Abstract: Autologous hematopoietic cell transplantation, or autotransplantation, is effective in light-chain amyloidosis (AL), but it is associated with a high risk of early mortality (EM). In a multicenter randomized comparison against oral chemotherapy, autotransplantation was associated with 24% EM. We analyzed trends in outcomes after autologous hematopoietic cell transplantation for AL in North America. Patients and Methods Between 1995 and 2012, 1,536 patients with AL who underwent autotransplantation at 134 centers were identified in the Center for International Blood and Marrow Transplant Research database. EM and overall survival (OS) were analyzed in three time cohorts: 1995 to 2000 (n = 140), 2001 to 2006 (n = 596), and 2007 to 2012 (n = 800). Hematologic and renal responses and factors associated with EM, relapse and/or progression, progression-free survival and OS were analyzed in more recent subgroups from 2001 to 2006 (n = 197) and from 2007 to 2012 (n = 157). Results Mortality at 30 and 100 days progressively declined over successive time periods from 11% and 20%, respectively, in 1995 to 2000 to 5% and 11%, respectively, in 2001 to 2006, and to 3% and 5%, respectively, in 2007 to 2012. Correspondingly, 5-year OS improved from 55% in 1995 to 2000 to 61% in 2001 to 2006 and to 77% in 2007 to 2012. Hematologic response to transplantation improved in the latest cohort. Renal response rate was 32%. Centers performing more than four AL transplantations per year had superior survival outcomes. In the multivariable analysis, cardiac AL was associated with high EM and inferior progression-free survival and OS. Autotransplantation in 2007 to 2012 and use of higher dosages of melphalan were associated with a lowered relapse risk. A Karnofsky score less than 80 and creatinine levels 2 mg/m 2 or greater were associated with worsened OS. Conclusion Post-transplantation survival in AL has improved, with a dramatic reduction in early post-transplantation mortality and excellent 5-year survival. The risk-benefit ratio for autotransplantation has changed, and randomized comparison with nontransplantation approaches is again warranted.

Abstract: Background Multiple Myeloma (MM) is a clinically heterogeneous disorder of clonal plasma cells. Elevated Lactate Dehydrogenase (LDH) has been shown to be an independent prognostic marker associated with drug resistance and shorter survival. Methods Utilizing data from the Multiple Myeloma Research Foundation (MMRF) CoMMpass database (IA12) which includes over 1000 newly-diagnosed MM (NDMM) patients with enriched tumor and matched constitutional samples analyzed using whole genome/exome and RNA sequencing, we identified patients with baseline LDH values. High LDH was defined as LDH greater than the upper limit of normal, ( 〉 4.68 microkatals/liter). We compared baseline characteristics and outcomes with autologous stem cell transplant (ASCT), based on LDH as categorical variable. We sought to determine if there is enrichment of high and standard risk cytogenetic changes when stratified by LDH. Results We identified 871 patients with NDMM who had baseline LDH values. 143 patients had high LDH and 728 patients had a normal baseline LDH. Consistent with prior reports, high LDH was associated with shortened survival, 660 days vs 795 days (p=0.02852) in patients with normal LDH. 385 patients underwent ASCT (High LDH N=44; Normal LDH N=341). Those with high LDH had an inferior OS when compared with those with normal LDH (median OS 800.5 vs 878.8 days, p=0.019). In order to understand this difference, we examined baseline characteristics. Of the 44 patients with high LDH who underwent ASCT, median age was 60 years and ECOG performance status was 1. 61.36% were females, 77% were Caucasian, 11% were African American. Induction therapy consisted of 4 drugs or more in 16%, 3 drugs in 61%, and 2 drugs in 23%. Bortezomib and immune modulating agents (IMIDS) were combined in 72%. In those who did not receive an IMID, a bortezomib-based induction was used in 16% and carfilzomib-based induction was used in 11%. 93.18% underwent transplant in the consolidative setting with a median time to transplant was 178 days. 21 of the 44 patients (47.72%) received post-transplant maintenance. 