A phase Ib trial of isatuximab, bendamustine, and prednisone in relapsed/refractory multiple myeloma.

INTRODUCTION: Patients with triple-class refractory (TCR) multiple myeloma (MM) often need cytoreductive chemotherapy for rapid disease control. Bendamustine is an outpatient-administered, bifunctional alkylator and isatuximab is an anti-CD38 monoclonal antibody with unique cytotoxicity characteristics. We hypothesized that isatuximab-bendamustine-prednisone would be well-tolerated regimen in TCR MM, and conducted single-center, phase Ib, investigator-initiated study. PATIENTS/METHODS: Patients had TCR MM and last daratumumab exposure ≥ 6 weeks. This study was conducted as a 3 + 3 design to establish the maximally tolerated dose (MTD) and/or recommended phase 2 dose (RP2D). Isatuximab 10 mg/kg IV was administered weekly (cycle 1), and every 2 weeks thereafter. Bendamustine was administered on days 1 and 2 at 3 dose levels (DL): 50, 75, and 100 mg/m2. Methylprednisolone was administered as 125 mg on day 1 and prednisone 60 mg days 2-4. Common definitions were used for DLTs, adverse events (CTCAE v 5.0), and disease response. RESULTS: Fifteen patients were treated (3 DL1, 6 DL2, 6 DL3). Median age was 71, 53% had high-risk cytogenetics, and 34% had prior BCMA-targeting therapy. One DLT was observed at DL2 (Grade 3 thrombocytopenia plus bleeding). There were no Grade 5 treatment-related AEs. The MTD was not reached. The overall response rate was 20% (3/15) including one stringent complete response. The median PFS was 2.5 months (95% CI 0.9-4.1 months). CONCLUSION: We demonstrated the safety and tolerability of isatuximab-bendamustine-prednisone. Toxicities were mild and manageable with limited intervention. The study was discontinued due to slow accrual. However, we observed responses even among highly refractory patients. CLINICAL TRIAL REGISTRATION: This study was registered on clinicaltrials.gov as NCT04083898 on 9/6/2019.

Somatic mutation phasing and haplotype extension using linked-reads in multiple myeloma.

Somatic mutation phasing informs our understanding of cancer-related events, like driver mutations. We generated linked-read whole genome sequencing data for 23 samples across disease stages from 14 multiple myeloma (MM) patients and systematically assigned somatic mutations to haplotypes using linked-reads. Here, we report the reconstructed cancer haplotypes and phase blocks from several MM samples and show how phase block length can be extended by integrating samples from the same individual. We also uncover phasing information in genes frequently mutated in MM, including DIS3, HIST1H1E, KRAS, NRAS, and TP53, phasing 79.4% of 20,705 high-confidence somatic mutations. In some cases, this enabled us to interpret clonal evolution models at higher resolution using pairs of phased somatic mutations. For example, our analysis of one patient suggested that two NRAS hotspot mutations occurred on the same haplotype but were independent events in different subclones. Given sufficient tumor purity and data quality, our framework illustrates how haplotype-aware analysis of somatic mutations in cancer can be beneficial for some cancer cases.

IL-10R inhibition reprograms tumor-associated macrophages and reverses drug resistance in multiple myeloma.

