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Transformative success of cancer immunotherapy has revolutionized cancer treatment and can induce long lasting responses in patients with cancers from a wide range of histologies. However, only a fraction of patients respond to immunotherapy and cancer cells escape immunosurveillance through molecular mechanisms that remain elusive. Proteasomes play a central role in the immune response by generating peptides from intracellular antigens which are presented on the cell surface for recognition by CD8+ cytotoxic T lymphocytes (CTLs). Malignant cells employ strategies to downregulate antigen presentation and impair CTL-mediated tumor recognition and lysis. Recently, we discovered that HDAC6-specific inhibitors increased intracellular proteasome activity and the generation of antigenic class I MHC peptides. However, current HDAC6 inhibitors have pharmacologic liabilities that limit efficacy, e.g., low potency and solubility, poor pharmacokinetic properties and potential genotoxicity. Therefore, we performed a cell-based, high-throughput screen (HTS) of 9,600 HDAC-specific compounds to identify novel compounds that increased proteasomal activity in myeloma cells. We identified 8 hits that increased proteasomal activity at least two-fold. Importantly, two novel molecules identified in the HTS increased proteasome activity more potently and more rapidly than the HDAC6-specific inhibitors Tubastatin-A and ACY-1215 (Ricolinostat) with comparatively low cytotoxicity. Proteasomes degrade chicken ovalbumin (Ova) to generate the immunodominant antigen SIINFEKL presented at the cell surface complexed with the MHC-class I molecule H-2Kb. Treatment of tumor cells with Tubastatin-A and ACY-1215 increased levels of the MHC-class I-SIINFEKL complex by ~3-fold. Tumor cells were pretreated with Tubastatin-A and ACY-1215 and then co-cultured with CTLs that had been genetically-engineered to express a SIINFEKL-restricted T-cell receptor (TCR). Pre-treatment of lymphoma or multiple myeloma cells with novel HDAC6 inhibitors also increased tumor lysis by CTLs that expressed the SIINFEKL-restricted TCR by 2-fold. Taken together, our results support repositioning pharmacologics that inhibit HDAC6 to activate proteasomal generation of antigenic peptides and boost antigen presentation as cancer immunotherapeutics. Citation Format: Priyanka S. Rana, James Ignatz-Hoover, James J. Driscoll. Discovery of novel HDAC6 inhibitors that enhance proteasomal activity to boost antigen presentation and trigger anti-myeloma T-cell immunity [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 6235.

Multiple myeloma (MM) remains an incurable, genetically heterogeneous disease characterized by the uncontrolled proliferation of transformed plasma cells nurtured within a permissive bone marrow (BM) microenvironment. Current therapies leverage the unique biology of MM cells and target the immune microenvironment that drives tumor growth and facilitates immune evasion. Proteasome inhibitors and immunomodulatory drugs were initially introduced to complement and have now supplanted cytotoxic chemotherapy as frontline anti-myeloma agents. Recently, monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor T cells were developed to revamp the immune system to overcome immune suppression and improve patient responses. While current MM therapies have markedly extended patient survival, acquired drug resistance inevitably emerges and drives disease progression. The logical progression for the next generation of MM therapies would be to design and validate agents that prevent and/or overcome acquired resistance to immunotherapies. The complex BM microenvironment promotes resistance to both current anti-myeloma agents and emerging immunotherapies. Myeloma cells are intertwined with a complex BM immune microenvironment that contributes to the development of adaptive drug resistance. Here, we describe recently FDA-approved and investigational anti-myeloma agents that directly or indirectly target the BM microenvironment to prevent or overcome drug resistance. Synergistic effects of anti-myeloma agents may foster the development of rationally-designed drug cocktails that prevent BM-mediated resistance to immunotherapies.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant, clonal plasma cell disorder, characterized by the presence of a monoclonal (M) protein in serum, 50 years, respectively. Although renal failure is a defining feature of MM, frequently patients (pts) with a variety of renal pathologies have less than 10% plasma cell burden in the bone marrow, therefore they cannot be categorized as MM to be eligible for an anti-myeloma therapy. However, it is clear that there is a causative relationship between MGUS and the pathologic process in kidneys in at least a subset patient and starting anti-myeloma therapy potentially can reverse or slow down the renal insult caused by MGUS. This led to the creation of the new entity and term, "monoclonal gammopathy of renal significance" (MGRS), to properly convey the nature of these relationship. Therefore, MGRS depicts a subset of MGUS and ascertains that the significance of the monoclonal gammopathy is no longer undetermined. The epidemiology and health care burden of MGRS remains largely unknown. The incidence of MGRS, based on reports from single institutions, is estimated about 6%-10% of cases of MGUS (Nelson Leung et al. Blood. 2012), which suggests a total prevalence of 0.5-1% in the total United States population, accounting for a significant health care burden of 1.5-3 million cases with MGRS. Since pathologic characterization of MGRS is recent, a novel study to define the epidemiology of this subset of MGUS, its temporal course in relation to chronic kidney disease kidney (CKD), the risk factors for progression to end stage renal disease (ESRD) is urgently needed. Methods: All pts from the University Hospitals Cleveland Medical Center, Cleveland, OH, diagnosed with CKD from 2000 to 2019 were included. We identified all cases with diagnosis of MGUS by ICD code. Time to end stage renal disease (TTESRD) was measured from the date of diagnosis of CKD to the date of diagnosis of ESRD and was censored at the date of last follow-up for those without ESRD with death as competing risk. The overall survival (OS) was measured from the date of diagnosis of CKD to the date of death The Fine and Gray method was used for comparisons of cumulative incidence of ESRD between groups. The effect of important factors on TTESRD was further evaluated using multivariable Fine and Gray method. Survivor distribution was estimated using Kaplan-Meier methods and the difference of OS between/among groups was examined by log-rank test. Results: The final data for the statistical analysis reported here contains 626 pts with MGUS and CKD and 15337 pts with CKD alone. The median follow up was 19.7 (range: 0.03, 128) months. Patient's characteristics and distribution of diabetes (DM), hypertension (HTN) and CKD stage at both cohorts are shown in Table-1. Progression to ESRD: There was no difference between rate of progression to ESRD (as the binary outcome) in the cohort of pts with CKD and MGUS and the cohort of CKD without MGUS, 4.8% vs. 6%, respectively (p: 0.2). Univariate analysis of TTESRD showed lack of MGUS, Black race, DM, and CKD stage at baseline as statistically significant factors associated to progression to ESRD (Fig.1). Multivariable analysis on TTESRD including factors (MGUS status, age, gender, race, CKD stage, diabetes and hypertension) demonstrated higher CKD stage at baseline, younger age at time of CKD diagnosis, male gender and black race as the significant factors are associated with shorter TTESRD (Fig.3). Progression by CKD stage advancement: The CKD stage at baseline was compared to the CKD stage at year 1 and year 5 during follow-up. The progression by stage was 28.5% at year 1 for pts without MGUS vs. 29.3% for those with MGUS (p = 0.73). The progression by stage was 38.7% at year 5 for pts without MGUS vs. 39.4 % for those with MGUS (p = 0.89).There was no difference between median OS for pts with CKD with or without MGUS (Fig-2) Conclusion: Here we presented the data of around 16,000 CKD pts based on the MGUS diagnosis in 19 years time span and we could not detect any higher trend for CKD pts with MGUS to develop ESRD or move to higher CKD stage. These data can suggest MGRS forms a quite thin slice of the whole MGUS population. Assessing finding of this study in a larger national database is warranted. Disclosures Caimi: Amgen: Other: Advisory Board; Kite Pharma: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding; Celgene: Speakers Bureau; Verastem: Other: Advisory Board; Bayer: Other: Advisory Board. de Lima:Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Pfizer: Other: Personal fees, advisory board, Research Funding; Celgene: Research Funding. Malek:Takeda: Other: Advisory board , Speakers Bureau; Sanofi: Other: Advisory board; Amgen: Honoraria; Medpacto: Research Funding; Clegene: Other: Advisory board , Speakers Bureau; Janssen: Other: Advisory board, Speakers Bureau; Bluespark: Research Funding; Cumberland: Research Funding.