10/21(48%) patients received triplet therapy (5/10 - lenalidomide, bortezomib, dexamethasone), 8/21 (38%) patients received lenalidomide alone. The median duration of maintenance was 217 days. Of the 341 patients with normal LDH who underwent ASCT, the median age was age 61 years, ECOG performance status was 1. 41.34% were females, 79% were Caucasian, 13% African American. Induction therapy consisted of 4 drugs in 8%, 3 drugs in 64%, 2 drugs in 24%. Combined Bortezomib-IMID in 76.24%, carfilzomib-IMID based therapy in 6%, and bortezomib-non-IMID based in 9.67%. 94.7% underwent an upfront consolidative with median time to transplant 164 days. Post-transplant maintenance was given in 213/341 (62.4%) of patients, in whom triplet therapy was given to 41/213 (19.2%), doublet therapy to 34/213 (16%), 130/213 (61%) received single agent. 107/213 (50%) received lenalidomide alone and 19/213 (6%) received bortezomib alone. Median duration of maintenance 266 days. There was no statistically significant difference in race, performance status, drug class and number of drugs used in induction therapy, time to transplant, whether or not patients received maintenance as well as maintenance duration between the groups when stratified by LDH. Female gender was enriched in the high LDH group (hypergeometric test, p=0.009). We used hypergeometric tests to assess for enrichment of high and standard risk cytogenetic changes. Del(17p13) was significantly enriched (p=0.011) in the high LDH subset where there were no statistically significant difference in the presence of t(4;14) (p=0.16) and t(14;16) (p=0.21). There was no difference in good risk hyperdiploid structural changes between the 2 groups. Conclusion Elevated LDH was confirmed as a poor prognostic factor in MMRF CoMMpass cohort. Among patients who underwent ASCT, those with high LDH have inferior survival, possibly driven by the presence of del(17p13). Since clinical outcomes remain poor despite the use of novel effective therapies and early consolidation with AHCT in patients with high baseline LDH, this group represents an unmet need for alternative therapy. Figure. Figure. Disclosures No relevant conflicts of interest to declare.

Abstract: Introduction At diagnosis, Multiple Myeloma (MM) is traditionally classified into two clinical and prognostic subgroups groups on the basis of initiating cytogenetic abnormalities: IGH translocations and hyperdiploidy. Currently, these events are clinically ascertained by Fluorescent In-Situ Hybridization (FISH). In recent years, comprehensive genome profiling studies have shown that MM pathogenesis is defined by a spectrum of acquired somatic lesions, many of which are biologically and clinically relevant. To this effect, targeted gene sequencing approaches are becoming routine in the upfront diagnostic settings. Here we present myTYPE, a MM-specific targeted next generation sequencing panel to identify germline and somatic substitutions, indels, Copy Number Aberrations (CNA) and IGH translocations. Methods A multiplex bait panel was designed to capture the exons of 120 genes implicated in MM pathogenesis, entire IGH locus as well as genome wide representation of single nucleotide polymorphisms (SNPs) (1 in 3Mb) to enable detection of arm level copy number events and recurrent focal events. These 120 genes were selected on the basis of 1) frequently mutated and driver genes in MM 2) genes in important signaling pathways, e.g the NFKB pathway 3) treatment targets and candidate genes for drug resistance, e.g. cereblon.To validate the efficacy of the assay, 16 constitutional bone marrow samples and 18 tumor samples were sequenced using myTYPE. For validation, 6/18 tumor/normal pairs sequenced using myTYPE were subject to WGS and remaining 12/18 tumor samples were subject to FISH. After sequencing, we obtained an overall median target coverage of 815x. Results After alignment, substitutions and indels were called using Caveman, Pindel and Strelka. CNAs were identified using Facets and IGH translocations were identified using Delly along with a modified version of BRASS. Below is a description of the genomic abnormalities captured by the myTYPE assay. SNVs and Indels For the 6 tumor/normal pairs sequenced using myTYPE and WGS, we obtained a total of 21 (median = 3) non-synonymous mutations using myTYPE. When limiting the WGS calls to myTYPE targets, we recovered 20/21 non-synonymous mutations identified by myTYPE. These involved SNVs