Multiple myeloma (MM) is the cancer of plasma cells within the bone marrow and remains incurable. Tumor-associated macrophages (TAMs) within the tumor microenvironment often display a pro-tumor phenotype and correlate with tumor proliferation, survival, and therapy resistance. IL-10 is a key immunosuppressive cytokine that leads to recruitment and development of TAMs. In this study, we investigated the role of IL-10 in MM TAM development as well as the therapeutic application of IL-10/IL-10R/STAT3 signaling inhibition. We demonstrated that IL-10 is overexpressed in MM BM and mediates M2-like polarization of TAMs in patient BM, 3D co-cultures in vitro, and mouse models. In turn, TAMs promote MM proliferation and drug resistance, both in vitro and in vivo. Moreover, inhibition of IL-10/IL-10R/STAT3 axis using a blocking IL-10R monoclonal antibody and STAT3 protein degrader/PROTAC prevented M2 polarization of TAMs and the consequent TAM-induced proliferation of MM, and re-sensitized MM to therapy, in vitro and in vivo. Therefore, our findings suggest that inhibition of IL-10/IL-10R/STAT3 axis is a novel therapeutic strategy with monotherapy efficacy and can be further combined with current anti-MM therapy, such as immunomodulatory drugs, to overcome drug resistance. Future investigation is warranted to evaluate the potential of such therapy in MM patients.

Treatment Access among Younger Medicaid Beneficiaries with Multiple Myeloma.

PURPOSE: Continuous Medicaid coverage prior to a cancer diagnosis has been associated with earlier detection and better outcomes, for patients with solid tumors. In this study, we aimed to determine if this was observed among patients with multiple myeloma, a hematologic cancer where there are no routine screening tests and most are diagnosed through acute medical events. MATERIALS AND METHODS: This is an analysis of the Merative MarketScan Multistate Medicaid Database, a claims-based dataset. In total, 1105 patients < 65 years old were included in the analyses. Among them, 66% had continuous enrollment (at least 6 months enrollment prior to myeloma), and 34% had discontinuous enrollment (2-6 months enrollment prior to myeloma). Multivariable Cox regression was used to estimate the association between continuous enrollment status and receipt of myeloma treatment within 1 year of index date. RESULTS: Only 54% of all Medicaid enrollees received myeloma therapy and only 12% received stem cell transplant within the 1st year. Those with continuous enrollment were less likely to receive any treatment (adjusted hazard ratio [aHR] 0.59; 95% confidence interval [CI] 0.59-0.70; P < .001) and to receive stem cell transplant (aHR 0.51; 95% CI 0.32-0.81; P = .005). CONCLUSION: Patients with continuous Medicaid coverage prior to diagnosis were less likely to receive myeloma therapy. Future studies should examine whether myeloma patients with continuous Medicaid enrollment have more chronic financial instability and/or higher medical needs and, thus, have higher barriers to care.

LINC01432 binds to CELF2 in newly diagnosed multiple myeloma promoting short progression-free survival to standard therapy.

Multiple Myeloma (MM) is a highly prevalent and incurable form of cancer that arises from malignant plasma cells, with over 35,000 new cases diagnosed annually in the United States. While there are a growing number of approved therapies, MM remains incurable and nearly all patients will relapse and exhaust all available treatment options. Mechanisms for disease progression are unclear and in particular, little is known regarding the role of long non-coding RNAs (lncRNA) in mediating disease progression and response to treatment. In this study, we used transcriptome sequencing to compare newly diagnosed MM patients who had short progression-free survival (PFS) to standard first-line treatment (PFS < 24 months) to patients who had prolonged PFS (PFS > 24 months). We identified 157 differentially upregulated lncRNAs with short PFS and focused our efforts on characterizing the most upregulated lncRNA, LINC01432. We investigated LINC01432 overexpression and CRISPR/Cas9 knockdown in MM cell lines to show that LINC01432 overexpression significantly increases cell viability and reduces apoptosis, while knockdown significantly reduces viability and increases apoptosis, supporting the clinical relevance of this lncRNA. Next, we used individual-nucleotide resolution cross-linking immunoprecipitation with RT-qPCR to show that LINC01432 directly interacts with the RNA binding protein, CELF2. Lastly, we showed that LINC01432-targeted locked nucleic acid antisense oligonucleotides reduce viability and increases apoptosis. In summary, this fundamental study identified lncRNAs associated with short PFS to standard NDMM treatment and further characterized LINC01432, which inhibits apoptosis.

Financial Toxicity and Willingness-to-Pay for Cancer Treatment Among People With Multiple Myeloma.