Multiple Myeloma (MM) is a cancer of terminally-differentiated plasma cells residing in the bone marrow. Myeloma cells frequently secrete monoclonal proteins that can be used to assess tumor volume and patient response to therapy. Monoclonal proteins are measured by gel electrophoresis and subsequent immunofixation of the observed M-spike for protein typing. However, this a time-consuming process that may take up to 3-5 days that delays physician-patient decision-making, determining response to treatment and can be a significant psychological stressor for patients. Hence, there is an unmet need to develop a more rapid, point-of-care method to determine M-spike levels. Gamma gap is the difference between total serum protein and albumin and includes a variety metabolic proteins, i.e., transferrin, as well as immunologic proteins, e.g., non-involved immunoglobulins, in addition to the M-spike. Since estimation of the non-M-spike portion of the gamma gap cannot be achieved on routine patient care, the gamma gap cannot serve as an accurate surrogate for M-spike protein levels. Here, we hypothesized that an artificial intelligence (AI) algorithm utilizing readily available clinical and laboratory data along with previous and same-day lab variables can accurately predict M-spike levels without the need for serum electrophoresis. Methods: A total of 171 MM patients with 1,472 observations were included in the study, where the upper limit of the observed M-spike was 3.5 gr/dL. Correlation of the observed M-spike with gamma gap was assessed by two correlation methods using the Pearson and Spearman tests. Forty three clinical and lab variables (including total serum protein and albumin) as predictors of M-spike were fed into the machine learning model. Two lagged variables as the last two preceding M-spike values by the same subject were included. When needed, imputation for missing values was applied through interpolation from subject-level linear trend analysis. The random forest model was used, where regression forests are an ensemble of different regression trees and are used for nonlinear multiple regression. The default number of trees was set to be n = 500, and the number of variables considered at each split after random selection was 13. The goal of using a large number of trees was to train enough that each feature had a chance to appear in several models. The data was randomly split into a training set (80%) and a test set (20%), and a regression tree was built with the training set and then validated using the test set. Bootstrapping was used to generate a collection of data sets (n=500), leading to a random forest of regression trees. Results and estimates were combined across trees. Importance was measured by leaving a covariate out of models, and comparing performance with its inclusion. All analyses were performed using R v3.6.2 and its libraries. Results: Median age of the study cohort was 73 years old, range: 42-96), and 44% were male. The median M-spike value was (0.7 gr/dL, range: 0.1-3.5). Fig. 1 shows the number of observations and magnitude distribution for M-spike levels among the patients included in our study. The correlation of the calculated gamma gap and observed M-spike levels was assessed by two methods (Fig.2). The Pearson coefficient was 0.43 for M-spike levels 1 gr/dL, respectively (Fig.2a). The Spearman coefficient was 0.41 for M-spike levels 1 suggesting a low overall correlation overall, especially for M-spike levels Conclusion: Here, we showed that the difference between total protein and albumin (i.e., gamma gap) is a rough estimate of M-spike, especially with lower values. AI algorithm trained by 43 readily available clinical and laboratory variables could predict the observed M-spike very robustly. Taken together, our results indicate that the AI-based method developed here can be further advanced for rapid, accurate, point-of-care measurement of M-spike protein levels in MM patients. Figure 1 Disclosures Malek: Cumberland: Research Funding; Sanofi: Other: Advisory board; Clegene: Other: Advisory board , Speakers Bureau; Takeda: Other: Advisory board , Speakers Bureau; Janssen: Other: Advisory board, Speakers Bureau; Bluespark: Research Funding; Amgen: Honoraria; Medpacto: Research Funding. Caimi:Amgen: Other: Advisory Board; Verastem: Other: Advisory Board; Celgene: Speakers Bureau; Bayer: Other: Advisory Board; ADC Therapeutics: Other: Advisory Board, Research Funding; Kite Pharma: Other: Advisory Board. de Lima:Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding; Kadmon: Other: Personal Fees, Advisory board; Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board.

Background High dose chemotherapy followed by autologous stem cell transplantation (ASCT) plays an important role in the treatment of transplant-eligible multiple myeloma (MM) patients and yields deep responses, prolongs progression-free survival (PFS) and overall survival (OS). Daratumumab (Dara), a humanized monoclonal antibody that binds to CD38+ on the surface of myeloma cells and is increasingly used upfront to treat MM. Up to 75% of mobilized CD34+ hematopoietic progenitors also express CD38 and, hence exposure to Dara may potentially impact stem cell mobilization, and, given the extended half-life of Dara, also impair engraftment. The Cassiopeia trial (Moreau, P. 2019) showed the utility of Dara in combination with bortezomib and thalidomide as upfront treatment for MM without a negative impact on stem cell collection yield. Similarly, the Griffin trial (Voorhees, PM, 2020) demonstrated the safety of upfront Dara when combined with bortezomib and lenalidomide also with no impact on stem cell collection or engraftment. However, others(Al Saleh, A. 2019) reported delayed neutrophil engraftment in patients treated with Dara. Given the conflicting findings of these studies and scarcity of data on the direct impact of Dara on erythroid and myeloid progenitors, we investigated the effect of Dara on stem cell collection yield, graft composition and time to engraftment among patients who underwent ASCT. Methods We evaluated all patients with MM who underwent ASCT at our institute between 2017-2020 and excluded patients undergoing 2nd transplant or tandem ASCT. Disease risk stratification was assessed as per International Staging System (ISS) for MM. Treatment response prior to transplant was assessed as per response criteria definitions by International Myeloma Working Group (IMWG). Stem cells were collected according to institutional protocol and prior to cryopreservation, 1x105 peripheral blood cells are plated in duplicate in semi-solid media- MethoCult™ H4434 (Stem Cell Technologies, Vancouver, BC) and cultured in 37°C, 5% CO2 following which CFU-GM (colony forming unit- granulocyte macrophage) and BFU-E (burst forming units- erythroid) colonies are scored on day 14 based on morphological recognition, and reported as 104 colonies per kg of recipient weight. CFU-C (colony forming unit combined) is calculated by combining BFU-E and CFU-GM. Results Patients (N=108) that underwent ASCT between 2017-2020 were identified and demographic data are summarized (Table 1). Sixteen patients received Dara as part of upfront treatment prior to stem cell collection. Median age was 62 years old for the entire group with no significant age difference between patients who received Dara vs. those who did not receive. Similarly, there was no difference in race, ISS stage, pre-transplant response, plerixafor or lenalidomide use between the groups. Pts who received Dara were more likely to have received more than one chemotherapy regimen prior to transplant (62.5% vs. 30%, p-value=0.014). Although, total and day 1 collection of CD34+ stem cells was lower in the Dara treated group (7.18 x 106/kg) compared to Dara untreated (8.78 x 106/kg), the difference was not statistically significant. (p-value=0.151). Stem cell product composition based on measurement of BFU-E, CFU-GM and CFU-C colonies were similar independent of Dara use. Prior exposure to Dara was also not predictive of day 1 stem cell collection failure (defined as < 5x106 CD34+ cells/kg) as determined by multivariate analysis. Median time to absolute neutrophil count (ANC) recovery (defined as ANC >1500) was 12 days in both groups (p-value=0.09). Median time to platelet recovery (defined as platelet count >20k) was 12 days in the Darauntreated group vs. 13 days Dara treated group (p-value=0.06). Discussion In this single institute experience, there was a trend towards lower CD34+ collection as well as lower progenitor scoring with Dara use but was not statistically significant and also there was no difference in time to ANC or platelet recovery. The majority of patients in this study received plerixafor for mobilization, which might abrogate the effect of Dara and lenalidomide on the graft and stem cell collection. Further studies to investigate the impact of Dara on CD38+ mobilized hematopoietic cells is warranted. Disclosures Manjappa: Pfizer: Research Funding. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Celgene: Speakers Bureau; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding. de Lima:BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding. Malek:Clegene: Other: Advisory board , Speakers Bureau; Janssen: Other: Advisory board, Speakers Bureau; Sanofi: Other: Advisory board; Amgen: Honoraria; Medpacto: Research Funding; Cumberland: Research Funding; Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau.

Background High-dose chemotherapy and autologous stem cell transplantation (ASCT) are integral components of the overall treatment for patients with multiple myeloma (MM) aged ≤ 65 years. The emergence of oligoclonal immunoglobulin bands (ie, immunoglobulins differing from those originally identified at diagnosis [termed clonal isotype switch (CIS)]) has been reported in patients with MM after high-dose chemotherapy followed by autologous stem cell transplantation. However, the clinical relevance and the correlation with immune reconstitution remains unclear. Patients and Methods Patients with MM who had undergone ASCT from 2007 to 2016 were included in the present study. The percentage of natural killer cells, B-cells, and T-cells was measured using flow cytometry in pre- and post-ASCT bone marrow samples. CIS was defined as the appearance of a new serum monoclonal spike on serum protein electrophoresis and immunofixation that differed from original heavy or light chain detected at diagnosis. Results A retrospective analysis of 177 patients with MM who had undergone ASCT detected CIS in 39 (22%). CIS after ASCT correlated with improved progression-free survival (52.2 vs. 36.6 months; P = .21) and overall survival (75.1 vs. 65.4 months; P = .021). Patients with a relapse had an isotype that differed from a CIS, confirming the benign nature of this phenomenon. CIS was also associated with lower CD8 T-cell percentages and a greater CD4/CD8 ratio (2.8 vs. 0.2; P = .001) compared with patients who did not demonstrate a CIS, suggestive of more profound T-cell immune reconstitution in this group. Conclusion Taken together, our data have demonstrated that a CIS is a benign phenomenon and correlates with a reduced disease burden and enriched immune repertoire beyond the B-cell compartment.

Multiple Myeloma (MM) is a cancer of terminally differentiated plasma cell resides in bone marrow, which is always preceded by clinically asymptomatic precursor states. The process of malignant transformation however is not fully understood. Analyses of cells from precursor state have provided evidence that it is a genetically advanced lesion, wherein tumor cells carry many of the genetic changes found in MM cells. Furthermore, mice xenografts from patient (pt) with precursor disease showed progressive growth on its own suggesting progression potential is counteracted by active extrinsic restraints that prevent its progression to MM (Das R et al. Nature Medicine, 2016). Hence, precursor progression to MM can be viewed as a dynamic process in which the clonal mass is the net result of pro-growth, pro-survival replicative capacity of the myeloma clones vs. anti-tumor immunity. The change in the net clonal mass sometimes is large enough to be detected by measurable fluctuations in serum monoclonal protein spike (M-spike) levels and reflects a highly dynamic battle between plasma cell clone and cell-mediated anti-myeloma immunity among those pts. The prognostic value of this highly dynamic state on risk of progression to MM is largely unknown. In this study we sought to assess the association between the dynamic M-spike pattern and the risk of progression from a precursor clone to MM. Methods: All pts with positive serum electrophoresis (SPEP) values measured from January 2011 to January 2021 for our institution were included for this study. All pts that had 3g/l or had clear evidence of progression by serial increasing M-spike values were excluded.. We assigned the pattern of M-spike values over time into two groups according to stability. To eliminate the test-to-test variability, we defined stable disease as lack of more than 20% difference from lowest M-spike, and fluctuating disease if the difference exceeds 20%. The time-to-treatment (TTT) was then measured from the first positive SPEP to the time of treatment and was censored at the date of last follow-up for pts who did not have anti-myeloma treatment with death as competing risk. The effect of M-spike pattern on TTT, treating as binary outcome, was also evaluated using logistic regression analysis. Univariate analysis of TTT was performed using Gray's method. All tests were two-sided and p-value ≤ 0.05 were considered statistically significant. Results: A total of 565 pts were studied, 193 with a fluctuating pattern and 372 with a stable pattern. Median age at first positive SPEP was 76 years old (range: 38-101), 271 (48%) of them were male; 427 (75%) were Caucasian and 123 (22%) African American. Baseline creatinine was 1.17 mg/dl (range 0.5-11.2 SD 0.94). Baseline albumin was 3.97 g/dl (range 1.6-5.2 SD 0.47), 336 pts (59%) were IgG, 75 (13%) IgA, and 142 (25%) had IgM M-spike; 326 (58%) pts had Kappa light chain and 239 (42%) had Lambda. Autoimmune diseases were more common in the stable disease pattern (17% vs. 10% p=0.028), the most frequent one was Rheumatoid arthritis in 33 pts (6%). Furthermore, baseline albumin was statistically higher in pts in the stable cohort (4.04 vs. 3.85g/dl, p= Conclusion: The dynamic pattern of M-spike seen here with fluctuating values over time (over time is two words) was significantly predictive of progression to MM in pts with a precursor disease state. These findings may reflect a different nature of tumor vs. immune system balance and possible impaired immunity in these pts which may have implications for future clinical trials that evaluate the efficacy of anti-myeloma immunotherapeutics. Furthermore, our finding suggest that fluctuations in M-spike levels may be factored into risk models that predict the progression to MM among pts with precursor clones. Larger studies are warranted to further study this concept. Figure 1 Figure 1. Disclosures Malek: Medpacto Inc.: Research Funding; Janssen: Other: Advisory board ; Takeda: Honoraria; Cumberland Inc.: Research Funding; Amgen: Honoraria; BMS: Honoraria, Research Funding; Bluespark Inc.: Research Funding; Sanofi: Other: Advisory Board.