and indels in key MM related drivers including NRAS, KRAS, FAM46C and TP53 among others. For the mutations identified by both myTYPE and WGS, there was a high correlation between the variant VAFs, R2= 0.99 and as expected is better in capturing subclonal mutations. IGH rearrangements and Copy Number Aberrations (CNA) Next we compared myTYPE and WGS results for recurrent CNAs in MM. We specifically looked at deletions of 1p, 13p, 16q, 17p and gains of 1q, 11q and found a 100% concordance of these aberrations identified by both assays. The remaining 12 samples sequenced using myTYPE also had orthogonal FISH. myTYPE identified a total of 7 IGH rearrangements, 4 of which are also reported by FISH. Three additional t(11;14) translocations were uniquely identified by myTYPE in cases that remained clinically uncharacterized. FISH was also used to probe deletions in 17q, 13q, 1p and 1q gain. All aberrations identified by FISH were also identified in myType. Additionally, 13q- in four samples and 1p- in one sample were uniquely identified by myTYPE. Conclusion In summary, we present a targeted assay capable of identifying somatic mutations, CNAs and IGH translocations of prognostic and diagnostic relevance in MM. When compared to conventional assays currently used in clinical practice, myTYPE identified at least one disease defining alterations in all samples screened. Evaluation of sensitivity and specificity will require larger clinical cohorts. Importantly, myTYPE enables comprehensive profiling, large sample multiplexing and short turn around times which renders it as an optimal assay for utilisation in the upfront clinical setting. Disclosures Korde: Amgen: Research Funding. Mailankody:Juno: Research Funding; Janssen: Research Funding; Takeda: Research Funding; Physician Education Resource: Honoraria. Landgren:Pfizer: Consultancy; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy.

Abstract: Introduction Smoldering multiple myeloma (SMM) is an asymptomatic precursor stage to active multiple myeloma (MM), comprised by a heterogenous group of patients with varying rates of progression. While the overall yearly progression rate is 10% the first 5 years, some patients progress at a considerably higher rate. A study from the Mayo Clinic showed that in a subset of 21 patients defined by ≥60% monoclonal bone marrow plasma cells (BMPC), 95% progressed within 2 years. It was subsequently concluded by the International Myeloma Working Group (IMWG) that patients with biomarkers predictive of a 2-year progression rate at 80%, and a median time to progression at 12 months were at ultra-high risk of progression and should be considered to have MM requiring treatment despite being asymptomatic. In 2014, ultra-high risk biomarkers were incorporated in the definition of MM, including BMPC ≥60%, free light chain (FLC) ratio ≥100 and ≥2 focal lesions on magnetic resonance imaging (MRI). While the updated myeloma definition changed the diagnosis of some patients with ultra-high risk SMM to MM, there remain patients classified as SMM progressing at a very high rate. In the present study, we aimed at further identifying ultra-high risk biomarkers predictive of a high rate of progression to active MM. Methods Patients with SMM presenting to Memorial Sloan Kettering Cancer Center between the years 2000 and 2017 were identified and included in the study. Diagnosis of SMM and progression to MM requiring therapy was defined according to the IMWG criteria at the time of diagnosis. Baseline patient and disease characteristics were collected at date of diagnosis with SMM, including pathology reports, laboratory results and imaging data. Time to progression (TTP) was assessed using the Kaplan-Meier method with log-rank test for comparisons. Optimal cut-off values for continuous variables were assessed with receiver operating characteristics (ROC) curve. Patients who had not progressed by the end of study or were lost to follow up were censored at the date of last visit. Univariate Cox regression was used to estimate risk factors for TTP with hazard ratios (HR) and 95% confidence intervals (CI). Significant univariate risk factors were selected for multivariate Cox regression. Results A total of 444 patients were included in the study. Median follow-up time was 78 months. During the study period, 215 (48%) patients progressed to active