PURPOSE: This study used willingness-to-pay (WTP) exercises to explore the relationships between race, financial toxicity, and treatment decision making among people with cancer. METHODS: A convenience sample of people with multiple myeloma who attended an academic medical center in 2022 was surveyed. Financial toxicity was assessed by the Comprehensive Score for financial Toxicity, with scores <26 indicating financial toxicity. WTP was assessed with (1) a discrete choice experiment (DCE), (2) fixed-choice tasks, and (3) a bidding game. RESULTS: In total, 156 people were approached, and 130 completed the survey. The majority of the sample was White (n = 99), whereas 24% (n = 31) was African American or Black. Forty-six percent (n = 60) of the sample were experiencing financial toxicity. In the DCE, the relative importance of cost was twice as high for those with financial toxicity (30% compared with 14%; P < .001). In the fixed-choice tasks, they were twice as likely to accept a treatment with shorter progression-free survival but lower costs (adjusted odds ratio [aOR], 2.47; P = .049). In the bidding game, the median monthly WTP of those with financial toxicity was half that of those without ($100 in US dollars [USD] compared with $200 USD; P < .001). Only in the bidding game was race statistically associated with WTP; after controlling for financial toxicity, African American or Black participants were three times as likely (aOR, 3.06; P = .007) to report a lower WTP. CONCLUSION: Across all three exercises, participants with financial toxicity reported lower WTP than those without. As financial toxicity disproportionally affects some segments of patients, it is possible that financial toxicity contributes to cancer disparities.

A single-cell atlas characterizes dysregulation of the bone marrow immune microenvironment associated with outcomes in multiple myeloma.

Multiple Myeloma (MM) remains incurable despite advances in treatment options. Although tumor subtypes and specific DNA abnormalities are linked to worse prognosis, the impact of immune dysfunction on disease emergence and/or treatment sensitivity remains unclear. We established a harmonized consortium to generate an Immune Atlas of MM aimed at informing disease etiology, risk stratification, and potential therapeutic strategies. We generated a transcriptome profile of 1,149,344 single cells from the bone marrow of 263 newly diagnosed patients enrolled in the CoMMpass study and characterized immune and hematopoietic cell populations. Associating cell abundances and gene expression with disease progression revealed the presence of a proinflammatory immune senescence-associated secretory phenotype in rapidly progressing patients. Furthermore, signaling analyses suggested active intercellular communication involving APRIL-BCMA, potentially promoting tumor growth and survival. Finally, we demonstrate that integrating immune cell levels with genetic information can significantly improve patient stratification.

Mixed-Methods Study on the Responsiveness of the Comprehensive Score for Financial Toxicity Among People With Multiple Myeloma.

PURPOSE: Financial toxicity is a contributor to the psychosocial burden of cancer care. There is no consensus measure of financial toxicity; however, recent studies have adopted the Comprehensive Score for Financial Toxicity (COST). Despite its growing popularity, data on the responsiveness to change of the COST instrument are lacking. To address this gap in the literature, we performed a sequential mixed-methods study of people with multiple myeloma. MATERIALS AND METHODS: In the quantitative phase of the study, we collected COST scores at two time points approximately 8 weeks apart from 72 patients. In the qualitative phase, we conducted semistructured interviews with a subset of 12 patients who reported the largest changes in scores. The qualitative data were analyzed using a deductive coding scheme developed using the Framework Method in the context of a commonly cited conceptual model of financial toxicity. RESULTS: The median absolute change in COST scores was four points (IQR, 2-6). Only 13% of the sample had the same COST scores at both assessments; 38% had an improved score and 50% had a worsened score. Only, seven of the 12 patients (58%) interviewed reported changes to one or more of the constructs in the conceptual model of financial toxicity. Most commonly, changes to out-of-pocket medical costs were reported (5/12). Changes to nonmedical expenses (n = 2) and subjective financial distress without changes to objective financial burden (n = 2) were also reported. CONCLUSION: Additional research is needed to explicate changes in COST scores over time.

