and a subsequent AML/MDS diagnosis, we randomly selected a matched (age, sex, and date of MM diagnosis) MM patient without a subsequent second malignancy diagnosis. The cumulative melphalan exposure was significantly higher (OR=2.8, 95% CI 1.7-5.2; P<.001) among cases (median 988mg; IQR 644-1640) compared with controls (median 578mg; IQR 360-967). Median time to AML/MDS development was 3.8years (IQR 2.8-5.8). Risk of AML/MDS was not statistically altered by M protein isotype, anemia, renal failure, hypercalcemia, lytic bone lesions, or radiation therapy. In this nationwide population-based study, we show that increased cumulative doses of alkylating therapy with melphalan increases the subsequent risk of developing AML/MDS in patients with MM. Given improved survival in MM patients over the last decade future studies will be important to better define long-term risks.

Prognostic Implication of Inflammatory Factor-Based Staging System in Multiple Myeloma in the New Agent Era

B ackground The advent of new agents has contributed to the prolonged survival of multiple myeloma (MM) patients. From the Durie-Salmon staging system, international staging system (ISS) and recently, revised ISS (R-ISS) have been developed to better prognosticate the survival of MM. R-ISS includes chromosomal abnormalities (CA) detected by interphase fluorescent in situ hybridization (iFISH) and lactate dehydrogenase (LDH) in addition to the ISS. However, the R-ISS has still some limitations in the real clinical settings, as it has enrolled patients exclusively on clinical trials which includes more young patients (age &lt; 65 years old), contains non-standardized iFISH results and has short median follow-up duration. The first-line drugs used in the patients could also affect the prognosis. Therefore, a more detailed and standardized but also convenient prognostic system is needed with clinical findings commonly observed in MM patients treated with new agents in the real clinical world. Patient and Method Adult patients who were confirmed multiple myeloma between January, 2011 to December, 2017 and patients who had received thalidomide and/or bortezomib or lenalidomide-based chemotherapy as a first-line treatment were included for the analysis. A total of 861 patients from 13 centers participating Korean multiple myeloma working party were analyzed. Baseline serum albumin, serum ß2-microglobulin, cytogenetics by iFISH, LDH (lactate dehydrogenase), ALC (absolute lymphocyte count), CRP (C-reactive protein) and ferritin were measured within 4 weeks before beginning the first line of chemotherapy. Each factors of age ≥ 65 years, serum ß2-microglobulin ≥ 5.5 mg/L, LDH &gt; normal, cytogenetic high risk by FISH (del17p, t(4;14), t(14;16)), ALC &lt; 1500/mm3, CRP ≥ 1.5 mg/dL, and ferritin ≥ 500 ng/mL were defined as abnormal findings, which were given 1 point (Table 1) and the sum of points were used to discriminate inflammatory factor-based staging system (IFBSS). IFBSS were defined as follows: Stage I (point 0), stage II (point 2-3), stage III (point 4-5), and stage IV (point 5-7). Overall survival (OS) was defined by the date of MM diagnosis to the date of death by any cause or follow-up loss. Results Baseline characteristics of the patients were as listed in Table 2. With a median follow-up duration of 22.70 months (range, 0.20-86.80 months), age ≥ 65 years, serum ß2-microglobulin ≥ 5.5 mg/L, LDH &gt; normal, cytogenetic high risk by FISH (del17p, t(4;14), t(14;16)), ALC &lt; 1500/mm3, CRP ≥ 1.5 mg/dL, and ferritin ≥ 500 ng/mL showed significant higher OS by univariate and multivariate analysis. Albumin &lt; 3.5 mg/dL were excluded into the staging system due the unpredictability to OS in univariate analysis (Table 3). Study groups of inflammatory factor-based scoring system comprised of 61 patients in stage I, 395 patients in stage II, 189 patients in stage III and 36 patients in stage IV. The median OS were not reached in stage I and II, stage III and IV showed a median OS of 36.57 months (95%CI, 33.96-.39.18) and 17.60 months (95%CI, 9.16-.26.04). The OS according to the IFBSS showed significant differences (P &lt; 0.001), which predicted OS better compared with conventional ISS and R-ISS (Table 4). Conclusion In the new agent era, inflammatory factors incorporated into the staging system can better discriminate prognosis of multiple myeloma patients compared to the ISS or R-ISS. Validation of this finding in a larger cohort is needed to expand usage of this new staging system. Disclosures Yoon: Novartis: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Kyowa Hako Kirin: Research Funding; Janssen: Consultancy; Yuhan Pharma: Research Funding; Genentech, Inc.: Research Funding; MSD: Consultancy.