MM, with a median TTP of 72 months. Cut-off points for BMPC, M-spike, and FLC ratio were determined with ROC curves to be 20%, 2 g/dL, and 18, respectively, for predicting high risk of progression. The following factors were associated with significantly increased risk of progression to active MM: BMPC 〉 20%, M-spike 〉 2g/dL, FLC ratio 〉 18, immunoparesis with depression of 1 and 2 uninvolved immunoglobulins respectively, elevated lactate dehydrogenase, elevated beta-2-microglobulin, and low albumin (Table 1). In the multivariate model, BMPC 〉 20% (HR 2.5, 95% CI 1.6-3.9), M-spike 〉 2g/dL (HR 3.2, CI 1.9-5.5), FLC ratio 〉 18 (HR 1.8, CI 1.1-3.0), albumin 〈 3.5 g/dL (HR 3.9, CI 1.5-10.0), and immunoparesis with 2 uninvolved immunoglobulins (HR 2.3, CI 1.2-4.3), predicted a decreased TTP (Table 1). A total of 12 patients had 4 or 5 of the risk factors from the multivariate model, 8 of these did not meet the 2014 IMWG criteria for MM. These patients had a significantly shorter TTP than patients with less than 4 risk factors (median TTP 11 vs 74 months, p 〈 0.0001, Figure 1). At 16 months, 82% of these patients had progressed, and within 2 years, 91% of the patients progressed. Only one patient remained progression free after 2 years, progressing at 31 months. Of patients with less than 4 risk factors, 19% progressed within the first 2 years. Conclusion In addition to baseline BMPC 〉 20%, M-spike 〉 2g/dL, FLC-ratio 〉 18, we found that albumin 〈 3.5g/dL and immunoparesis of both uninvolved immunoglobulins at the time of diagnosis with SMM were highly predictive of a decreased TTP to MM requiring therapy. These biomarkers are readily available and routinely assessed in clinic. Patients with 4 or 5 of these risk factors represent a new ultra-high risk group that progress to active disease within 2 years, further expanding on the definition of ultra-high risk SMM. In accordance with the rationale on ultra-high risk biomarkers as criteria established by the IMWG in 2014, such patients should be considered to have MM requiring therapy. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Takeda: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria. Lesokhin:Squibb: Consultancy, Honoraria; Serametrix, inc.: Patents & Royalties: Royalties; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Janssen: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Shah:Amgen: Research Funding; Janssen: Research Funding. Mezzi:Amgen: Employment, Equity Ownership. Khurana:Amgen: Employment, Equity Ownership. Braunlin:Amgen: Employment. Werther:Amgen: Employment, Equity Ownership. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Celgene: Consultancy, Research Funding.

Abstract: Background: For multiple myeloma (MM) patients, depth of response after induction therapy and after autologous hematopoietic stem cell transplantation (AHCT) has been shown to be important for progression free (PFS) and overall survival (OS) in some studies. Furthermore, the impact of minimal residual disease (MRD) on outcomes and treatment decisions has been widely discussed. We aimed to evaluate outcomes by depth of response after induction and AHCT. Methods: MM patients who received their first AHCT within 1 year of starting induction were identified from the institutional registry. MRD was assessed by non-10 color flow cytometry. Response was defined by the International Myeloma Working Group criteria. Summary statistics were used to describe the population. Kaplan-Meier methodology estimated PFS and OS by response status pre-AHCT and at post-AHCT restaging. Results: Between 2012 - 2014, 182 MM patients met our inclusion criteria, with 83% alive at last follow-up. The median age at AHCT was 60 years (range 29-76) with 57% male. By the International Staging System (ISS), 50% were stage I, 26% stage II, and 24% stage III. High risk cytogenetics were detected in 24%. Isotype was IgG in 55%, IgA 21%, Kappa Free Light Chain (KFLC) 11%, and lambda FLC (LFCL) 9%. First induction therapy included bortezomib in 90% and lenalidomide in 79%. Median time to AHCT was 5.5 months (range 2.8-11.7). The median follow-up from AHCT was 3.7 years (range 0.22 - 4.6 years), with 84% of patients receiving lenalidomide maintenance, and 9% receiving an additional autologous or allogenic transplant at relapse. Response prior to the initial AHCT was a complete remission (CR) in 