A structured oral chemotherapy teaching tool to improve adherence in adults with multiple myeloma: A pilot randomized controlled trial.

INTRODUCTION: Many of the newer treatments for adults with newly-diagnosed and relapsed multiple myeloma (MM) are orally administered. Adherence is a challenge, and little is known about strategies to optimize adherence. MATERIALS AND METHODS: Forty-seven patients initiating orally-administered anti-myeloma therapy were enrolled and randomized in a pilot study to receive either standard of care teaching or the Multinational Association of Supportive Care in Cancer Oral agent Teaching Tool (MOATT), a structured teaching tool. Adherence was measured electronically with a Medication Event Monitoring System (MEMS) cap. Optimal adherence was defined as an adherence rate of ≥90% over the six months study duration. Patients completed surveys regarding cancer therapy satisfaction and self-efficacy for medication management at one month and six months following the initiation of treatment in both arms. RESULTS: The mean adherence of patients over six months was 86.9%; 43.9% of the cohort were classified as non-adherent using the 90% threshold of adherence. Mean adherence was similar among standard of care teaching (87.9%) versus the MOATT intervention tool (85.6%) as was cancer therapy satisfaction and self-efficacy for medication management. DISCUSSION: In our pilot, the MOATT tool was not found to be feasible or acceptable. There were no preliminary differences noted between standard of care teaching versus the structured MOATT teaching tool with regards to overall adherence rates, cancer therapy satisfaction, or self-efficacy in medication management. Overall adherence rates were suboptimal in our study. Future research should work to identify aspects of educational interventions which are effective, and investigate different strategies which can be used to supplement patient education and potentially optimize medication adherence in patients with MM.

Duvelisib for Critically Ill Patients With Coronavirus Disease 2019: An Investigator-Initiated, Randomized, Placebo-Controlled, Double-Blind Pilot Trial.

Background: Despite improvements in prevention and treatment, severe coronavirus disease 2019 (COVID-19) is associated with high mortality. Phosphoinositide 3-kinase (PI3K) pathways contribute to cytokine and cell-mediated lung inflammation. We conducted a randomized, placebo-controlled, double-blind pilot trial to determine the feasibility, safety, and preliminary activity of duvelisib, a PI3Kδγ inhibitor, for the treatment of COVID-19 critical illness. Methods: We enrolled adults aged ≥18 years with a primary diagnosis of COVID-19 with hypoxic respiratory failure, shock, and/or new cardiac disease, without improvement after at least 48 hours of corticosteroid. Participants received duvelisib (25 mg) or placebo for up to 10 days. Participants had daily semi-quantitative viral load measurements performed. Dose modifications were protocol driven due to adverse events (AEs) or logarithmic change in viral load. The primary endpoint was 28-day overall survival (OS). Secondary endpoints included hospital and intensive care unit length of stay, 60-day OS, and duration of critical care interventions. Safety endpoints included viral kinetics and AEs. Exploratory endpoints included serial cytokine measurements and cytometric analysis. Results: Fifteen patients were treated in the duvelisib cohort, and 13 in the placebo cohort. OS at 28 days was 67% (95% confidence interval [CI], 38%-88%) compared to 62% (95% CI, 32%-86%) for placebo (P = .544). Sixty-day OS was 60% versus 46%, respectively (hazard ratio, 0.66 [95% CI, .22-1.96]; P = .454). Other secondary outcomes were comparable. Duvelisib was associated with lower inflammatory cytokines. Conclusions: In this pilot study, duvelisib did not significantly improve 28-day OS compared to placebo for severe COVID-19. Duvelisib appeared safe in this critically ill population and was associated with reduction in cytokines implicated in COVID-19 and acute respiratory distress syndrome, supporting further investigation. Clinical Trials Registration: NCT04372602.

Disparities in Multiple Myeloma Treatment Patterns in the United States: A Systematic Review.

We performed a systematic review of the literature investigating the demographic and insurance-related factors linked to disparities in multiple myeloma (MM) care patterns in the United States from 2003 to 2021. Forty-six observational studies were included. Disparities in MM care patterns were reported based on patient race in 76% of studies (34 out of 45 that captured race as a study variable), ethnicity in 60% (12 out of 20), insurance in 77% (17 out of 22), and distance from treating facility, urbanicity, or geographic region in 62% (13 out of 21). A smaller proportion of studies identified disparities in MM care patterns based on other socioeconomic characteristics, with 36% (9 out of 25) identifying disparities based on income estimate or employment status and 43% (6 out of 14) based on language barrier or education-related factors. Sociodemographic characteristics are frequently associated with disparities in care for individuals diagnosed with MM. There is a need for further research regarding modifiable determinants to accessing care such as insurance plan design, patient out-of-pocket costs, preauthorization criteria, as well as social determinants of health. This information can be used to develop actionable strategies for reducing MM health disparities and enhancing timely and high-quality MM care.

Continuous Elotuzumab, Pomalidomide, and Dexamethasone Maintenance Following Second Autologous Transplantation for Multiple Myeloma: Results of a Prospective Phase 2 Multicenter Trial.

Second autologous hematopoietic cell transplantation (AHCT2) is a useful therapeutic modality for fit patients with multiple myeloma who have durable remission after upfront AHCT. Retrospective studies have suggested a significant benefit of incorporating maintenance therapy post-AHCT2, but prospective data on specific regimens are lacking. The purpose of this study was to investigate the use of elotuzumab, pomalidomide, and dexamethasone (EPd) as salvage therapy prior to and maintenance after AHCT2 for relapsed multiple myeloma. This prospective single-arm phase II trial investigating the use of EPd in combination with AHCT2 in patients with relapsed multiple myeloma was conducted at 2 academic centers in North America. The primary outcome was 1-year progression-free survival (PFS). Twenty-five patients were enrolled on the study. Sixteen patients received EPd induction; six patients (38%) progressed during salvage therapy and were removed from the trial prior to AHCT2. Following a planned safety analysis, the protocol was amended, and EPd induction was removed from the study schema. An additional 9 patients underwent induction off-study and were enrolled on trial for AHCT2 and EPd maintenance. A total of 18 patients underwent AHCT2 and received EPd maintenance. Two patients discontinued treatment because of toxicity, one attributed to elotuzumab and the other to pomalidomide. The 1-year PFS was 72%, and the median PFS was 19 months. The study was closed early owing to poor accrual; 6 patients remained on therapy at time of analysis. EPd maintenance after AHCT2 was safe and tolerable. The 1-year PFS and median PFS were similar to values in previous retrospective reports of outcomes following AHCT2. Further studies are needed to define the optimal use of and protocol for AHCT2 in fit patients with relapsed multiple myeloma.

Venous Thromboembolism Risk in Patients With Newly Diagnosed Multiple Myeloma Treated with Carfilzomib or Bortezomib in Combination With Lenalidomide and Dexamethasone.

BACKGROUND: Multiple myeloma (MM), as well as some treatments for MM, increase the risk of venous thromboembolism (VTE). Prior literature suggests carfilzomib, lenalidomide, and dexamethasone (KRd) may have a higher incidence of thromboembolic events compared with bortezomib, lenalidomide, and dexamethasone (VRd). We aimed to evaluate VTE risk with KRd induction compared to VRd at a large academic medical center in the United States. MATERIALS AND METHODS: We retrospectively reviewed patients with newly diagnosed MM presenting at a single institution. Patients were followed for objectively diagnosed VTE events for 6 months following the start of induction therapy. RESULTS: A total of 209 patients were included, with 69 (33%) receiving KRd and 140 (67%) receiving VRd. Overall, 18 patients (9%) had a VTE event, with 5 (7%) in the KRd cohort and 13 (9%) in the VRd cohort (P = .80). Treatment with KRd was not associated with an increased risk of VTE compared to VRd (HR 0.74; 95% CI 0.26-2.08; P = .57). CONCLUSION: In this cohort, KRd was not associated with an increase in VTE risk compared to VRd, contrary to prior literature.