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.

PS1386 CARFILZOMIB AS PART OF A DOSE DENSE, LESS DOSE INTENSE TOTAL THERAPY APPROACH FOR HIGH RISK MYELOMA

Background: Jonsdottir et al. (Blood Adv. 2017) recently suggested that, among the population of Sweden, a prior malignancy diagnosis (PMD) before the onset of MM increases the risk for developing a subsequent primary malignancy (SPM) after multiple myeloma (MM). Their analysis, however, did not account for death before the onset of a SPM as a competing risk. Therefore, their risk estimates might overestimate the magnitude of SPM development. Aims: To complement and extend on their observations, we revisited their analysis on the impact of a PMD on the first onset of a SPM in MM by employing competing risk regression. Methods: We identified all MM patients diagnosed between 1994–2012 from the nationwide population-based Netherlands Cancer Registry (NCR). PMDs and SPMs-excluding basal cell carcinomas-relative to MM were identified from the NCR. Synchronous malignancies diagnosed ≤6 months prior to or after MM diagnosis, and malignancies diagnosed from autopsies were excluded. SPMs were classified into subtypes according to the 3rd edition of the International Classification of Diseases for Oncology. We used competing risk regression as per Fine and Gray 3/4 with death before the onset of a SPM as a competing risk 3/4 to estimate sub-distribution hazard ratios (SHRs) with 95% confidence intervals (CIs) for the association between a PMD in MM patients and the development of a first SPM overall. These associations were also calculated for the subtypes as per SPM. We used Cox regression to calculate hazard ratios (HRs) with 95% CIs for the association between a PMD and the risk of mortality. All analyses were adjusted for baseline MM characteristics (i.e. sex, age, and period of diagnosis). All patients were followed from date of MM diagnosis to date of first SPM, death or end of follow-up (February 1, 2017), whichever came first. A P < 0.05 indicated statistical significance. Results: Our analytic cohort included 16,710 MM patients, of whom 1,760 (10.5%) had at least one PMD. Patients with a PMD were older at MM diagnosis, as compared to those without (median age 76 vs. 70; P < 0.001). At a median time of 3.8 years from MM diagnosis to first SPM (range 0.5–19.4), 138 of 1,760 (7.8%) MM patients with a PMD developed a SPM, as compared to 1,079 of 14,950 (7.2%) MM patients without (P = 0.341). Overall, there was no evidence for an increased rate of a first SPM in MM patients with a history of PMD, as compared to those without a history of PMD (adjusted SHR, 1.15; 95% CI, 0.96–1.38; P = 0.131; Table). However, subgroup analyses showed that there was an increased rate of breast cancer as first SPM in patients with a history of PMD (adjusted SHR, 2.45; 95% CI, 1.04–5.78; P = 0.040; Table) and melanoma of the skin (adjusted SHR, 3.05; 95% CI, 1.26–7.37; P = 0.014; Table). Finally, there was no statistically significant association of a PMD with the risk of mortality (adjusted HR, 1.04; 95% CI, 0.98–1.10; P = 0.177).Summary/Conclusion: In this population-based study, there was no apparent overall association between a history of a PMD and the development of a SPM among MM patients. However, subtype analyses showed increased rates for breast cancer and melanoma of the skin. Our results are not entirely in line with those of Jonsdottir et al. Of note, since we accounted for death before the onset of a SPM as a competing risk, our estimates are unlikely to be plagued by overestimation. Moreover, our results may guide cancer surveillance for early detection and appropriate management of SPMs, as MM survivorship is expected to increase due to continues therapeutic advances.

PS1385 THE IMPACT OF A PRIOR MALIGNANCY ON THE DEVELOPMENT OF A SUBSEQUENT MALIGNANCY IN MULTIPLE MYELOMA REVISITED: A COMPETING RISK ANALYSES