13.7% (MRD negative 6.6%, positive 4.4%, unknown 2.7%), very good partial remission (VGPR) 38%, partial remission (PR) 40%, stable disease (SD) 5%, and progressive disease (PD) 4%. At post-AHCT restaging, responses had improved to 42% CR (MRD negative 23%, positive 6%, unknown 13%), 35% VGPR, 19% PR, 2% SD, and 3% PD. Median PFS from AHCT for the entire cohort was 3.2 years (95% CI 2.4 - 4 years) with 1-year and 3-year PFS 85% and 52%, respectively. Median OS was not reached (NR) (95% CI 4.4 years - NR) with 1-year and 3-year OS 97% and 88%, respectively (Figure 1). PFS from AHCT was significantly longer in patients with an MRD negative CR prior to AHCT with median PFS not reached (95% CI 1.7 - NR) compared to MRD positive/unknown CR, VGPR, and ≤ PR [3.64 years (95% CI 1.09-3.64), 3.46 years (95% CI 2.4 - NR), and 2.44 years (1.68-3.56 years), respectively, p=0.048] (Figure 2A). From post-AHCT restaging, PFS was also significantly longer in patients with an MRD negative CR prior to AHCT with median PFS not reached compared to MRD positive/unknown CR, VGPR, and ≤ PR [3.49 years (95% CI 0.86-3.49), 3.56 years (95% CI 2.5 - NR), and 2.4 years (1.6-3.33 years), respectively, p=0.026] (Figure 2B). However, there was no difference in PFS based on the post-AHCT restaging with median PFS in MRD negative CR, MRD positive/unknown CR, VGPR, and ≤ PR of 3.49 years (95% CI 2-NR), not reached (95% CI 1.4-NR), 2.96 years (95% CI 1.7-NR), and 2.86 years (95% CI 1.7 - NR) (p=0.78, Figure 2C), respectively. OS from AHCT was not significantly different by pre-AHCT response, and the median was not reached in any group (p=0.33, Figure 3A). Finally, the median OS from post-AHCT restaging by pre-AHCT response or by post-AHCT response was also not reached in any group (p=0.32 and 0.31, respectively; Figure 3B & C). Conclusion: For MM patients, AHCT deepened responses and increased the CR rate. We were unable to show a significant difference in outcomes at post AHCT restaging, which may be due to the effect of maintenance therapy, the small numbers of MRD negative patients, or the sensitivity of the MRD assay available during this time period, though potentially show that MRD positive patients do as well as MRD negative patients after AHCT. We plan to add additional patients treated in the more recent years who were assessed by more sensitive methods. Disclosures Shah: Janssen: Research Funding; Amgen: Research Funding. Korde:Amgen: Research Funding. Lesokhin:Janssen: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria; Serametrix, inc.: Patents & Royalties: Royalties; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Squibb: Consultancy, Honoraria. Mailankody:Janssen: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding; Juno: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding.

Abstract: Background Minimal residual disease (MRD) negativity is a strong predictor for outcome in multiple myeloma. Next generation sequencing (NGS) for immunoglobulin heavy chain and kappa light chain VDJ rearrangements has become increasingly more common for MRD assessment. One of the known challenges with NGS for VDJ rearrangements is the vast diversity of sequences that are present, resulting in a need for a multiplex approach as common primers cannot be used to amplify all rearrangements. Also, somatic hypermutation may affect the annealing of primers and decrease the capture rate. The NGS VDJ assay developed by Adaptive Biotechnologies targets all theoretical combinations of VDJ sequences and has been used in several recent large randomized trials in multiple myeloma. The reported ~80% capture rate of the first version of the Sequenta/Adaptive 1.3 assay limited the ability to track MRD status post therapy. The assay has recently been updated and validated to increase resilience to somatic hypermutation. As there is no published reference data using this assay, we were motivated to assess VDJ capture in the clinical setting. Methods In total, 147 patients with newly diagnosed multiple myeloma (NDMM, n=101) or relapse/refractory multiple myeloma (RRMM, n=46) seen at Memorial Sloan Kettering Cancer Center were identified and included in the study. At bone marrow collection, patient samples were sorted for mononuclear cells and a subset of samples were sorted for CD138+ plasma cells. Stored bone marrow samples from these patients underwent