High-Dose Melphalan (HDM) followed by stem cell transplant (SCT) remains the standard-of-care for transplant-eligible patients newly-diagnosed with multiple myeloma (MM). However, ~1/3 of patients relapse Traditional disease-measurement methods based on International Myeloma Working Group (IMWG) criteria rely on the secretory function of myeloma cells and measure monoclonal protein levels. Following induction therapy, pre-transplant monoclonal protein levels are usually very low, and further reduction in myeloma secretory function are not detectable. In addition, the long half-life of monoclonal proteins makes assessing short-term disease changes problematic. Methods to accurately detect minor changes in disease burden following a low dose of melphalan (LDM) as a marker of melphalan sensitivity are needed to better predict patient responses to LDM. Next-generation sequencing (NGS), is an alternative approach that may allow for the highly sensitive, rapid, real-time detection of minuscule changes in tumor volume that are not influenced by the long half-life of monoclonal proteins. Here, we propose to use NGS-based tumor assessment to evaluate changes in disease volume following LDM before proceeding to HDM-SCT. Evidence is lacking to determine whether a single LDM generates a decrease in myeloma burden that is measurable by NGS. Our central hypothesis is that NGS of bone marrow aspirates from newly-diagnosed, post-induction transplant-eligible MM patients will provide a method to precisely determine the effect of LDM on disease burden. ClonoSEQ assay is an FDA-cleared, highly sensitive, specific, and standardized method to detect and monitor MRD, in MM patients. clonoSEQ leverages the power of NGS and offers an accurate and reliable way to assess how disease burden changes over time in response to treatment. Therefore, we propose a proof-of-principle study to assess the validity of this strategy and to provide essential data for future trial design investigating individualized approaches based on NGS sequencing and low doses of therapeutic agents. We will test the central hypothesis that LDM, administered at 16 mg/m 2, generates a detectable reduction in tumor burden measured by NGS. A detectable reduction in tumor burden is defined as a ≥ 20% decrease in NGS clonal count in at least 30% of subjects. We will administer propylene glycol-free melphalan formulation (EVOMELA) due to greater stability upon reconstitution than AlKERAN formulation in order to diminish the variability in the effective administered dose. The primary and secondary objectives and endpoints of the study are listed in Table-1,2. Statistical Considerations: Clonoseq detects measurable residual disease at the level of a single cell given sufficient sample input. The specific hypothesis of this pilot trial is LDM produces a measurable disease reduction that is readily detectable by clonoSEQ with at least a 20% reduction in at least 30% of patients. Assuming a 100% yield for VJD clonal sequencing and calibration efficacy by clonoSEQ, the sample size required to test the null hypothesis of 5% patients with positive MRD test against alternative 30% patients with positive MRD test is 16 patients. The sample size estimation is using two-sided chi-square test with 80% power. The sample size estimation is n = 21, when power = 90% based on one sample Binomial distribution theory. We will assume 20% failure rate for VJD clonal sequencing and calibration efficacy by clonoSEQ. Therefore, by enrolling 20 patients, we expect that at least 16 patients will have MRD assessable by NGS method. Figure 1 Figure 1. Disclosures Malek: BMS: Honoraria, Research Funding; Amgen: Honoraria; Bluespark Inc.: Research Funding; Sanofi: Other: Advisory Board; Cumberland Inc.: Research Funding; Takeda: Honoraria; Janssen: Other: Advisory board ; Medpacto Inc.: Research Funding. Metheny: Incyte: Speakers Bureau; Pharmacosmos: Honoraria. de Lima: Miltenyi Biotec: Research Funding; Pfizer: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Incyte: Membership on an entity's Board of Directors or advisory committees.

Randomized clinical trials (RCTs) are considered the highest level of evidence to define the efficacy of newly developed treatments before their adoption into clinical practice. RCTs incorporate exclusion criteria that eliminate specific patient populations in order to reduce the incidence of serious adverse events and enhance the efficacy of a given anti-cancer strategy. However, exclusion criteria may lead to a significant gap between patients (pts) enrolled on RCTs and real world pt populations, which represent the ultimate stakeholders in cancer treatment. The analysis of real-world evidence to answer clinical questions has recently gained increased interest. Assessing different dimensions of this gap may help overcome barriers in trial recruitment and enhance the applicability of RCTs in daily practice. There has been significant advancement in treating multiple myeloma (MM) over the past two decades bringing multiple new mechanisms of action to the bedside. We selected ten recent RCTs: ASPIRE, TOURMALNE-MM01, ELOQUENT-2, ENDEAVOR, POLLUX and CASTOR, OCEAN, ICARIA, APOLLO and ELOQUENT-3 studies, which are pharma-sponsored landmark trials that provided the basis for FDA approval of anti-myeloma agents. Our objective was to quantify the gap in eligibility criteria between the ten RCTs and real world populations by examining these trials using a single institution database. Methods: Pts with relapsed MM that were initiated on a second (or later line) of therapy that were recognized, retrospectively. Eligibility criteria of the ten landmark RCTs was applied during the 21 day period before the index treatment date. Pts that received Len-containing regimens were tested as to be enrolled on trials with Len/Dex control arm, patients that received Bor-containing regimens were examined to be enrolled on Bor/Dex trials and subjects who had Pom-containing regimen were screened for Pom/Dex trials. Pts were then classified as "Trial eligible" or "Trial ineligible", accordingly and were monitored longitudinally from the index treatment date until death, loss to follow-up, or end of the follow up period. Ten commonly used eligibility criteria were examined (Fig. 1). Any cancer in the three years prior to the index treatment date was counted as "history of other malignancies", i.e., skin and prostate cancer were excluded. Concurrent infection was defined as use of any antibiotic other than acyclovir, ciprofloxacin or bactrim. To calculate area under the curve of the polygon graphs Shoelace algorithm was used. Results : 516 pts were studied between 2010 and 2020 and 153 were excluded due to missing values. 224, 136 and 98 pts were treated with Len-, Bor- or Pom-containing regimens, respectively. Overall, the trial-eligible cohort was more likely to have autologous stem cell transplant and to have had longer treatment-free period before index treatment date (p-value: 0.009). There was a substantial variation in the ineligibility rate for these ten RCTs among the study population (Fig. 1). The most common items that excluded a patient from a RCT were: other malignancy, current infection and renal dysfunction. Differences between trial-eligible and trial-ineligible pts stratified by trial are listed in Tables 1, 2 and 3 for trials with Len, Bor and Pom as control arms, respectively. The median follow-up for the Len, Bor and Pom cohorts was 31, 30 and 22 months, respectively. Trial-ineligible pts displayed a significantly worse OS (2-year rate 58% vs. 78%, p-value: 0.001) and 49% higher chance of death (HR 1.69, 90%, CI: 1.17-2.62) compared with trial-eligible cohort. Conclusion: Here, we assessed the multidimensional gap that exists between patient cohorts enrolled on RCTs and real world cohorts for ten landmark MM trials. We present a quantitative deviation score as a tool to calibrate the generalizability of these landmark trials against a single institution. Importantly, we show that trial-eligibility alone significantly correlates with superior OS across a variety of MM clinical trials across all ten MM RCTs. Furthermore, our results reveal that ineligibility rates were quite different among the ten trials which significantly limit cross-trial comparisons. We propose a uniform methodology to assess patient exclusion criteria and narrow the efficacy gap observed between RCTs and real world evidence. Figure 1 Figure 1. Disclosures Metheny: Pharmacosmos: Honoraria; Incyte: Speakers Bureau. Malek: Medpacto Inc.: Research Funding; Amgen: Honoraria; Janssen: Other: Advisory board ; Takeda: Honoraria; BMS: Honoraria, Research Funding; Cumberland Inc.: Research Funding; Bluespark Inc.: Research Funding; Sanofi: Other: Advisory Board.