Background:Jonsdottir et al. (Blood Adv. 2017) recently suggested that, among the population of Sweden, a prior malignancy diagnosis (PMD) before the onset of MM increases the risk for developing a subsequent primary malignancy (SPM) after multiple myeloma (MM). Their analysis, however, did not account for death before the onset of a SPM as a competing risk. Therefore, their risk estimates might overestimate the magnitude of SPM development.Aims:To complement and extend on their observations, we revisited their analysis on the impact of a PMD on the first onset of a SPM in MM by employing competing risk regression.Methods:We identified all MM patients diagnosed between 1994–2012 from the nationwide population‐based Netherlands Cancer Registry (NCR). PMDs and SPMs‐excluding basal cell carcinomas‐relative to MM were identified from the NCR. Synchronous malignancies diagnosed ≤6 months prior to or after MM diagnosis, and malignancies diagnosed from autopsies were excluded. SPMs were classified into subtypes according to the 3rd edition of the International Classification of Diseases for Oncology. We used competing risk regression as per Fine and Gray 3/4 with death before the onset of a SPM as a competing risk 3/4 to estimate sub‐distribution hazard ratios (SHRs) with 95% confidence intervals (CIs) for the association between a PMD in MM patients and the development of a first SPM overall. These associations were also calculated for the subtypes as per SPM. We used Cox regression to calculate hazard ratios (HRs) with 95% CIs for the association between a PMD and the risk of mortality. All analyses were adjusted for baseline MM characteristics (i.e. sex, age, and period of diagnosis). All patients were followed from date of MM diagnosis to date of first SPM, death or end of follow‐up (February 1, 2017), whichever came first. A P &lt; 0.05 indicated statistical significance.Results:Our analytic cohort included 16,710 MM patients, of whom 1,760 (10.5%) had at least one PMD. Patients with a PMD were older at MM diagnosis, as compared to those without (median age 76 vs. 70; P &lt; 0.001). At a median time of 3.8 years from MM diagnosis to first SPM (range 0.5–19.4), 138 of 1,760 (7.8%) MM patients with a PMD developed a SPM, as compared to 1,079 of 14,950 (7.2%) MM patients without (P = 0.341). Overall, there was no evidence for an increased rate of a first SPM in MM patients with a history of PMD, as compared to those without a history of PMD (adjusted SHR, 1.15; 95% CI, 0.96–1.38; P = 0.131; Table). However, subgroup analyses showed that there was an increased rate of breast cancer as first SPM in patients with a history of PMD (adjusted SHR, 2.45; 95% CI, 1.04–5.78; P = 0.040; Table) and melanoma of the skin (adjusted SHR, 3.05; 95% CI, 1.26–7.37; P = 0.014; Table). Finally, there was no statistically significant association of a PMD with the risk of mortality (adjusted HR, 1.04; 95% CI, 0.98–1.10; P = 0.177).Summary/Conclusion:In this population‐based study, there was no apparent overall association between a history of a PMD and the development of a SPM among MM patients. However, subtype analyses showed increased rates for breast cancer and melanoma of the skin. Our results are not entirely in line with those of Jonsdottir et al. Of note, since we accounted for death before the onset of a SPM as a competing risk, our estimates are unlikely to be plagued by overestimation. Moreover, our results may guide cancer surveillance for early detection and appropriate management of SPMs, as MM survivorship is expected to increase due to continues therapeutic advances.image

The Real-World Frequency of 24-Hour Urine Protein Electrophoresis (UPEP), Serum Free Light Chain (SFLC), and Serum Protein Electrophoresis (SPEP) Testing in Patients with Multiple Myeloma (MM)

IntroductionUp to 20% of MM patients present with light-chain-only multiple myeloma (LCMM), which is not detectable using serum protein electrophoresis testing. 24-hour urinalysis may be the guideline-endorsed method for monitoring LCMM, but impracticalities can limit its use. We sought to assess how patients with MM and LCMM were followed for progression in the community setting by specimen type using real-world data, analyzing the frequency of testing for patients with MM (based on SPEP) or LCMM (based on UPEP or SFLC).MethodsThis retrospective cohort study used information from the Flatiron Health database, which is derived from electronic health record data; Institutional Review Board approval with a waiver of informed consent was obtained. The cohort included 4591 patients followed for MM and LCMM from 01/01/2011 to 06/30/2018 at community oncology clinics across the United States. The cohort was limited to patients with a confirmed diagnosis of MM on or after 01/01/2011, who received at least one line of therapy and did not receive a stem cell transplant. Patients whose start of MM treatment (captured through chart review) was > 30 days before the start of structured activity in the database were excluded as this may indicate missing therapy data. The specimen type was the test used to follow patients for progression throughout their disease course. Tests were eligible to define the specimen type if they occurred ≤ 90 days before or any time after an initial MM diagnosis. If a patient had multiple test types within this timeframe, the specimen type was determined using a hierarchy (at least one detectable SPEP [≥ 1 g/dL] > at least one detectable 24-hour UPEP [≥ 200 mg] > SFLC [any numeric value]), consistent with International Myeloma Working Group (IMWG) criteria. A LCMM diagnosis was assumed when a detectable M spike (≥1 g/dL) via SPEP could not be found 90 days before or any time after the initial MM diagnosis date, but a detectable lab value was found within that timeframe via 24-hour UPEP (≥ 200mg) or a SFLC (any numeric value).ResultsAmong all patients in the cohort with MM (N=4591), 27.7% (N=1272) received a UPEP test, 58.1% (N=2666) received a SFLC test, and 79.2% (N=3635) received a SPEP test at baseline, defined as occurring within 90 days on either side of the MM diagnosis date. Patients with a UPEP specimen type had less frequent testing than patients with a SPEP or SFLC specimen type. For patients with a UPEP specimen type (N=229), the median of the median time between two tests was 95 days, compared to 42 days for patients with a SFLC specimen type (N=1274) and 35 days for patients with a SPEP specimen type (N=2536). 32.7% (N=1503) of the cohort had LCMM; of those patients, 84.8% were followed by SFLC while only 15.2% were followed by UPEP.Conclusions24-hour urine tests for UPEP are not used often in routine clinical practice despite IMWG guidelines: the guidelines may not reflect a realistic standard of care in the real-world setting. While performing UPEP in addition to SFLC regularly may be the ideal practice for monitoring LCMM, impracticalities such as issues with collection technique and proper storage of urine samples may be hindering its regular use in the real world. The SFLC test may present a more realistic alternative for evaluation of disease status in patients with LCMM, and its ease of use could facilitate more frequent serial testing. This in turn could improve the measurement of progression at more regular intervals, potentially reducing patient exposure to therapies that are no longer effective. To our knowledge, this is the first study to investigate the differences in utilization of UPEP, SFLC, and SPEP testing conducted to follow MM and LCMM progression in the real world. [Display omitted] DisclosuresFoster:Flatiron Health: Employment. Lipitz:Flatiron Health: Employment. Torres:Flatiron Health: Employment. Carson:Roche: Consultancy; Flatiron Health: Employment; Washington University in St. Louis: Employment.

Biologic Disease-Modifying Antirheumatic Drugs and Risk of Multiple Myeloma

INTRODUCTIONBiologic disease-modifying antirheumatic drugs (DMARDs) are used more frequently and earlier in the course of rheumatologic conditions in a treat-to-target approach. These medications act on proteins and cytokines with potential pro- and anti-malignancy roles, including tumor necrosis factor-alpha (TNF), human interleukin (IL) receptors and B- and T-cell functions. There is concern for hematologic malignancy with some but not all biologic DMARDs. Little is known about possible associations between these medications and development of multiple myeloma (MM). Our purpose was to determine risk of MM in relation to biologic DMARD treatment, duration of use and by biologic target in a large cohort of patients with rheumatologic conditions. METHODSWe conducted a nested case-control study within a cohort of adults undergoing active treatment for rheumatoid arthritis, psoriatic arthritis and ankylosing spondylitis. Patients were sampled from a population of commercially-insured U.S. health plan enrollees in the Truven Health MarketScan Research Database between 2009 and 2015. MM cases were ascertained using validated algorithms for administrative data. Up to ten controls from the overall cohort were matched to each MM case on age, sex and rheumatologic indication using incidence density sampling with replacement. Index date was defined as the date of MM diagnosis for a case and corresponding time at-risk for matched controls. Exposure was defined as both treatment and duration of biologic DMARD use including TNF inhibitor (etanercept, infliximab, adalimumab, golimumab, certolizumab pegol), IL-6 receptor antagonist (tocilizumab), T-cell targeted (abatacept) and B-cell depleting (rituximab) agents and were determined from health claims and pharmacy dispensing data. Data on rheumatologic indication, comorbid conditions and treatment with prescription nonsteroidal anti-inflammatory drugs (NSAIDs), corticosteroids and conventional synthetic DMARDs (hydroxychloroquine, sulfasalazine, methotrexate, leflunomide) were documented in the 12 month baseline period and during follow up as potential confounders. An exposure lag time of 365 days was used to minimize protopathic bias. Multivariable conditional logistic regression models were used to calculate adjusted odds ratios (OR) and 95% confidence intervals (CI) for risk of MM associated with biologic DMARDs. RESULTSFrom a retrospective cohort of 56866 adult patients with rheumatologic conditions, 287 MM cases and 2760 matched controls were identified. Compared to controls, a higher proportion of cases had Charlson comorbidity scores of 2 or greater (24% vs 18%) and used oral corticosteroids during follow up (67% vs 61%). Cases and controls were similar with respect to use of prescription NSAIDs (56% vs 59%) and use of conventional DMARDs (63% vs 67%). Use of biologic DMARDs overall was similar between cases and controls (14% vs 15%), although cases had a slightly lower proportion of etanercept users (5% vs 7%) and a slightly higher proportion of tocilizumab users (1.4% vs 0.4%). Biologic DMARD users were younger, more likely to have psoriatic arthritis or ankylosing spondylitis, lower comorbidity and greater use of concomitant NSAIDs and oral corticosteroids.Risk of MM was neither associated with biologic DMARD use overall (OR 0.84; 95% CI 0.57, 1.26; P=0.40) nor with longer duration of biologic DMARD use (>2.5 years: OR 0.72; 95% CI 0.34, 1.52; P=0.39). However, compared to patients treated with only conventional DMARDs, those receiving concomitant conventional plus biologic DMARDs had a 48% lower risk of developing MM (OR 0.52; 95% CI 0.30, 0.88; P=0.02). Associations with MM appeared to differ by specific biologic DMARD agent with estimates suggesting a lowered risk of MM with use of etanercept (OR 0.55; 95% CI 0.30, 1.02; P=0.06) and greater risk with use of tocilizumab (OR 4.33; 95% CI 1.33, 14.19; P=0.02) that was statistically significant, although confidence intervals were wide. CONCLUSIONSThe potential influence of biologic DMARDs on multiple myeloma is complex. We found that immune suppression with conventional plus biologic DMARDs is inversely associated with MM risk in patients with rheumatologic conditions, but this association differed by biologic drug target. Further research is needed to understand the roles of DMARDs targeting TNF and IL-6 in relation to subsequent myeloma pathogenesis. DisclosuresPatel:Celgene: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Janssen: Honoraria.

Changing Incidence of Major Cardiovascular Events in Multiple Myeloma Patients over Time

Background: While multiple myeloma (MM) comprises only 2% of all cancer diagnoses, the prevalence of the disease in the US has markedly increased from 46,865 patients in 2000 to 124,733 in 2015. New therapeutic classes have led to longer survival, and allowed older patients to undergo life-prolonging therapy. Survivorship issues are now becoming relevant for this population, as ongoing therapy may have as yet unappreciated long term sequelae. MM is a disease of older patients, with a median diagnosis age of 69, and the incidence is greatest among African Americans (AA), populations at higher risk of cardiovascular disease (CVD). We therefore designed a retrospective study to quantify the incidence of new CVD in this population, as well as changes in incidence over time, hypothesizing that CVD incidence would increase due to both longer survival times, and increased utilization of potentially cardiotoxic drugs.Methods: Using the California Cancer Registry linked to the California Patient Discharge Database, we identified 15,404 patients diagnosed with MM between 1991-2012 with follow-up through 2014. CVD was defined as a hospital admission for coronary artery disease (CAD), congestive heart failure (CHF), or stroke (CVA) using ICD9 codes or if the cause of death due to CVD was the first report of CVD. Patients with prior CVD or in whom CVD was diagnosed within 60 days of MM diagnosis were excluded. All patients had a minimum of 60 days of follow up. Changes in CVD rates were assessed by era: 1991-97 (era 1), 1998-2002 (era 2), 2003-07 (era 3) and 2008-12 (era 4). The cumulative incidence of CVD was estimated from date of MM diagnosis to first CVD event, accounting for the competing risk of death. Adjusted hazard ratios (aHR) for developing CVD were estimated accounting for the competing risk of death per the methods by Fine and Grey.Results: Of the 15,404 patients, 8,056 (52%) were male, 9154 (59%) were non-Hispanic white (NHW), 1890 (12%) were African American, 2839 (18%) were Hispanic, and 1360 (9%) were Asian. Median age at diagnosis was 65, with 12% of patients <50 and11%>80. Stem cell transplant was utilized by 2989 (19%) patients. The most common insurers were private/military (42%), followed by Medicare (31%), Medicaid/other public (7%), and unknown (19%) insurance. The median age of patients who developed CVD was 68 vs 63 who were never admitted for CVD (p<0.001). The 2 and 5 year cumulative incidence of developing CVD was 15.8% (95% confidence interval (CI): 15.2% - 16.3%) and 26.3% (CI: 25.6% - 27.0%). This was significantly less in era 4 (2008-12): 12.6% (11.6% - 13.7%) and 22.3% (20.9% - 23.8%) (p<0.001) (Figure). When examining types of CVD, CVA was less common in era 1 (1991-97) compared to eras 2-4 (5 year cumulative incidence rates in eras 1-4 respectively: 3.9% [3.4% - 4.5%], 4.6% [4.0% - 5.4%], 5.0% [4.3% - 5.7%], 4.6% [3.9% - 5.4%]) (p=0.002). CAD was less common in era 4 (5 year cumulative incidence rates in ears 1-4 respectively: 10.3% [9.4% - 11.2%], 11.5% [10.5% - 12.7%], 10.8% [9.9% - 11.9%], 9.4% [8.5% - 10.5%]) (p = 0.003). CHF was less common in era 4 (5 year cumulative incidence rates in eras 1-4 respectively: 17.9% [16.7% - 19.1%], 18.6% [17.3% - 20.0%], 17.7% [16.5% - 19.0%], 13.8% [12.6% - 15.0%].In multivariable analysis, increased age, male sex, AA race/ethnicity, increased Elixhauser comorbidity score were associated with increased risk of CVD. Surprisingly, after accounting for age Medicare insurance was associated with increased risk of CVD, while socioeconomic status was not. Use of stem cell transplant was associated with decreased risk, likely due to pre-transplant screening for CVD. Diagnosis during era 4 (2008 - 12) was associated with decreased risk of new CVD (adjusted hazard ratio 0.70 [CI: 0.63, 0.77]).Conclusion: CVD is a common complication in MM patients: within 5 years of a MM diagnosis, over 25% develop CVD requiring hospitalization. Contrary to our hypothesis, we did not find increased CVD admissions in the most recent era. Decreased admissions due to CHF and CAD in the most recent era of diagnosis may indicate a greater awareness of this issue, routine thromboprophylaxis with anti-platelet agents in patients being treated with immunomodulatory agents, or changes in secular trends in the diagnosis and treatment of CVD. CVD is an ongoing source of morbidity for MM patients requiring further study and the vigilance of clinicians. [Display omitted] DisclosuresRosenberg:Amgen: Research Funding, Speakers Bureau.

Risk Factors for Acute Myeloid Leukemia and Myelodysplastic Syndromes in Patients with Multiple Myeloma: An Updated Analysis

Risk factors for acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS) in patients with multiple myeloma (MM) are not well understood. We have previously shown that monoclonal gammopathy of undetermined significance (MGUS) is associated with an excess risk of AML/MDS, indicating an inherent excess risk of AML/MDS in plasma cell disorders. In addition, randomized studies have shown that lenalidomide maintenance is associated with increased relative risk of AML/MDS. The excess risk of AML/MDS in lenalidomide treated patients has been found to be most prominent in patients that also receive alkylating agents. A recent randomized clinical study shows that patients undergoing delayed autologous transplant have the same overall survival as patients undergoing upfront autologous transplant with high dose melphalan at 3 years of follow-up. Also emerging data shows that patients with minimal residual disease (MRD) negativity have very similar progression free survival independent of therapy. Thus, patients treated with modern combination therapy who obtain MRD negativity might not have additional benefit from upfront autologous transplant. We were motivated to better define the relationship of alkylating therapy to risk of secondary malignancies.Information was obtained regarding all subsequent hematologic malignancies in all patients diagnosed with MM from January 1, 1958 to December 31, 2011 identified from the Swedish Cancer Registry. Each patient with MM and a subsequent AML/MDS diagnosis (i.e., cases) was matched to another MM patient without AML/MDS for year of birth, sex, and date of MM diagnosis (i.e., control group). Detailed information on baseline characteristics at diagnosis and treatment was collected from medical records. Characteristics at MM diagnosis, radiation therapy, and high dose melphalan with autologous stem cell transplant (ASCT) were compared between groups with Kruskal-Wallis and Chi-square tests. Cumulative chemotherapy doses were analyzed with one way ANOVA. Post hoc analysis with Fisher´s least significant difference (LSD) was performed.A total of 26,627 patients were diagnosed with MM in Sweden during the study period. Of these, 113 patients developed subsequent AML/MDS. Data was found for 87 and they were matched to 69 controls. The demographic and clinical characteristics for both groups are listed in Table. The median age at MM diagnosis was 73 years (38 females and 49 males) for cases and 70 years (31 females and 38 males) for controls. The median time from MM diagnosis to AML/MDS diagnosis was 3.8 years (IQR 2.8 - 5.8). The mean cumulative melphalan dose was significantly higher (1,321 mg , SD ± 1,165 mg) for cases, than for the controls (709 mg , SD ± 565 mg)(p= <0.001). Post hoc analysis confirmed that cases had a statistically significant higher mean cumulative melphalan dose compared to controls, p <0.01.In this large nationwide population based study including almost 27,000 MM patients diagnosed during over >50 years period in Sweden, we confirm our previous preliminary findings that higher mean cumulative dose of melphalan was associated with increased risk of developing AML/MDS. With the average myeloma patient living over 10-15 years from diagnosis, strategies to avoid secondary complications is becoming more important. Our results showing that melphalan is associated with an increased risk of AML/MDS, call for studies using response driven (i.e. MRD based) therapy in myeloma; and high dose melphalan is rather offered to patients who are MRD positive, and/or as relapse therapy. [Display omitted] DisclosuresLandgren:Pfizer: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees.

Burden of CRAB Events By Relapse in Patients with Newly Diagnosed Multiple Myeloma Not Eligible for Stem Cell Transplant

▪Background: For decades, CRAB criteria (hypercalcemia, renal impairment, anemia, and bone disease) have been used to diagnose multiple myeloma (MM), but little is known about the economic burden of CRAB in patients with MM who have relapsed. The only category 1 doublet regimens recommended by NCCN Guidelines for non-transplant candidates are lenalidomide-based (NCCN Myeloma v4.2018). This study aims to evaluate CRAB event rates and the associated economic burden among newly diagnosed MM (NDMM) patients on doublet therapy who were not eligible for stem cell transplant (SCT) and were followed to next line of therapy.Methods: This retrospective study identified patients with ≥ 2 claims of MM (ICD-9-CM code: 203.0x; ICD-10-CM code: C90.0x) ≥ 30 days apart and ≥ 1 treatment (first claim date was used as index date) between January 1, 2011 and December 31, 2015 from the Medicare database. Eligible patients were required to have continuous enrollment from 6 months pre-index or first MM diagnosis date until ≥ 12 months post-index date unless patients died < 12 months post-index date (the follow-up period); ≥ 1 full cycle of therapy; no evidence of prior MM diagnosis or treatment (including autologous SCT [ASCT]); and no evidence of ASCT in the follow-up period. First line of therapy (LOT1) included all treatments prescribed within 60 days of the index date, and patients were included in the doublet therapy cohort based on the index treatment regimen. Progression to a subsequent LOT (LOT2) was defined by the earliest occurrence of an addition or switch to new non-maintenance treatment > 60 days post-index date, restart of any non-maintenance MM treatment after a > 180-day gap, or a dose increase from maintenance to relapse therapy. CRAB event rate per 1,000 person-years (PYs), CRAB event-related healthcare resource utilization (HRU) per patient per month (PPPM), and costs PPPM were evaluated during the LOT1 (the time from index date to end of LOT1) and LOT2 (the time from initiation of LOT2 to end of LOT2) among patients on doublet therapy with LOT1 and those who progressed to LOT2, respectively. Mean was calculated for the continuous variables, while categorical variables were presented as percentage values. Since the LOT2 population was a subset of the LOT1 population and they were not mutually exclusive cohorts, no statistical comparisons were made.Results: The study included 4,970 patients with MM not eligible for ASCT, of which 3,065 (61.7%) patients were prescribed doublet therapy in LOT1. Among these patients on doublet therapy, 1,122 (36.6%) initiated LOT2. The mean age was approximately 77 years, and most patients were white (LOT1, 77.0%; LOT2, 79.7%). The majority of the patients had hypertension (LOT1, 88.3%; LOT2, 86.1%), followed by anemia (LOT1, 79.0%; LOT2, 75.6%) and osteoarthritis (LOT1, 75.7%; LOT2, 76.7%), as comorbidities during the 6 months prior to the index date. CRAB event rates declined from LOT1 to LOT2, with the highest event rate per 1,000 PYs observed for anemia (LOT1, 1,965.1; LOT2, 1,808.2), followed by bone disease (LOT1, 258.1; LOT2, 244.1), renal impairment (LOT1, 167.9; LOT2, 159.9), and hypercalcemia (LOT1, 106.9; LOT2, 99.6); a decline in event rate was observed from LOT1 to LOT2 (Figure 1). CRAB event-related HRU PPPM increased from LOT1 to LOT2, including number of inpatient visits (LOT1, 0.1; LOT2, 0.2), length of inpatient stay (LOT1, 0.8 days; LOT2, 1.0 days), and number of outpatient hospital visits (LOT1, 2.0; LOT2, 2.2). However, the number of outpatient office visits PPPM decreased from LOT1 to LOT2 (LOT1, 0.9; LOT2, 0.8). Similarly, there was a trend toward increased CRAB event-related healthcare costs PPPM from LOT1 to LOT2 (Figure 2) including inpatient (LOT1, USD 1,548; LOT2, USD 2,031), outpatient hospital (LOT1, USD 214; LOT2, USD 301), outpatient office (LOT1, USD 77; LOT2, USD 89), and total medical costs (LOT1, USD 2,120; LOT2, USD 2,593).Conclusions: This study shows that CRAB events were more expensive to treat as patients relapse. Delaying disease progression may be associated with lower HRU and potential cost savings, thereby reducing the burden of MM. A potential limitation of this study is that claims data do not include clinical parameters. Future studies should be considered to evaluate the impact of age and comorbidities on the economic burden associated with CRAB events. This study also highlights the value of delaying progression and the time to next treatment. DisclosuresPandya:Celgene Corporation: Consultancy; STATinMED Research: Employment. Clancy:Celgene Corporation: Employment, Equity Ownership, Research Funding. Shrestha:STATinMED Research: Employment, Equity Ownership. Wang:STATinMED Research: Employment, Equity Ownership.

Real-world economic outcomes of early progression in newly diagnosed multiple myeloma (NDMM) patients (Pts).

194 Background: Despite improved survival with advanced multiple myeloma (MM) treatments (Tx), 15–20% of pts experience early relapse. We assessed the economic impact of early progression among non-stem-cell transplant NDMM pts. Methods: NDMM pts with ≥ 1 Tx (1st claim date: index date) from 01Jan2011–31Dec2015 were identified from the 100% Medicare database. Eligible pts had ≥ 1 full cycle of therapy and continuous health plan enrollment from 6 months pre-index or first MM diagnosis date until ≥ 12 month post-index date unless pts died &lt; 12 months post-index date. First line of therapy (LOT1) included all Txs prescribed ≤ 60 days post-index date. Among pts who progressed to LOT2, median time to next Tx (TTNT) was estimated from a Kaplan–Meier curve as duration from LOT1 start until the earliest of an addition/switch/restart of non-maintenance MM Tx, or dose increase from maintenance to relapse therapy. Pts who progressed to LOT2 prior to and after median TTNT were included in the early and delayed progression cohorts, respectively. Annual all-cause and MM-related healthcare costs estimated from a generalized linear model were compared between doublet therapy pts in LOT1 in the early and delayed progression cohorts. Results: Of 3,768 MM pts with LOT1, 36.1% progressed to LOT2 with median TTNT of 302 days; 81.3% pts initiated doublet therapy in LOT1, of which 19.2% (n = 589) and 17.3% (n = 533) were included in the early and delayed progression cohorts, respectively. Pts in the early progression cohort were younger and incurred higher all-cause inpatient ($17,332 vs $10,455), outpatient hospital ($18,183 vs $15,097), emergency department ($462 vs $395), office ($37,728 vs $29,174), and total costs ($130,948 vs $108,003) compared with the delayed progression cohort. Similarly, the early progression cohort had higher MM-related total costs ($87,284 vs $72,150) including inpatient and outpatient costs (all P&lt; 0.001). All-cause and MM-related pharmacy costs were similar between cohorts. Conclusions: Early progression after LOT1 is associated with substantially higher economic burden indicating the need for future studies of therapies that delay progression and potentially result in cost savings.

Risk factors for blood stream infections in multiple myeloma: A population-based study of 1154 patients in Denmark.

Multiple myeloma (MM) patients are at high risk of developing infections. The risk factors for blood stream infections (BSI) in MM patients are, however, less described. The aim of this study was to analyze the epidemiology of and risk factors for BSI in an unselected MM population. Nationwide Danish MM data of 1154 patients diagnosed from 2010 to 2013 were linked with nationwide data on blood cultures (BCs; from 2010 to 2016) to assess the peak period of having a BC taken and BC positive for pathogenic microorganisms. The highest number of BC was taken in the period from day -30 to day +180 from date of MM diagnosis. Risk factors for having a BC sampling within the peak period were as follows: immunoparesis (HR 1.5 [1.1-2.1]; P=.007), ISS-III (HR 1.3 [1.0-1.7]; P=.035), high creatinine (HR 1.4 (1.0-2.0); P=.046), and high lactate dehydrogenase (LDH) (HR 2.8 (1.6-4.7; P<.001). Risk factors for positive BC during the peak period were ISS-III (HR 2.0 (1.1-3.7); P=.023) and high LDH (HR 3.4 [1.1-10.3]; P=.028). Our results show that MM patients with aggressive disease presentation are at the highest risk of developing BSI. Furthermore, our study implies that MM is diagnosed in relation to a serious infection for a large number of patients.