DNA extraction and were sequenced with the Adaptive NGS VDJ assay. The same samples were also sequenced for genomic events using our internal NGS panel myTYPE. myTYPE is a custom capture panel targeting the most frequent multiple myeloma associated-somatic mutations, copy number alterations, and IGH translocations. Logistic regression was used to calculate odds ratios (ORs) with 95% confidence intervals (CIs) of detection success in relation to clinical parameters such as age, gender, percent bone marrow plasma cells, as well as immunoglobulin heavy and light chain types, and myTYPE positivity. Results There overall capture rate for a unique VDJ sequence was 80%, 75% in NDMM samples and 89% in RRMM samples, respectively. The VDJ capture rate in samples that were myTYPE positive, e.g. samples with at least one genomic aberration detected by myTYPE, was 94%. In univariate analysis, the ORs of detecting a clonal VDJ sequence was 1.8 (95% CI 1.3-2.5) and 1.5 (1.2-1.9) for every 10% increase in plasma cells on bone marrow aspirate and biopsy, respectively. For every 1g/dL increase in M-spike, the OR of VDJ capture was 1.6 (1.2-2.2). Samples with at least one genomic aberration detected by myTYPE had a significantly higher detection rate of VDJ sequence, the OR of VDJ capture in myTYPE positive samples was 8.8 (3.2-31.3). Conversely, age, gender, type of immunoglobulin heavy chain (IgG or IgA), or light chain type (kappa or lambda) had no significant effect on the VDJ detection rate (Table). In multivariate analysis, myTYPE positivity was found to be an independent predictor of VDJ capture, with an OR of 4.9 (1.6-18.4, p=0.009) for myTYPE positive samples. The ORs were 1.4 (1.1-2.2, p=0.052) for an increase in 10% plasma cells on bone marrow aspirate and 1.5 (0.97-2.3, p=0.083) every 1g/dL increase in M-spike. Conclusion The VDJ capture rate using the updated Adaptive NGS VDJ assay was 94% in multiple myeloma samples of high quality as indicated by myTYPE positivity. The capture success rate was higher in samples with a greater disease burden. As expected, the assay was less sensitive in samples with insufficient DNA content. Our results are supportive of the use of this NGS VDJ in multiple myeloma, but also illustrate the importance of optimal sample ascertainment and processing. Disclosures Jacob: Adaptive Biotechnologies: Employment, Equity Ownership. Korde:Amgen: Research Funding. Mailankody:Juno: Research Funding; Physician Education Resource: Honoraria; Janssen: Research Funding; Takeda: Research Funding. Lesokhin:Serametrix, inc.: Patents & Royalties: Royalties; Squibb: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Janssen: Research Funding; Genentech: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Pfizer: Consultancy; Amgen: Consultancy, Research Funding; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding.

Abstract: Introduction: BCMA targeted CAR T cell therapy has shown promising results in patients with relapsed/refractory multiple myeloma (MM). Herein, we report on the safety and efficacy of MCARH171, a second generation, human derived BCMA targeted autologous 4-1BB containing CAR T cell therapy, including a truncated epidermal growth factor receptor safety system (Smith EL. Mol Ther 2018). Methods: This is a phase I first in human, dose escalation trial of MCARH171. Patients received conditioning chemotherapy with cyclophosphamide (Cy) 3 gm/m2 as a single dose or fludarabine 30 mg/m2 daily and Cy 300 mg/m2 daily for 3 days followed by MCARH171 infusion in 1-2 divided doses. The trial followed a standard 3+3 design with 4 dose levels where patients received the following mean doses per cohort: (1) 72x106, (2) 137x106, (3) 475x106, (4) 818x106 viable CAR+ T cells. The primary objective was to demonstrate safety, and secondary objectives included efficacy and expansion, and persistence of CAR T cells using PCR from the peripheral blood. The last accrued patient received MCARH171 on Dec 6, 2017 and the data cut-off is July 16, 2018. The study is closed to accrual. Results: 11 patients with relapsed and/or refractory MM were treated. Median number of prior lines of therapy was 6 (range: 4-14), and all patients received prior therapy with a proteasome inhibitor, IMiD, anti-CD38 monoclonal antibody, and high dose melphalan/stem cell transplant. Nine (82%) patients had high-risk cytogenetics