Phase I-II Trial of Early Azacitidine after Matched Unrelated Donor Hematopoietic Cell Transplantation.

Graft-versus-host disease (GVHD) is a major complication after allogeneic hematopoietic cell transplantation (allo-HCT). The hypomethylating agent azacitidine (AZA) has been shown to be effective in preclinical and clinical studies for the prevention of acute GVHD (aGVHD). We sought to determine the maximum tolerated dose (MTD) of AZA when given on days 1 to 5 of a 28-day cycle for 4 cycles, starting on day +7 after allo-HCT, as well as its impact on aGVHD and chronic GVHD (cGVHD), relapse, and overall survival (OS) in patients undergoing matched unrelated donor allo-HCT. This study was a single-arm, single-center, open-label phase I-II study with a total of 15 and 38 patients enrolled in the phase I and II portions of the trial, respectively. A standard 3+3 study design was used in phase I, and all patients in phase II received AZA at the MTD determined in phase I. The MTD of AZA starting at day +7 post-transplantation was 45 mg/m2. Phase II of the study was halted after enrolling 38 of the planned 46 patients following an interim analysis that suggested futility. Overall, AZA at 45 mg/m2 exhibited a side effect profile consistent with prior reports and had a minimal impact on engraftment. The cumulative incidence of clinically significant aGVHD by day +180 was 39.9% (95% confidence interval [CI], 22% to 53.7%). The incidence of all-grade cGVHD was 61.4% (95% CI, 40.3% to 75%). At 1 year, OS was 73.7% (95% CI, 60.9% to 89.1%), and the disease relapse rate was 11.4% (95% CI, .2% to 21.3%). Our results suggest that early post-allo-HCT AZA has limited efficacy in preventing aGVHD and cGVHD but could have a beneficial effect in preventing disease relapse.

Frailty and survival among veterans treated with abiraterone or enzalutamide for metastatic castration-resistant prostate cancer.

INTRODUCTION: Abiraterone and enzalutamide are treatments for metastatic castration-resistant prostate cancer (mCRPC). Due to a lack of head-to-head trials, they are prescribed interchangeably. However, the drugs have different pharmacokinetics and thus may have differing efficacy and adverse effects influenced by patient functional status and comorbid diseases. Additionally, mCRPC mainly affects older adults and since the prevalence of frailty increases with age, frailty is an important patient factor to consider in personalizing drug selection. MATERIALS AND METHODS: We conducted a retrospective observational study of US veterans treated with abiraterone or enzalutamide for mCRPC from September 2014 to June 2017. Frailty was assessed using the Veterans Affairs Frailty Index (VA-FI), which utilizes administrative codes to assign a standardized frailty score. Patients were categorized as frail if VA-FI scores were > 0.2. The primary outcome was difference in overall survival (OS) between the two treatment groups. Cox regression modeling and propensity score matching was used to compare between abiraterone and enzalutamide treatments. RESULTS: We identified 5,822 veterans, 57% of whom were initially treated with abiraterone and 43% with enzalutamide. Frail patients (n = 2,314; 39.7%) were older, with a mean age of 76.1 versus 74.9 years in the non-frail group (n = 3,508; 60.3%, p < 0.001) and had shorter OS compared to non-frail patients regardless of treatment group (18.5 vs. 26.6 months, p < 0.001). Among non-frail patients there was no significant difference in OS between abiraterone and enzalutamide treatment (27.7 vs 26.1 months, p = 0.07). However, frail patients treated with enzalutamide versus abiraterone had improved OS (20.7 vs 17.2 months, p < 0.001). In a propensity score matched analysis of frail patients (n = 2,070), enzalutamide was associated with greater median OS (24.1 vs 20.9 months, p < 0.001). In patients with dementia, enzalutamide was associated with longer OS (19.4 vs. 16.6 months, p = 0.003). DISCUSSION: In this study of 5822 US veterans with mCRPC, treatment with enzalutamide was associated with improved OS compared to abiraterone among frail veterans and veterans with dementia, but not among non-frail veterans. Future studies should evaluate interactions between frailty and cancer treatments to optimize selection of therapy among frail adults.

A Single Reference Interval for Interpreting Serum Free Light Chains across Patients with Varying Renal Function.

BACKGROUND: Serum free light chain (sFLC) assays are interpreted using a sFLC-ratio-based reference interval (manufacturer's interval) that was defined using a cohort of healthy patients. However, renal impairment elevates the sFLC-ratio, leading to a high false positive rate when using the manufacturer's interval. Prior studies have developed renal-specific reference intervals; however, this approach has not been widely adopted due to practical limitations. Thus, there remains a critical need for a renally robust sFLC interpretation method. METHODS: Retrospective data mining was used to define patient cohorts that reflect the spectrum of renal function seen in clinical practice. Two new reference intervals, one based on the sFLC-ratio and one based on a novel principal component analysis (PCA)-based metric, were developed for the FREELITE assay (Binding Site) on the Roche Cobas c501 instrument (Roche). RESULTS: Compared to the manufacturer's reference interval, both new methods exhibited significantly lower false positive rates and greater robustness to renal function while maintaining equivalent sensitivity for monoclonal gammopathy (MG) diagnosis. While not significantly different, the point estimate for sensitivity was highest for the PCA-based approach. CONCLUSION: Renally robust sFLC interpretation using a single reference interval is possible given a reference cohort that reflects the variation in renal function observed in practice. Further studies are needed to achieve sufficient power and determine if the novel PCA-based metric offers superior sensitivity for MG diagnosis. These new methods offer the practical advantages of not requiring an estimated glomerular filtration rate result or multiple reference intervals, thereby lowering practical barriers to implementation.

Dynamic frailty risk assessment among older adults with multiple myeloma: A population-based cohort study.

Multiple myeloma (MM) is a cancer of older adults and those who are more frail are at high risk of poor outcomes. Current tools for identifying and categorizing frail patients are often static and measured only at the time of diagnosis. The concept of dynamic frailty (i.e. frailty changing over time) is largely unexplored in MM. In our study, adults with newly-diagnosed MM who received novel drugs between the years 2007-2014 were identified in the Surveillance, Epidemiology, and End Results (SEER)-Medicare linked databases. Using a previously published cumulative deficit approach, a frailty index score was calculated at diagnosis and each landmark interval (1-yr, 2-yr, 3-yr post diagnosis). The association of frailty with overall survival (OS) both at baseline and at each landmark interval as well as factors associated with worsening frailty status over time were evaluated. Overall, 4617 patients were included. At baseline, 39% of the patients were categorized as moderately frail or severely frail. Among those who had 3 years of follow-up, frailty categorization changed post diagnosis in 93% of the cohort (78% improved and 72% deteriorated at least at one time point during the follow up period). In a landmark analysis, the predictive ability of frailty at the time of diagnosis decreased over time for OS (Harrell's C Statistic 0.65 at diagnosis, 0.63 at 1-yr, 0.62 at 2-yr, and 0.60 at 3-yr) and was inferior compared to current frailty status at each landmark interval. Our study is one of the first to demonstrate the dynamic nature of frailty among older adults with MM. Frailty may improve or deteriorate over time. Current frailty status is a better predictor of outcomes than frailty status at time of diagnosis, indicating the need for re-measurement in this high-risk patient population.