Despite the rich armamentarium of novel agents that are available to treat multiple myeloma (MM), high dose melphalan (HDM) and stem cell transplant (SCT) remain an essential therapy that achieves long-term durable remissions. However, most patients relapse following HDM-SCT due to the persistence of minimal residual disease (MRD). Therefore, there remains an unmet clinical need to overcome chemoresistant MRD and potentially achieve a cure for MM patients. Here, we describe a phase Ib trial designed to epigenetically priming with pre-transplant oral panobinostat to increase MRD sensitivity to HDM-SCT. The contribution of dysregulated gene silencing to epigenomic alterations in cancer development provides a strong rationale for the use of epigenetic modulators, such as the histone deacetylase (HDAC) inhibitor panobinstat as anti-myeloma therapy. Access to DNA is primarily governed by chromatin structure such that its configuration is under control of histone acetylators and deacetylators. Inhibition of histone deacetylases weakens the histone-DNA bonds and decondenses chromatin, i.e., epigenetic priming, which potentially enhances sensitivity to melphalan. Pre-clinical studies have demonstrated a strong synergistic effect between panobionostat (LBH589) and melphalan in in vitro as well as in vivo studies utilizing patient-derived xenograph models, i.e., SCID-hu model of human MM, LAG-1(Sanchez et al. Leukemia research. March 2011). Furthermore, HDAC inhibitors suppress multi-drug resistance protein-1 (MRP1) and it can count as another mechanism of synergy for this class of drugs and alkylating agents in hematologic disorders (Tsubaki M. et al. Leukemia research. Oct 2012). Taken together, these studies support HDAC inhibitors in combination with melphalan to augment anti-myeloma efficacy of HDM-SCT. Here, we propose the combination through a pre-SCT epigenetic priming phase with high dose panobinostat and a post-SCT lower dose panobinostat consolidation phase (Study Schema). Trial design: We propose a Simon 3+3 design to test panobinostat at three dose levels of 20, 30 and 40 mg every other day for four doses prior to high dose melphalan as study schema illustrates. There will not be any intra-patient dose escalation. The study will be extended to another 15 patients at the maximum tolerated dose for the pre-SCT phase. All patients regardless of the pre-SCT panobinostat dose level will received fixed dose of Panobinostat. Primary and Secondary objectives and endpoints are listed in Table 1. Rationale for high dose panobinostat in epigenomic phase: Previous reports of HDACi combined with standard-dose chemotherapy (e.g., Ifosfomide, Carboplatin, and Etoposide for lymphoma or 7+3 for acute myeloid leukemia) had shown prolonged myelosuppression as the main adverse effect, but no significant increase in the non-hematological toxicities. Therefore, we predict the use of peripheral blood progenitor cells in the offered study has potential to circumvent the increased myelotoxicity associated with pre-SCT high dose panobinostat, and it may render the opportunity to test higher doses such as 40 mg every other day before SCT as epigenetic priming strategy. Rational for low dose panobinostat dosing for the consolidation phase: The Panobinostat consolidation design will follow the positive landmark trial by the Australian group (Mithraprabhu S. et al. British J. Hemat. Apr 2021). In their study panobinostat was given at 20 mg three times weekly on alternate weeks for 6 months started 8-12 weeks post-transplant was administered. Forty eight percent of patients improved their depth of response after a median range of 4.3 months of panobinostat. In responders, T lymphocyte histone acetylation increased after both three cycles and six cycles of panobinostat when compare to baseline, with no differences in no-responders. Figure 1 Figure 1. Disclosures Malek: Janssen: Other: Advisory board ; Bluespark Inc.: Research Funding; BMS: Honoraria, Research Funding; Amgen: Honoraria; Cumberland Inc.: Research Funding; Sanofi: Other: Advisory Board; Medpacto Inc.: Research Funding; Takeda: Honoraria. Metheny: Incyte: Speakers Bureau; Pharmacosmos: Honoraria. Stricker: Secura Bio: Current Employment. OffLabel Disclosure: Panobinostat has been used as single agent therapy before and after transplant in this trial.

Randomized clinical trials (RCT) are imperative for testing novel cancer therapies and advancing the science of cancer care. Exclusion criteria are employed to minimize toxicity and maximize benefit. However, the selection process introduces a deviation between enrolled patients (pts) and the real world population. Estimating how much the selected population deviates from the MM cohort at large may increase inclusiveness and could help define barriers to recruiting to MM studies. There has been significant advancement in treating Multiple Myeloma (MM) during the last decade. Over 16 FDA-approved anti-myeloma regimens are now available. We selected the recent 6 RCTs (ASPIRE, TOURMALNE-MM01, ELOQUENT-2, ENDEAVOR, POLLUX and CASTOR studies) which were pharma-sponsored landmark trials that provided the basis for FDA approval of a new agent or established a new indication for formerly FDA-approved drug. We intended to quantify the gap between the trial population and real world by examining the eligibility criteria of these trials compared against a single institution database. Methods: Pts with relapsed MM initiating second or later line of therapy containing lenalidomide (Len) or bortezomib (Bor) were identified retrospectively. The 3-week period before the index treatment date was used to apply the eligibility criteria of the mentioned 6 trials. Pts who received Len-containing regimens were tested as to be enrolled on trials with Len/Dex control arm (ASPIRE, TOURMALINE-MM1, POLLUX, and ELOQUENT-2) and pts who had Bor-containing regimens were reviewed to be enrolled on Bor/Dex trials (CASTOR and ENDEAVOR). Pts were classified as "Trial eligible" or "Trial ineligible", accordingly. Pts were followed up longitudinally from the index treatment date until death, loss to follow-up, or the end of the study period (Jan, 2018). Ten frequently used eligibility criteria were studied (Fig-1). History of other malignancies, except skin and prostate cancer, was defined as any cancer requiring therapy other than anti-myeloma regimen in the 3 years prior to the index treatment date. Current infection referred to the use of any medication other than acyclovir, ciprofloxacin or Bactrim. Shoelace algorithm was used to calculate area under the curve of the polygon graphs. Results: 516 pts were studied between 2010 and 2018; 153 pts were excluded due to missing values, while 224 and 136 pts were treated with Len-containing and Bor-containing regimens, respectively. Overall, the trial-eligible cohort was more likely to have autologous stem cell transplant and to have had longer treatment-free period before index treatment date (p-value: 0.012). There was a substantial variation in the ineligibility rate for these 6 RCTs among the study population (Fig-1). The most common items that excluded a patient from a RCT were: Other malignancies, current infection and renal dysfunction. Within the Len cohort the trial-specific Glomerular Filtration Rate (GFR) threshold for renal function was highest in ASPIRE trial (Cr clearance> 50 ml/min) causing high rate of exclusion (29% vs. 8% in other trials). Only TOURMOULINE-MM01 and ASPIRE trials had bor-refractory status as the exclusion criteria leading to 36% ineligibility rate. The differences between the trial-eligible and trial-ineligible pts stratified by trial are listed in Table-1 and 2 for trials with Len and Bor as the control arms, respectively. The median follow-up for the Len and Bor cohort was 31 and 30 months, respectively. The trial-ineligible pts had significantly worse OS (2-year survival rate 69% vs. 82%, P-value: 0.001) and 43% higher chance of death (hazard ratio 1.43, 90% confidence interval (CI): 1.08-2.02) compared with trail-eligible cohort. Conclusion: Here we assessed the eligibility criteria of 6 landmark MM studies and showed that ineligibility rates were quite different amongst these trials suggesting significant limitations in cross-trial comparison. Furthermore, trial-eligibility per se was associated with improved survival. We therefore proposed a quantitative deviation score calibrating the generalizability of the results of these trials to a single institution cohort. Such a tool can lead to efforts to broaden eligibility criteria and possibly narrow the gap between reported clinical trial efficacy and the observed effectiveness in real-world MM pts. Disclosures de Lima: Kadmon: Other: Personal Fees, Advisory board; Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board; Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding. Malek:Medpacto: Research Funding; Takeda: Other: Advisory board , Speakers Bureau; Bluespark: Research Funding; Cumberland: Research Funding; Sanofi: Other: Advisory board; Janssen: Other: Advisory board, Speakers Bureau; Clegene: Other: Advisory board , Speakers Bureau; Amgen: Honoraria.

Proteasome inhibitor-based strategies hold promise in transplant but have yielded varying results. Carfilzomib, a second-generation proteasome inhibitor, may possess advantages over bortezomib, the first-generation proteasome inhibitors. The purpose of this study was to evaluate the safety, toxicity, and preliminary efficacy of carfilzomib in highly HLA-sensitized kidney transplant candidates. Renal transplant candidates received escalating doses of carfilzomib followed by plasmapheresis (group A) or an identical regimen with additional plasmapheresis once weekly before carfilzomib dosing. Thirteen participants received carfilzomib, which was well tolerated with most adverse events classified as low grade. The safety profile was similar to bortezomib desensitization; however, neurotoxicity was not observed with carfilzomib. Toxicity resulted in permanent dose reduction in 1 participant but caused no withdrawals or deaths. HLA antibodies were substantially reduced with carfilzomib alone, and median maximal immunodominant antibody reduction was 72.8% (69.8% for group A, P = .031, 80.1% for group B, P = .938). After depletion, rebound occurred rapidly and antibody levels returned to baseline between days 81 and 141. Bone marrow studies revealed that approximately 69.2% of plasma cells were depleted after carfilzomib monotherapy. Carfilzomib monotherapy-based desensitization provides an acceptable safety and toxicity profile while leading to significant bone marrow plasma cell depletion and anti-HLA antibody reduction.

Over the past 15 years, proteasome inhibitors (PIs), namely bortezomib, carfilzomib (Cfz) and ixazomib, have significantly improved the overall survival and quality-of-life for multiple myeloma (MM) patients. However, a significant portion of MM patients do not respond to PI therapies. Drug resistance is present either de novo or acquired after prolonged therapy through mechanisms that remain poorly defined. The lack of a clear understanding of clinical PI resistance has hampered the development of next-generation PI drugs to treat MM patients who no longer respond to currently available therapies. Here, we designed and synthesized novel epoxyketone-based PIs by structural modifications at the P1′ site. We show that a Cfz analog, 9, harboring a hydroxyl substituent at its P1′ position was highly cytotoxic against cancer cell lines displaying de novo or acquired resistance to Cfz. These results suggest that peptide epoxyketones incorporating P1′-targeting moieties may have the potential to bypass resistance mechanisms associated with Cfz and to provide additional clinical options for patients resistant to Cfz.

8039 Background: Immunosuppression and osteoclast activation are two hallmarks of the bone marrow environment in Multiple Myeloma (MM). Corticosteroids have been used historically as part of anti-myeloma regimens due to their anti-plasma cell activity, however they potentially could suppress immune system and activate osteoclast further; therefore there is an unmet need for corticosteroid-free approaches in the era of emerging anti-cancer immunotherapy modalities. There is an abundance of Transforming Growth Factor-beta (TGF-β), a crucial cytokine in suppression of immune system as well as catabolic bone remodeling, in the MM microenvironment. Vactosertib (Vacto) is a small molecule TGF-β type I receptor inhibitor that has shown single agent activity against myeloma in the syngeneic 5T33MM murine mouse model. Here, we report the phase Ib trial of Vacto in combination with pomalidomide (Pom) without any corticosteroids (NCT03143985). Methods: pts with relapsed MM with at least two lines of therapies enrolled on a 3 + 3 dose escalation design and received Vacto, 60 mg/d, 120 mg/d, 100 mg BID and 200 mg BID in combination with standard dose of Pom (4mg) without corticosteroids. The primary objectives of the study was to assess safety and recommended phase 2 dose. Vacto tablets, taken once or twice daily for 5 days followed by 2 days without treatment, is administered in 28-day cycles, until progression of disease or intolerable toxicity. Results: 15 pts were enrolled on the study (Table). The most common non-hematologic adverse event (AE) was grade II fatigue and pain in one pt, one episode of grade III renal failure that took less than 7 days to get back to baseline on another patient, sinus bradycardia that reversed to sinus rythem and an Afib that was rate controlled with beta blocerks. No grade IV non-hematologic AE was observed. Three pts had grade III hematologic AE, no grade IV hematologic AE. Three out of 15 pts experienced progression of disease (PFS-6: 80%). Conclusions: The phase Ib data shows safety of this agent in combination with Pom. The efficacy assessment (PFS-6: 80%) is higher than the historical control (PFS-6: 20% in randomized Phase II study by Richardson et al. Blood. 2014) with Pom only (PFS-6: 20%) or Pom with corticosteroids (PFS-6: 40%). Further advancement of this agent in clinical trial pipelines for MM is planned. Clinical trial information: NCT03143985. [Table: see text]

While clinical benefit of the proteasome inhibitor (PI) bortezomib (BTZ) for multiple myeloma (MM) patients remains unchallenged, dose-limiting toxicities and drug resistance limit the long-term utility. The E3 ubiquitin ligase Skp1–Cullin-1–Skp2 (SCFSkp2) promotes proteasomal degradation of the cell cycle inhibitor p27 to enhance tumor growth. Increased SKP2 expression and reduced p27 levels are frequent in human cancers and are associated with therapeutic resistance. SCFSkp2 activity is increased by the Cullin-1-binding protein Commd1 and the Skp2-binding protein Cks1B. Here we observed higher CUL1, COMMD1 and SKP2 mRNA levels in CD138+ cells isolated from BTZ-resistant MM patients. Higher CUL1, COMMD1, SKP2 and CKS1B mRNA levels in patient CD138+ cells correlated with decreased progression-free and overall survival. Genetic knockdown of CUL1, COMMD1 or SKP2 disrupted the SCFSkp2 complex, stabilized p27 and increased the number of annexin-V-positive cells after BTZ treatment. Chemical library screens identified a novel compound, designated DT204, that reduced Skp2 binding to Cullin-1 and Commd1, and synergistically enhanced BTZ-induced apoptosis. DT204 co-treatment with BTZ overcame drug resistance and reduced the in vivo growth of myeloma tumors in murine models with survival benefit. Taken together, the results provide proof of concept for rationally designed drug combinations that incorporate SCFSkp2 inhibitors to treat BTZ resistant disease.

The efficacy of bortezomib monotherapy in desensitizing kidney transplant candidates with preformed donor-specific antibodies remains unclear. We evaluated the effect of bortezomib on preformed antibodies and upstream components of the B cell response in a primate model sensitized by fully mismatched allogeneic skin transplants to provide mechanistic insights regarding the use of bortezomib as a means of desensitization. Bortezomib treatment given intravenously twice weekly for 1 month (1.3 mg/m2 per dose) clearly reduced the numbers of antibody-producing cells and CD38+CD19+CD20− plasma cells in the bone marrow (P

Introduction: Multiple myeloma (MM) is a plasma cell neoplasm associated with heterogeneous somatic alterations. Despite the development of novel anti-myeloma agents that have significantly prolonged patient survival, disease relapse remains a daunting problem. Our goal was to employ whole-exome sequencing (WES) to better describe the mutational landscape in MM beyond the tumor cell and identify genomic factors that might predict relapse. WES was performed using autograft samples obtained from MM patients that were then treated with high dose melphalan and autologous hematopoietic cell transplant (HCT). We identified a panel of genes that were most frequently mutated in all patients and then identified those genes mutated with greater frequency in patients that relapsed. A relapse burden signature was generated based upon the genes that were most frequently mutated genes in relapsed patients. Finally, the relapse burden signature was correlated with patient progression-free survival (PFS) and overall survival (OS) following autologous HCT. Methods. DNA was extracted from one ml of cryopreserved, mobilized hematopoietic cell product obtained from patients (N=93) that underwent HCT and was provided by the Case Comprehensive Cancer Center Hematopoietic Biorepository Core. Targeted sequencing was performed using the Tempus xE whole exome platform (Tempus, Chicago, IL). Variants were identified using a variant allele frequency (VAF) ≥0.1 for each sample. Variants were tabulated for each gene in each patient. Patients were grouped according to their relapse status; "No Relapse" (N=39) and "Relapse" (N=54) which corresponded to their post-HCT outcome. Relapse time was defined as time from transplant to event. Variants identified in each gene and patient group were counted and ranked. A relapse burden signature was defined and included twenty-two genes over-represented in the relapse group compared to the non-relapse group by > 10%. Genes in the relapse burden signature were subjected to gene set enrichment analysis (GSEA) and cross referenced against Gene Ontology (GO) categories. PFS and OS were defined as the time from transplant until the event of interest, with censoring at time of last follow up. Patients were regrouped according to their mutation burden in the relapse signature genes ("High burden" defined as >=six signature genes with variants) and their OS and PFS were analyzed with an R package (survival) to generate Kaplan-Meier curves and statistical significance based on a Chi-square test between low and high burden patients. Results: In total, 3,523 genes were identified as containing variants. Table 1 lists the top thirty genes that were identified and ranked based upon total number of mutations (mutational count) and most frequently mutated in relapsed and non-relapsed patients (sample count). We then identified those genes that were more frequently mutated by at least 10% in relapsed patients compared to non-relapsed patients (Fig. 1A). GSEA revealed that the relapse burden gene signature was associated with protein O-linked glycosylation, glycan processing, Golgi lumen and innate immune response activating cell surface receptor signaling pathways (Table 2). Interestingly, multiple mucin family members (Muc2, Muc3A, Muc12 and Muc19) were represented in the relapse burden signature. GO analysis indicated that the individual mucin genes were associated with the same signaling pathways that had been associated with the relapse burden signature by GSEA (Table 3). Importantly, a high relapse burden signature was correlated with a statistically significant reduction in both PFS and OS (Fig. 1B, C). Conclusion: Taken together, our results support the feasibility of WES to generate a relapse burden signature that predicts the risk of MM patients for relapse following HCT. Moreover, the mutational landscape associated with relapse, i.e. the specific genes mutated, has provided insights on the mechanisms of relapse. It is noteworthy that the relapse burden signature genes identified here were mutated at a much greater frequency than genes associated with clonal hematopoiesis of indeterminate potential (CHIP). The identification of patient subgroups at heightened risk of relapse can better guide treatment decisions. Future studies will be conducted to evaluate the effect of pathways identified here on myeloma cell survival and to validate actionable therapeutic targets. Disclosures Malek: Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau; Medpacto: Research Funding; Janssen: Other: Advisory board, Speakers Bureau; Sanofi: Other: Advisory board; Clegene: Other: Advisory board , Speakers Bureau; Amgen: Honoraria; Cumberland: Research Funding. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Kite pharmaceuticals: Other: Advisory Board; Celgene: Speakers Bureau; ADC therapeutics: Other: Advisory Board, Research Funding. de Lima:Celgene: Research Funding; BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Pfizer: Other: Personal fees, advisory board, Research Funding.

12104 Background: Immunomodulatory drugs (IMiDs) are backbone of myeloma therapy for patients with Multiple Myeloma (MM). The incidence of IMiD-associated rash is up to 27% in some reports impeding maximal benefit of this agent. The optimal management of IMiDs-associated skin is unclear. The concurrent weekly Dexamethasone (Dex) does not diminish the incidence of skin eruptions with IMiDs (Sviggum, et al. 2006), therefore we designed a low dose daily and tapering corticosteroid regimen to tame this immune response upon restarting IMiDs and allow desensitization and reinstitution of the same IMiD. Furthermore, we assessed the impact of this desensitization regimen on clinical outcome. Methods: A total of 160 patients were evaluated. The incidence of rash was found to be 13% (n = 21). A cohort of age- and gender-matched without rash (n = 39) was randomly selected. The effects of rash on overall and progression free survival (OS and PFS) were further estimated using Cox regression controlling the effects of age and gender. Results: Median time to development of rash after IMiD initiation was 28 days (range, 2-232). Rashes were graded as low (I-II) in 89% (n = 17) and high (III-IV) in 19% of pts. All pts were managed by temporary treatment interruption and upon clearance of rash, re-institution of the same IMiD concomitantly with a standardized 3-week steroid rash prophylaxis protocol (prednisone at 10 mg daily for 10 days, followed by 5 mg daily for 10 days, followed by 5 mg on alternate days for 10 days). As a result, all patients were able to restart the same IMiD with none re-experiencing any dermatologic adverse effect afterward. Comparing to no-rash controls, there was no significant difference in PFS (0.13) or OS (p = 0.12) in multivariate regression model. Conclusions: Proposed 3-week corticosteroid regimen showed 100% success rate in reinstituting IMiDs in our cohort. It may provide a highly effective and practical short term immunosuppression required to enable patients to restart IMiDs and enjoy comparable outcome to pts without skin rash.

Introduction Hematopoietic cell transplantation (HCT)-specific comorbidity index (Sorror et al. Blood 2005) is highly recommended by National Marrow Donor Program as a risk assessment tool before HCT. Prior malignancies has one of the highest weighted score of 3 in this risk model. The isolated prognostic value of prior malignancies has not been evaluated in Multiple Myeloma (MM) patients (pts) who underwent autologous HCT (AHCT) in large databases. We hereby used national cancer database (NCDB) to evaluate this. Methods NCDB covers more than 70% of newly diagnosed cancer pts in the U.S. We reviewed NCDB, using ICD-O code of 9732, to identify pts who were diagnosed with MM between 2010 and 2014, underwent systemic treatment within 90 days of the diagnosis, and subsequently AHCT. Prior malignancy was not incorporated into Charlson comorbidity index at NCDB and reported separately. Average annual transplant volume of a cancer center for MM is calculated among pts who met the inclusion criteria. Overall survival (OS) was estimated by the Kaplan-Meier method and compared with the log-rank test. Cox hazard analysis was performed to identify independent predictors of OS. Results We reviewed 12,427 pts and included 4358 pts who met inclusion criteria. Of which, 2481 (57%) were male, 693 (16%) were black, and 412 (10%) had at least one malignancies prior to MM. Median age at the diagnosis and time to initiation of systemic treatment after the diagnosis were 60 years (range: 25 – 80) and 17 days (range: 1 – 90), respectively. The Charlson comorbidity index was 0, 1, and ≥2 for 3646 (84%), 558 (13%), 154 (3%) pts, respectively. Durie-Salmon stage (DSS) at diagnosis was 1, 2, and 3 for 562 (13%), 1040 (24%), 2756 (63%) pts, respectively. Patient and treatment characteristics are compared between prior and no prior malignancy cohorts in table 1. Median follow-up time of pts was 36 months. Five-year OS of MM pts with and without prior malignancies was 75.6% (95% CI: 69.6 – 82.2) and 73.9% (95% CI: 71.6 – 76.2), respectively (p = 0.7) (Figure 1A). On multivariable analysis, each 10-year increase in age (HR 1.14, 95% CI: 1.02 – 1.26, p = 0.017), each 1 increase in comorbidity index (HR 1.24, 95% CI: 1.08 – 1.42, p=0.002) and year of MM diagnosis (HR 1.15, 95% CI: 1.06 – 1.24, p = 0.0008), DSS 3 vs 1 or 2 (HR 1.38, 95% CI: 1.16 – 1.64, p=0.0002), immunotherapy prior to AHCT (HR 0.72, 95% CI: 0.61 – 0.86, p = 0.0001), and each 10 increase in annual AHCT volume of a cancer center for MM (HR 0.98, 95% CI: 0.97 – 0.99, p = 0.016) were independent predictors of OS (Table 2). Conclusion In this large cohort analysis, prior malignancy was not a predictor of OS for MM pts who underwent AHCT. The role of prior malignancies in defining "transplant eligibility" requires future evaluation and the weighted value of this item in the comorbidity index should be considered for downward revision.

Introduction Immunomodulatory drugs (IMiDs) are backbone of myeloma therapy in induction and maintenance therapy after transplant for patients (pts) with Multiple Myeloma (MM). The incidence of IMiD-associated rash is up to 27% (Nardone, et al, Clinical Lymphoma Myeloma and Leukemia. 2013) and importantly heralds a favorable prognosis (Kojima, et al. Blood. 2016) suggesting more robust immune stimulation by this class of drugs; however, lack of optimal management strategy of this toxicity can deprive large subset of pts from maintenance therapy after transplant and lead to potential detrimental impact on survivals. The concurrent weekly dexamethasone (Dex) does not diminish the incidence of skin eruptions with IMiDs (Sviggum, et al. Archives of dermatology. 2006), therefore we designed a low dose daily and tapering corticosteroid regimen to tame this immune response upon restarting IMiDs and allow desensitization and reinstitution of the same IMiD which may not be achieved by standard weekly Dex. Here, we present our experience with this regimen. Methods In this retrospective study, pts with MM treated with lenalidomide and pomalidomide were reviewed for any IMiD-associated dermatologic toxicity. We followed the same corticosteroid regimen for all IMiD-related rash in our clinic without changing Dex dosing. Result A total of 160 pts were evaluated. The incidence of rash was found to be 13% (n=21). IMiDs were instituted as part of induction regimen in 71% (n=15) and as maintenance therapy after transplant in 29% (n=6) of pts. Median time to development of rash after IMiD initiation was 28 days (range, 2-232). The rashes were characterized as morbilliform in 86% (n=18), urticaria in 9.5% (n=2) and blisters in 5% (n=1) of pts. Pruritis or pain was associated with 86% of rashes (n=15). According to NCI-CTCAE, rashes were graded as low (I-II) in 89% (n=17) and high (III-IV) in 19% of pts. All pts were managed by temporary treatment interruption and upon clearance of rash, re-institution of the same IMiD concomitantly with a standardized 3-week steroid rash prophylaxis protocol (prednisone at 10 mg daily for 10 days, followed by 5 mg daily for 10 days, followed by 5 mg on alternate days for 10 days). As a result, all pts were able to restart the same IMiD either at same (n=5, 24%) or reduced (n=16, 76%) dose with none re-experiencing any dermatologic adverse effect afterward. There was no association between rash development and changes in creatinine clearance (p=0.42). Median eosinophil count at rash development was observed to be significantly higher as compared to eosinophil count at IMiD initiation (380 × 106 vs 130 × 106 respectively, p=0.01). Conclusion The proposed 3-week corticosteroid regimen showed 100% success rate in terms of reinstituting IMiDs, therefore it may provide a highly effective and practical short term immunosuppression required to enable pts to restart IMiDs.

Donor-specific antibodies (DSAs) have a deleterious effect on allografts and remain a major immunologic barrier in transplantation. Current therapies to eliminate DSAs are ineffective in highly HLA-sensitized patients. Proteasome inhibitors have been employed as a strategy to target bone marrow plasma cells (BMPCs), the source of long-term antibody production; however, their efficacy has been limited by poorly defined drug-resistance mechanisms. Here, we performed transcriptomic profiling of CD138+ BMPCs that survived in vivo desensitization therapy with the proteasome inhibitor carfilzomib to identify mechanisms of drug resistance. The results revealed a genomic signature that included increased expression of the immunoproteasome, a highly specialized proteasomal variant. Western blotting and functional studies demonstrated that catalytically active immunoproteasomes and the immunoproteasome activator PA28 were upregulated in carfilzomib-resistant BMPCs. Carfilzomib-resistant BMPCs displayed reduced sensitivity to the proteasome inhibitors carfilzomib, bortezomib, and ixazomib, but enhanced sensitivity to an immunoproteasome-specific inhibitor ONX-0914. Finally, in vitro carfilzomib treatment of BMPCs from HLA-sensitized patients increased levels of the immunoproteasome β5i (PSMB8) catalytic subunit suggesting that carfilzomib therapy directly induces an adaptive immunoproteasome response. Taken together, our results indicate that carfilzomib induces structural changes in proteasomes and immunoproteasome formation.

Aim: Clinical success of the proteasome inhibitor bortezomib for multiple myeloma (MM) treatment highlights the potential of therapeutically targeting the ubiquitin (Ub) + proteasome system. However, bortezomib treatment invariably leads to therapeutic resistance through mechanisms that remain elusive and that limit long-term clinical efficacy. We hypothesized that individual E3 Ub ligases were differentially expressed in MM patients that did or did not respond to bortezomib. E3 ligases bind intracellular protein substrates leading to their subsequent ubiquitination that then triggers proteasomal degradation of the substrate. The aim of the present study was to analyze the gene expression profiles (GEPs) from MM patients and identify E3 Ub ligases that correlated with clinical response to bortezomib. Methods: MM tumor cells were collected by bone marrow biopsy from newly diagnosed patients, and RNA isolated and GEPs were correlated with individual patient response to bortezomib. Results: Expression of the E3 Ub ligase Skp1-Cullin-1-F-box (SCF)-Skp2 was significantly increased in MM patients that did not respond to bortezomib. However, SCF-Skp2 expression was not increased in GEPs from patients that did not respond to other anti-myeloma agents. Conclusion: Drugs that target the E3 Ub ligase SCF-Skp2 may overcome bortezomib resistance and display refined specificity with reduced adverse toxicities.

Advent of novel anti-myeloma agents and broader use of stem cell transplant has led to significant improvement in survival of patients (pts) with Multiple Myeloma (MM). However, there are well-described issues with affordability of novel drugs and rapidly escalating price of these agents (Shih et al. JCO 2017), leading to significant disparity among different sociodemographic groups. Hereby, we interrogated the National Cancer Database (NCDB) (which covers 70% of MM patient diagnosed nationwide) to assess impact of insurance type on survival. We also sought to investigate if autologous transplant may overcome socioeconomic effects on survival, by potentially minimizing the need for chronic use of expensive drugs. Methods: Data from 117,926 MM pts diagnosed with MM (ICD-O 9732) between 2005 and 2014 were analyzed. Results: Median age at diagnosis was 67 (19-90); 55% were males. 57% of pts lived in areas where the median income was Conclusions: Although insurance type and regional income are associated with MM survival among pts who relied on non-transplant modalities, there was no significant impact of these socioeconomic factors on survival of pts that received an autologous transplant in this large database. This finding merits further investigation.

// Mohamed A.Y. Abdel Malek 1,2,3,* , Sajjeev Jagannathan 1,2,* , Ehsan Malek 1,2 , Douaa M. Sayed 4 , Sahar A. Elgammal 3 , Hanan G. Abd El-Azeem 3 , Nabila M. Thabet 3 and James J. Driscoll 1,2,5,6 1 The Vontz Center for Molecular Studies, University of Cincinnati College of Medicine, Cincinnati, OH 2 Division of Hematology and Oncology, University of Cincinnati College of Medicine, Cincinnati, OH 3 Department of Clinical Pathology, Faculty of Medicine, Assiut University, Assiut, Egypt 4 Department of Clinical Pathology, South Egypt Cancer Institute, Assiut University, Assiut, Egypt 5 Department of Cancer Biology, University of Cincinnati College of Medicine, Cincinnati, OH 6 University of Cincinnati Cancer Institute, Cincinnati, OH * These authors contributed equally to this work Correspondence: James J. Driscoll, email: // Keywords : GRP78, Aggresome+Autophagosome Pathway, Proteasome, Myeloma, Chemoresistance Received : November 06, 2014 Accepted : December 17, 2014 Published : December 26, 2014 Abstract Despite the clinical benefit of the proteasome inhibitor bortezomib, multiple myeloma (MM) patients invariably relapse through poorly defined mechanisms. Myeloma cells inevitably develop chemoresistance that leads to disease relapse and patient-related deaths. Studies in tumor cell lines and biopsies obtained from patients refractory to therapy have revealed that myeloma cells adapt to stress by inducing expression of glucose-regulated protein 78 (GRP78), an endoplasmic reticulum (ER) chaperone with anti-apoptotic properties. Treatment of myeloma cells with bortezomib increased GRP78 levels and activated GRP78-dependent autophagy. Expression profiling indicated that GRP78-encoding HSPA5 was significantly upregulated in bortezomib-resistant cells. Co-treatment with the anti-diabetic agent metformin suppressed GRP78 and enhanced the anti-proliferative effect of bortezomib. Bortezomib treatment led to GRP78 co-localization with proteotoxic protein aggregates, known as aggresomes. Pharmacologic suppression, genetic ablation or mutational inactivation of GRP78 followed by bortezomib treatment led to the accumulation of aggresomes but impaired autophagy and enhanced anti-myeloma effect of bortezomib. GRP78 was co-immunoprecipitated with the KDEL receptor, an ER quality control regulator that binds proteins bearing the KDEL motif to mediate their retrieval from the Golgi complex back to the ER. Taken together, we demonstrate that inhibition of GRP78 functional activity disrupts autophagy and enhances the anti-myeloma effect of bortezomib.

The proteasome inhibitor bortezomib is an effective anti-cancer agent for the plasma cell malignancy multiple myeloma but clinical response is hindered by the emergence of drug resistance through unknown mechanisms. Drug sensitive myeloma cells were exposed to bortezomib to generate drug resistant cells that displayed a significant increase in subunits of the energy sensor AMP-activated protein kinase (AMPK). AMPK activity in resistant cells was increased and bortezomib resistant cells contained a ~4-fold greater level of autophagosomes than drug sensitive cells. Real-time measurements indicated that bortezomib reduced the oxygen consumption rate in drug sensitive cells more readily than in resistant cells. Genetic ablation of AMPK activity reduced the bortezomib effect on autophagy. The autophagy-related gene (Atg)5 is required for autophagosome formation and enhances cellular susceptibility to apoptotic stimuli. Atg5 knockout eliminated bortezomib-induced autophagosome formation and reduced susceptibility to bortezomib. Bortezomib treatment of myeloma cells lead to ATG5 cleavage through a calpain-dependent manner while calpain inhibition or a calpain-insensitive Atg5 mutant promoted bortezomib-resistance. In contrast, AICAR, an AMPK activator, enhanced bortezomib-induced cleavage of ATG5 and increased bortezomib-induced killing. Taken together, the results demonstrate that ATG5 cleavage provokes apoptosis and represents a molecular link between autophagy and apoptosis with therapeutic implications.

The therapeutic response and clinical outcome of patients diagnosed with the same cancer type and that receive identical treatment is highly variable to reflect the genetic heterogeneity within tumor cells. Non-coding RNAs (ncRNAs) are recently discovered molecules that regulate eukaryotic gene expression and represent a significant advance towards a better understanding of the mechanisms that govern cellular growth. NcRNAs are essential for the proper regulation of cell proliferation and survival under physiologic conditions and are deregulated in many pathologies, e.g., human cancers. NcRNAs have been associated with cancer diagnosis, staging, treatment response, metastasis and survival and include distinct subtypes, e.g., long ncRNAs (lncRNAs) and microRNAs (miRNAs). LncRNAs have been linked to essential growth-promoting activities and their deregulation contributes to tumor cell survival. A prominent example is the Hox transcript antisense intergenic lncRNA, HOTAIR, that cooperates with the polycomb repressive complex to reprogram chromatin organization. HOTAIR expression is deregulated in a spectrum of cancers and HOTAIR expression correlates with patient survival. Here, we highlight emerging evidence that supports a role for lncRNAs in cancer with implications for the development of novel diagnostics and therapeutics.

Brain metastases remain a daunting adversary that negatively impact patient survival. Metastatic brain tumors affect up to 45% of all cancer patients with systemic cancer and account for ~20% of all cancer-related deaths. A complex network of non-coding RNA molecules, microRNAs (miRNAs), regulate tumor metastasis. The brain micro-environment modulates metastatic tumor growth; however, defining the precise genetic events that promote metastasis in the brain niche represents an important, unresolved problem. Understanding these events will reveal disease-based targets and offer effective strategies to treat brain metastases. Effective therapeutic strategies based upon the biology of brain metastases represent an urgent, unmet need with immediate potential for clinical impact. Studies have demonstrated the ability of miRNAs to distinguish normal from cancerous cells, primary from secondary brain tumors, and correctly categorize metastatic brain tumor tissue of origin based solely on miRNA profiles. Interestingly, manipulation of miRNAs has proven effective in cancer treatment. With the promise of reduced toxicity, increased efficacy and individually directed personalized anti-cancer therapy, using miRNA in the treatment of metastatic brain tumors may prove very useful and improve patient outcome. In this review, we focus on the potential of miRNAs as diagnostic and therapeutic targets for the treatment of metastatic brain lesions.

Background: Observation is currently the standard of care for patients with smoldering and indolent multiple myeloma (MM). However, the evidence has been building up recently to support early initiation of treatment. We performed a meta-analysis of previous clinical trials involving smoldering/indolent MM patients who were treated with novel anti-myeloma agents to examine progression free survival (PFS) and safety profile of the treatment regimens. Methods: A systematic literature search was conducted independently by 2 authors (F.C. and T.Z.K.) in PubMed, MEDLINE, EMBASE, Cochrane, and abstracts from major oncology meetings. Keywords used in the search included "myeloma", "smoldering MM", "indolent MM", "asymptomatic MM". The title and abstract of studies identified in the search were reviewed by 2 authors (F.C. and T.Z.K.) independently to exclude studies that were not clinical trials and included patients with MGUS or symptomatic MM. Entire text of the remaining articles, including the references, was examined to identify studies which reported Cox regression analysis for PFS or Kaplan-Meier curve of PFS to be able to extract HR, 95% CI, and P value, as previously described by Tierney JF et al. (Trials, 2007). Historical control arm is extracted from intermediate and high risk patients in an observational clinical trial by Khan R et al. (Haematologica, 2015) and used for the phase 2 clinical trials. The Jadad scale was used to assess the methodological quality of phase 3 trials. The random-effects model was used to synthesize the data. Heterogeneity was assessed using Cochran's Q statistic and I2 statistics, p≤0.1 and I2>50% considered statistically significant, respectively. We examined publication bias quantitatively using the Begg and Mazumdar adjusted rank correlation test and qualitatively by visual inspection of funnel plots of the logarithmic HR versus their standard errors. Results: We reviewed title/abstracts of 3327 studies, identified 31 manuscripts/meeting abstracts to read entire text, and incorporated 9 trials (four phase 3 and five phase 2) in the meta-analysis based on inclusion criteria. These studies cumulatively reported 677 patients with smoldering/indolent MM. Six trials were performed in USA, 2 were multi-country trials, and 1 was in Europe. Median number of patients in the trials was 68 (range: 29 - 181) and median follow-up was ranged between 26 and 121 months. The characteristics of these studies are shown in table 1. Overall response rate and grade ≥3 adverse events for trials with thalidomide vs. lenalidomide vs. monoclonal antibody based treatment arms were 41% and 59% vs. 65% and 32% vs. 36% vs 44%. On meta-analyses of all studies, treatment vs observation of smoldering/indolent MM was statistically significant predictor of PFS (HR 0.41, 95% CI: 0.31 - 0.56, p < 0.001) (Figure 1). The results showed considerable heterogeneity (Cochran's Q test P = 0.037, I2 = 51%). There was no evidence of publication bias both quantitatively (P = 0.30) and on visual inspection of the funnel plot (Figure 2). We performed preplanned stratified analysis of studies based on location, trial phase, and treatment arm (Table 2). Subgroup analyses according to treatment regimens identified the trials with thalidomide based treatment arms as the source of heterogeneity (I2 = 55% vs I2 = 0%, P = 0.027). Trials with lenalidomide and monoclonal antibody based treatment arms showed significantly greater prognostic impact on PFS (HR 0.22, 95% CI: 0.14 - 0.35 and HR 0.41, 95% CI: 0.22 - 0.94, respectively) compared to trials with thalidomide based treatment arms (HR 0.53, 95% CI: 0.33 - 0.83). Conclusion: In this first meta-analysis of patients with smoldering/indolent MM, we found that novel anti-myeloma agents prolongs the PFS with an acceptable toxicity profile. Disclosures Malek: Amgen: Speakers Bureau; Adaptive: Consultancy; Janssen: Speakers Bureau; Medpacto: Research Funding; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy.

Multiple Myeloma (MM) is a neoplasm of terminally differentiated plasma cells which proliferate in a permissive bone marrow environment characterized by immunosuppression and osteoclast activation. Although malignant plasma cells do not harbor any mutation in the Transforming Growth Factor-beta (TGF-β) pathway, increased TGF-β secreted by MM cells lead to impaired immune surveillance and promotion of catabolic bone remodeling allowing myeloma progression (Kyrtsonis MC et al. 1998). Here, we conducted preclinical studies in the syngeneic 5T3MM immunocompetent mouse model assessing the efficacy of vactosertib (Vacto), a TGF-β type I receptor antagonist, single agent activity as well as synergistic activity with the third generation immunomodulatory drug, pomalidomide (Pom) and a subsequent corticosteroid-free phase I study to test safety and preliminary efficacy of this combination. (NCT03143985). Methods Preclinical: Mice bearing 5T33MM cells expressing luciferase were treated with Vacto/Pom and the combination for 3 weeks, and evaluated for MM growth by bioluminescence imaging (BLI). Cellular and molecular assays were performed in human RPMI8226 and U266 as well as murine 5T33MM cells via apoptosis, real-time PCR and Western blotting. Peripheral blood monoclonal protein concentration, M-spike, was measured by ELISA. Distal femur trabecular bone structure was assessed by 3D micro-CT. Phase I: pts with relapsed MM with at least two lines of therapies enrolled on a modified Fibonacci 3 + 3 dose escalation design and received escalating dosages of Vacto, 60 mg/d, 120 mg/d and 100 mg BID and 200 mg BID in combination with standard dose of Pom (4mg) without corticosteroids. The study objectives were to assess safety, recommended phase 2 dose, and efficacy of Vacto/Pom in compared to historical control of Pom without corticosteroids (PFS-6: 20% in randomized Phase II study by Richardson et al. Blood. 2014). Vacto tablets, taken daily for 5 days followed by 2 days off, was administered in 28-day cycles, repeated for 6 cycles or until progression of disease or intolerable toxicity. There was no fasting requirement after the first two dose levels. Results: Preclinical: Vacto attenuated the growth and viability of human and murine MM cells by inducing apoptosis and inhibited TGF-β-induced activation of Smad2/3 in MM cells in vitro. In the 5T33MM preclinical model, Vacto inhibited MM progression, as single agent, as measured by peripheral blood monoclonal protein concentration and BLI before and after treatment. Vacto also prolonged survival (Figure-1), prevented weight loss and increased trabecular bone thickness (Figure-2) in mice bearing MM in compare to control. Vacto alone or combination with Pom also attenuated TGF-β activation of Smad2/3, reduced the expansion of CD11b⁺Gr-1⁺ myeloid derived suppressor cells (MDSCs) in the bone marrow, and diminished the population of Foxp3⁺ regulatory T cells in the spleen (Figure-1). Vacto showed anti-myeloma effect at level of 700-750 nM on myeloma cells from three MM pts (Figure-3). Phase I: As of July 30th 2019, 10 pts were enrolled in the study (Table-1). Three pts were refractory to bortezomib and four pts were refractory to lenalidomide. The most common non-hematologic adverse event (AE) was grade II fatigue and pain in one pt with one episode of grade III renal failure that took less than 7 days to get back to baseline, no grade IV non-hematologic AE was observed. Two pts had grade III hematologic AE, no grade IV hematologic AE. Two out of 10 patients experienced progression of disease (PFS-6: 80%) (Figure-4, 5). Conclusions: Vacto is a small molecule TGF-β type I receptor inhibitor that has shown single agent activity against myeloma in the syngeneic 5T33MM murine mouse model, in human myeloma cell lines and primary patient samples. Its effect on the tumor microenvironment is augmented in combination with Pom in the Cereblon-negative immunocompetent murine model. The phase I data shows safety of this agent in combination with Pom. The preliminary efficacy assessment is PFS-6: 80% which is higher than historical control (Richardson et al. Blood. 2014) with Pom only (PFS-6: 20%) or Pom with corticosteroids (PFS-6: 40%). Further advancement of this agent in clinical trial pipelines for MM is planned. Disclosures Malek: Amgen: Speakers Bureau; Adaptive: Consultancy; Janssen: Speakers Bureau; Medpacto: Research Funding; Sanofi: Consultancy; Takeda: Consultancy; Celgene: Consultancy. Hwang:MedPacto: Employment. Metheny:Takeda: Speakers Bureau; Incyte: Speakers Bureau. OffLabel Disclosure: Experimental therapeutics: Vactosertib

Background: Smoldering multiple myeloma (SM) is a heterogenous clinical entity with a variable rate of progression to symptomatic multiple myeloma (MM). Identification of demographic characteristics and outcomes of SM patients have been hampered by the lack of specific ICD code for SM. Here, we analyzed the National Cancer Database (NCDB) for this purpose, which covers >70% of cancer patients in the U.S. Methods: We reviewed patients in the NCDB who were diagnosed with MM between 2010 and 2014. Patients who did not receive any treatment within 3 months after the diagnosis and still alive were considered to have had SM (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 SM 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 reviewed 68,234 patients and identified 12,984 patients with SM. Among SM patients, 3002 (23%) were black, 6796 (52%) were male, and median age at diagnosis was 69 years (range: 22 - 90). SM patients' insurance types were private for 4164 (32%), Medicare for 7420 (57%), Medicaid for 669 (5%), and 260 (2%) were uninsured. Majority of the cases were reported from non-academic hospitals (59%). Patient and treatment characteristics are summarized in Table 1. SM was diagnosed in black patients a median of 4 years younger than in white patients (median age 66 vs 70 years, p Four-year cumulative incidence of progression to MM for SM patients at ages of 70 years was 34% (95% CI: 32 - 35) vs 28% (95% CI: 26 - 29, p Four-year OS of SM patients after progression and MM patients without known preceding SM who received treatment were 63% (95% CI: 61 - 65) and 54% (95% CI: 54 - 55), respectively (p70 vs 60-70 and Conclusion: Taken together, our result shows higher rate of MM progression in younger SMM patients than old ones as well as earlier age of SMM diagnosis in Blacks. Also, this study highlights the importance of known SMM stage before MM in prolonging survival which can be indicative of benefit from screening programs. Disclosures Metheny: Incyte: Speakers Bureau; Takeda: Speakers Bureau. Malek:Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Adaptive: Consultancy.

Despite advent of a rich anti-myeloma armamentarium, autologous hematopoietic cell transplant (HCT) has been increasingly utilized to achieve prolonged survival for patients (pts) with multiple myeloma (MM). Short-term metabolic abnormalities have been associated with this treatment modality. Electrolyte abnormalities may lead to increased patient morbidity by prolonging hospital stay as well as central line use. The incidence, temporal course, severity, and impact of metabolic derangement during the peri-engraftment period on clinical outcomes have not thoroughly been studied in MM pts. Here, we sought to investigate the dynamics of electrolyte changes throughout the course of transplant and assess its association with decline and rise in peripheral blood cell count. Methods: All consecutive MM pts that underwent inpatient autologous SCT from January 2012 through July 2016 in our institutions were included. Engraftment Speed (ES) was calculated as the period between the first rise in the absolute neutrophil count (ANC) to engraftment (fist of 3 consecutive days in which ANC>500 mm3). Time to "no need for electrolyte replacement" was calculated from the day of stem cell infusion to the last day of replacement. Survival distribution was estimated using Kaplan-Meier methods. The effect of electrolyte abnormalities on OS and PFS was estimated using a Cox model after controlling for the effects of age, gender, number of prior therapies, and time from diagnosis to transplant. Results: Patient characteristics are listed in Table 1. Pre- and post-SCT nadir values, total amount of replaced electrolyte and replacement frequency are listed in Table 2. The most frequently replaced electrolyte was K followed by Mg, Ca, and P. As expected, there was a direct correlation between magnitude of drop in K, Ca, and Mg and total amount of replacement (Pearson coefficient: 0.673, p = 0.001). Pts dropped a median of 17 ml/min in GFR throughout the transplant process and the nadir occurred on median of transplant day 6. Median ANC nadir occurred on day 6 (range: 2-8) while ANC One hundred and six pts (90%) had all-grade diarrhea while 37 pts (31%) had grade II or higher. Grade II and higher diarrhea was associated with significant drop in K but not with drop in P, Ca or Mg. (Figs. 1, 2). All-grade nausea occurred among 113 pts (95%), while grade II and higher nausea complicated the transplant course in 42 pts (35%). All-grade oral mucositis happened in 68 pts (57%), while 27 pts (23%) suffered from grade II and higher. There was no statistically significant difference between the drop in P, Ca, Mg or K based on severity of nausea or oral mucositis. A multivariate model to assess the impact of potential risk factors on electrolyte abnormalities, included age, gender, CD34+ cell dose, pre-HCT performance status and presence of severe GI toxicity (Table 3). Median ES was 3 days (range: 0-5) and 40 pts (36%) had ES ≤ 2 days. Engraftment occurred at a median of 11 days (standard deviation (SD): 1.50 days, after HCT). The median time-to-nadir for both P and K was 10 days (SD: 3.10 days and 4.28 days for P and K, respectively). The drop in P was statistically higher in the group with ES ≤ 2 days in comparison to the group with ES > 2 days (Median: 1.4 vs. 0.9 mg/dL, p-value: 0.000) as well as the drop in K (median: 1.1 vs. 0.7 mmol/L, p=0.039). There was no difference in the Ca or Mg drop between the two ES groups. (Fig. 1). There was also no statistical significance in frequency of post-engraftment Hb2 had post-engraftment Plt Conclusions: Our results indicate that there is a significant correlation between the magnitude of drop in potassium and phosphorous following stem cell transplant and a steep rise in neutrophil counts around engraftment period. These events are consistent with a "genesis syndrome" which is characterized by a rapid, massive transfer of electrolytes into proliferating cells as has been previously described in certain high-grade lymphomas and leukemias. Disclosures Malek: Celgene: Consultancy; Takeda: Consultancy; Sanofi: Consultancy; Medpacto: Research Funding; Janssen: Speakers Bureau; Amgen: Speakers Bureau; Adaptive: Consultancy.