and 9 (82%) were refractory to their immediate prior line of treatment. One patient was not evaluable for DLTs given the need for early radiation and steroids for impending spinal cord compression by tumor. There are no DLTs reported. Cytokine release syndrome (CRS) grade 1-2 occurred in 4 patients (40%), grade 3 occurred in 2 (20%), and there was no grade 4-5 CRS. Grade 2 encephalopathy occurred in 1 patient (10%) in the setting of high fevers which resolved in less than 24 hours. There was no grade 3 or higher neurotoxicity observed. Tocilizumab was administered to 3 patients; 2 in cohort 2, and 1 in cohort 3. Laboratory values correlating with CRS reaching grade 3 or requiring Tocilizumab (N=4) compared to those with no or milder CRS (N=6) included peak CRP (mean: 28.5 vs 4.6 mg/dL, p 〈 0.001), IFNg (mean peak fold increase: 271 vs 11-fold, p 〈 0.0001), and peak IL6 before Tocilizumab, as IL6 elevation artificially increases after use (mean: 435 vs 68.7 pg/mL, p 〈 0.005). No significant change was seen in ferritin or fibrinogen compared to baseline. Overall response rate was 64% and the median duration of response was 106 days (range: 17 to 235 days). The peak expansion and persistence of MCARH171 as well as durable clinical responses were dose dependent. Patients who were treated on the first two dose cohorts (≤150 X106 CAR T cells) had a lower peak expansion in the peripheral blood (mean 14,098 copies/µL; N=6), compared to patients who were treated on the third or fourth dose cohort 3-4 (≥450 X106 CAR T cells; N=5), where the mean peak expansion was 90,208 copies/µL (p 〈 0.05). Among the 5 patients who received higher doses (450 X106), 5/5(100%) patients responded. The duration of responses was also related to the cell dose, with 3 of 5 patients (60%) treated in the cohorts receiving ≥450 X106 had clinical responses lasting 〉 6 months compared to only 1 of 6 (16.7%) patients who received lower doses. Two patien have ongoing responses (VGPR) at 7.5+ and 10+ months of follow up. To normalize for dose administered we compared the pharmacokinetics of only patients treated at dose levels 3-4 ( ≥450 X106 CAR T cells). Here, we demonstrate that peak expansion correlated to clinical efficacy, with the 3 durable responders all having peak expansion 〉 85,000 copies/µL (mean: 131,732 copies/µL); compared to transient responders, where the maximum peak expansion was 33,213 copies/µL (mean: 27,922; Figure 1). Conclusions: MCARH171 has an acceptable safety profile with no DLTs reported. A dose-response relationship with toxicity was not clearly observed, as noted by distribution of tocilizumab use across dose cohorts. However, a dose-response relationship was observed with promising clinical efficacy at dose levels of ≥450 X106 CAR T cells. Controlling for dose level, peak expansion correlated with durability of response. These results further support the development of CAR T cells for heavily pre-treated patients with relapsed and refractory MM. Disclosures Mailankody: Janssen: Research Funding; Takeda: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria. Korde:Amgen: Research Funding. Lesokhin:Takeda: Consultancy, Honoraria; Squibb: Consultancy, Honoraria; Janssen: Research Funding; Genentech: Research Funding; Serametrix, inc.: Patents & Royalties: Royalties; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding. Hassoun:Oncopeptides AB: Research Funding. Park:Juno Therapeutics: Consultancy, Research Funding; Amgen: Consultancy, Membership on an entity's Board of Directors or advisory committees; Pfizer: Consultancy; AstraZeneca: Consultancy; Adaptive Biotechnologies: Consultancy; Kite Pharma: Consultancy; Novartis: Consultancy; Shire: Consultancy. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Palomba:Pharmacyclics: Consultancy; Celgene: Consultancy. Riviere:Fate Therapeutics Inc.: Research Funding; Juno Therapeutics, a Celgene Company: Membership on an entity's Board of Directors or advisory committees, Research Funding. Landgren:Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Research Funding; Pfizer: Consultancy; Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Research Funding. Brentjens:Juno Therapeutics, a Celgene Company: Consultancy, Membership on an entity's Board of Directors or advisory committees, Patents & Royalties, Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding.