ALBERT

Description: Introduction: We have previously reported that clinically relevant, dramatic reductions occur in intestinal bacterial diversity during allogeneic hematopoietic stem cell transplant (allo-HSCT). These are likely attributable to antibiotic exposure, nutritional alterations, and intestinal mucosa injury from high-dose chemotherapy. Patients undergoing autologous hematopoietic stem cell transplantation (AHCT) also receive antibiotics and experience nutritional alterations due to mucositis and other gastrointestinal toxicities. We hypothesized that the pattern of dysbiosis seen in AHCT patients would reflect the changes in allo-HSCT patients. Here, we present a novel analysis of microbiota diversity in AHCT patients from two independent institutions. Methods: We retrospectively identified a cohort of 365 patients (median age 60 years) who underwent AHCT for treatment of hematologic malignancy between May 2009 to February 2018 at two large-volume transplant centers in the US. The population was diverse in terms of histology, conditioning regimens and remission status prior to transplant, with 179 (49%) patients diagnosed with multiple myeloma, 153 (42%) patients diagnosed with lymphoma, and 33 (9%) patients with other diseases. Stool samples from the selected patients were collected approximately weekly during inpatient hospitalization. Sequencing of the V4-V5 region of the bacterial 16S rRNA genes from all samples was performed on the Illumina platform at a central site. Microbial diversity was measured by the Simpson reciprocal a-diversity index (S). We defined the pre-AHCT period as days -10 to 0, and computed median values for patients with multiple samples within that period. We additionally defined monodomination of the microbiota as a single operational taxonomic unit comprising 〉30% of bacterial abundance. For comparison, we sequenced samples from 17 healthy volunteers and used a public dataset of sequences from 313 healthy volunteers from the NIH Human Microbiome Project (HMP). Median pre-transplant microbial diversity in the healthy patient and AHCT groups was compared by a pairwise Wilcox test to a retrospective cohort of allo-HSCT patients. Results: We evaluated 857 samples from 365 adult patients undergoing AHCT, with 316 patients from Memorial Sloan Kettering Cancer Center (MSKCC) and 49 patients from Duke University Medical Center (DUMC). Median pre-transplant diversity in AHCT patients from both centers was significantly lower than in normal controls (Fig 1A) (HMP vs MSKCC AHCT, S=12.05 vs. 9.19, p75% by day +14. Conclusion: Microbial diversity is reduced prior to transplant in both AHCT and allo-HSCT patients. Loss of diversity after AHCT occurs across centers and the degree of injury is comparable to the dysbiosis in allo-HSCT patients. Preliminary analysis suggests that lower diversity may correlate with worse progression-free survival (PFS) in myeloma patients in our diverse AHCT cohort. Given the known associations of alterations in microbiota composition with toxicities and overall survival in allo-HSCT patients, further evaluation of microbiota injury and its associations with toxicities, PFS, and overall survival (OS) in AHCT patients is warranted. Figure 1: A: The median Simpson reciprocal a-diversity index (S) of pre-transplant (days -10 to 0) samples of AHCT and allo-HSCT patients from two centers, as well as two cohorts of healthy volunteers, was plotted and a pairwise Wilcox test was performed, with p-values as indicated. B: (S) was plotted against time relative to allo-HSCT (on L) and AHCT (on R), for samples collected from day -10 to day +30. Larger values indicate greater diversity. C: Microbiota composition and changes in bacterial monodominance after transplant (days -14 to +28); the most common genus post-transplant is Streptococcus. Figure 1. Figure 1. Disclosures Peled: Seres Therapeutics: Research Funding. Sauter:Juno Therapeutics: Consultancy, Research Funding; Sanofi-Genzyme: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Novartis: Consultancy; Precision Biosciences: Consultancy; Kite: Consultancy. Shah:Amgen: Research Funding; Janssen: Research Funding. Perales:Novartis: Other: Personal fees; Incyte: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees and Clinical trial support; Merck: Other: Personal fees; Takeda: Other: Personal fees; Abbvie: Other: Personal fees. Jenq:Ziopharm Oncology: Consultancy; Seres Therapeutics, Inc.: Membership on an entity's Board of Directors or advisory committees; MicrobiomeDx: Consultancy; Seres Therapeutics, Inc.: Patents & Royalties.

Description: 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

Description: Background: Several studies have indicated that the depth and duration of treatment response in multiple myeloma are both reduced in the relapsed setting. With further lines of therapy, responses continue to weaken in depth and shorten in duration. The National Comprehensive Cancer Network (NCCN) Guidelines suggest that regimens may be repeated in the relapsed setting if there has been a duration of at least 6 months since that regimen was given; however, there is limited information regarding treatment response and duration in the setting of re-treating patients with agents previously utilized. Moreover, preliminary data has suggested that carfilzomib-based regimens in the frontline may be able to attain deeper and longer responses than alternative therapies, which has led to carfilzomib being used more frequently in the frontline. This motivated us to investigate the treatment response, depth, and safety of re-challenging patients with carfilzomib in the relapsed setting. Methods: In this retrospective chart review, we identified all patients who were treated with multiple courses of carfilzomib-based regimens at Memorial Sloan Kettering Cancer Center between January 1, 2014 and November 30, 2018. Our primary objectives were to assess the response, duration of response and treatment, and safety of re-exposure to carfilzomib-based regimens. Responses were assessed as per IMWG 2016 consensus criteria (Lancet Oncol 2016). In this review we describe the clinical course, safety, and efficacy of re-challenging patients with carfilzomib in the relapsed and refractory settings. Results: Fifteen patients were identified as having received multiple, independent lines of carfilzomib-based therapy. The median age of the cohort was 58 years (49-76) with 53% male (8); two patients had R-ISS stage 1, eight stage 2, and five stage 3 disease. Five of these patients received their initial carfilzomib in the frontline as part of KRD; four of whom attained a sCR with the fifth attaining a VGPR. The remaining ten patients received their initial carfilzomib in the second-line (4) or 3rd and subsequent lines (6). Upon re-exposure to carfilzomib, patients were heavily treated with a median of four lines of therapy (2-15). All but three patients had at least one adverse cytogenetic abnormality; eight with 17p-, five with 13q-, three with t4;14, and six with 1q+. Regimens utilized in the relapsed setting included KRD (N=4), KPD (N=3), Cyklone (N=2), KD + HDAC inhibitor (N=3), KD (N=1), KCD (N=1), and KRD + daratumumab (N=1). Four patients received carfilzomib at a dose of 27 mg/m2 while the remaining 10 received 〉 36 mg/m2. Responses were seen in all but four patients (two VGPR, five PR, and four MR), with one patient experiencing progression during carfilzomib with no response; notably, this patient only attained a MR to primary carfilzomib therapy and their second exposure was the 15th line of therapy. The median time to next therapy was 4.8 months (1.9-19.4) with one patient being bridged to autologous hematopoietic cell transplantation (HCT), one to allogeneic HCT, and three are currently receiving ongoing carfilzomib treatment (13.9, 2.8, 2.5 months with VGPR, MR, and PR, respectively). Exacerbation of baseline hypertension was identified in three patients, but these instances were treated successfully with standard medications with no further complications. No additional cardiovascular events were identified in the frontline or re-treatment settings. Conclusions: We report that in a heavily pre-treated, high risk patient cohort, patients previously treated with carfilzomib-based regimens may be safely re-challenged with carfilzomib. Importantly, none of these patients experienced cardiovascular adverse effects other than exacerbation of underlying hypertension, further supporting the ability to safely re-treat a select group of patients with carfilzomib. We conclude that depending on the patient and treatment history, re-challenging with carfilzomib at relapse may be appropriate salvage therapy, particularly as a bridge towards HCT and/or clinical trials. Disclosures Hassoun: Novartis: Consultancy; Janssen: Research Funding; Celgene: Research Funding. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Lesokhin:Genentech: Research Funding; Serametrix Inc.: Patents & Royalties; Janssen: Research Funding; GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Landau:Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Amgen: Research Funding; Caelum: Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria. Shah:Janssen Pharmaceutica: Research Funding; Amgen: Research Funding. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Giralt:Amgen: Consultancy, Research Funding; Spectrum Pharmaceuticals: Consultancy; Miltenyi: Research Funding; Jazz Pharmaceuticals: Consultancy; Actinium: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Novartis: Consultancy; Johnson & Johnson: Consultancy, Research Funding; Kite: Consultancy. Landgren:Karyopharm: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Theradex: Other: IDMC; Merck: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Description: 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.

Description: Background: Programmed cell death 1 (PD-1) protein downregulates T cell activation and is related to immune tolerance. PDL1 up regulation, T cell infiltration, and T cell exhaustion are features, which suggest susceptibility to PD-1 blockade antibodies. Blockade of PD-1 or its ligand PD-L1 has shown promising responses in several malignancies. Although little clinical activity has been seen in patients with relapsed multiple myeloma (MM), the role of the PD-1 pathway and T cell exhaustion in newly diagnosed MM has not been explored. Objective: To determine whether T-cell infiltrate or expression of PD-1 correlates with clinical features and prognosis among patients with newly diagnosed multiple myeloma. Methods: We screened a clinically annotated database of 341 patients seen at MSKCC between 1998 and 2012 that had Multiple Myeloma, received a bone marrow transplant and were consented to a biospecimen research protocol for availability of pre-treatment bone marrow specimens. A total of 64 bone marrow biopsy specimens were identified. Immunohistochemistry (IHC) was performed in formalin-fixed paraffin-embedded specimens using an anti human CD3 monoclonal antibody (mAb) (Dako, Clone F7.2.38) and an anti human PD-1 mAb (Cell Marque, catalog #315M-95). CD3 and PD1 IHC staining were graded as negative (

Description: Background: Melphalan in combination with dexamethasone is an active and the standard regimen in AL amyloidosis. Unfortunately very often patients relapse and other drugs are needed. Bendamustine is a bifunctional alkylating agent approved for the treatment of CLL, NHL, and MM in Europe and the US. But its safety and efficacy in AL amyloidosis is not known. In an effort to investigate the activity of Ben/Dex and improve the outcome of patients with relapsed AL we conduct a multi-center, Phase 2 study of Ben/Dex in AL (NCT01222260) and report data of an updated unplanned interim analysis. First data were reported at ASH 2014 (Abstr.3480). Methods: All patients had relapsed AL after a median of 2 prior therapies (range 1-4). Patients with very advanced cardiac involvement (NYHA Class IIIB/IV) were excluded. Patients with NYHA Class IIIA, NT-proBNP ≥ 1800 ng/L or BNP ≥ 400 ng/L, abnormal cTnT or cTnI could be included after evaluation by cardiology to determine the risk associated with the treatment. Patients with a CrCl ³ 15 mL/min were considered for the trial if they were not in active renal failure. This Phase IIa clinical trial uses a two-stage optimal Simon design enrolling 13 patients in the first stage. Since at least three patients experienced hematologic PR or better, the trial proceeded to the second stage treating an additional 16 patients. If 9 or more patients out of the total of 29 patients evaluable for response experience a hematologic PR or better, the treatment will be considered worthy of further development. The primary objective is to determine the partial hematologic response rate (PR). Secondary objectives included overall hematologic response (OHR) rate, organ response rate (OrRR) (Palladini et al., JCO 2012), time to failure (TTF), toxicities (adverse events at least possibly related to treatment), overall survival (OS) and the assessment of expression of genes associated with ER stress. Patients were assigned to bendamustine according to CrCl: CrCl ≥ 60 mL/min: 100 mg/m2 IV on day 1 and 2 of each cycle, CrCl 59-15 mL/min: 90 mg/m2 IV on day 1 and 2 of each cycle. The option to dose escalate was available to qualifying subjects including escalating to dose level (+)1: 120 mg/m2 (if CrCl ≥ 60 mL/min at the time of inclusion into the study) and 100 mg/m2 (if CrCl 59 - 15 mL/min at the time of inclusion into the study). Dexamethasone was started at 20-40mg weekly according to the performance status of the patient. The duration of each cycle was 28 days. Results: As of 7/15/15, 26 patients have received treatment and 28 patients have been enrolled. Median age of enrolled patients was 66 (range 44-77). Enrolled patients received a median of 1.5 prior regimens (range 1-4). Twelve of the enrolled patients received prior autologous stem cell transplant. Median number of cycles for treated patients is 3.5 (range is 1-12), with 4 patients still receiving treatment. Of note, only 2 patients discontinued treatment due to disease progression. Only 9 patients discontinued treatment due to AE. Most common drug-related AEs (all grades, 〉25%) included fatigue (39%), nausea (35%) and Anemia (27%),. No grade ≥3 drug-related AE occured in 〉20% of patients. Of note, no cardiac events were observed, including any increase in NT-proBNP.Of 24 patients eligible for response evaluation, 11 (46%) have responded hematologically, including (≥PR 42%, CR 4%). The median time to best response of treatment (partial response or better) was 1.57 months (range 0.97 to 15.1 months). The CR occurred in a patient after 5 cycles suggesting that this heavily pretreated patient population needs longer treatment to achieve response. Better responses were especially observed in less heavily treated patients. With a median follow-up of 13.4 months (range 1.5 to 30.3 months) the median OS has not been reached yet (Figure 1). The median PFS is 11.5 months (95% CI,1.5-29.1months) (Figure 2). Conclusions: In our updated unplanned interim analysis we found that Bendamustine in combination with dexamethasone is feasible and effective in pretreated AL amyloidosis with impaired organ function (NYHA IIIB and creatinine clearance of 30-15 mL/min were allowed). Cardiac events related to Bendamustine were not observed. Preliminary hematologic response rates are promising in this pretreated patient population, and organ assessments are ongoing. Further study of this approach is warranted. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Lentzsch: Axiom: Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees. Off Label Use: Will discuss the use of Bendamustine and Dexamethasone under clinical trial NCT01222260. Comenzo:Takeda Millennium: Research Funding; Prothena: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Karyopharm: Research Funding. Zonder:Celgene: Membership on an entity's Board of Directors or advisory committees, Other: research support; Prothena: Membership on an entity's Board of Directors or advisory committees; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees. Osman:Millennium / Takeda: Research Funding.

Description: INTRODUCTION Using Carfilzomib, Lenalidomide and Dexamethasone (KRd) combination therapy in newly diagnosed multiple myeloma patients lead to ~40% minimal residual disease (MRD) negativity rate. Here, we use KRd in combination with daratumumab (DKRd); and treatment response is assessed with extensive correlative science including parallel bone-marrow-based and blood-based MRD tracking, together with targeted DNA sequencing of baseline bone marrow samples. Primary end-point is to rule out 60% and to target up to 80% MRD negativity rate. METHODS This is a single-arm, Phase II clinical trial based on Simon's optimal two-stage design. The first cohort (twice-a-week carfilzomib) (N=41) has the following treatment schedule: 8 cycles of treatment; 28-day cycles with carfilzomib 20/36 mg/m2 days 1, 2, 8, 9, 15 and 16; lenalidomide 25 mg days 1-21; dexamethasone 40 mg weekly cycles 1-4, 20 mg after cycle 4; and daratumumab 16 mg/kg days 1, 8, 15, and 22 cycles 1-2, days 1 and 15 cycles 3-6, and day 1 cycles 7-8. The second cohort (once-a-week carfilzomib) (N=41): 8 cycles of treatment; 28-day cycles with carfilzomib 20/56 mg/m2 days 1, 8, and 15; lenalidomide, dexamethasone, and daratumumab are given at the same doses/schedules as the first cohort. For fit patients, stemcell collection is recommended after 4 to 6 cycles of therapy; DKRd therapy is resumed after collection to a total of 8 cycles DKRd. Treatment response is being assessed with parallel bone-marrow-based (10-color single tube flowcytometry, invivoscribe V(D)J sequencing) as well as blood-based (MALDI-TOF and QTOF-mass spectrometry [MS]) for MRD tracking. Baseline bone marrow samples are evaluated with targeted DNA sequencing for FISH-Seq and somatic mutational characteristics (myTYPE). Here, we present the first stage (N=28) of the first cohort (twice-a-week carfilzomib). We are waiting for the results to mature before the second stage (N=13) of the first cohort can open. The second cohort (once-a-week carfilzomib) is opening for enrollment in August 2018 (N=41). RESULTS The first stage of the first cohort is fully enrolled; 28 patients meeting eligibility criteria were enrolled onto study (14 males, 14 females) between October 2017 and July 2018. Baseline characteristics include; median age 60 years (range 32-80 years); 12(43%) patients had high-risk FISH/SNP signature defined as one or more of the following: 1q+, t(4,14), t(14,16), t(14,20), and 17p-. At the submission of this abstract, 20 patients have completed one or more cycles DKRd; among these, 3 patients have completed all 8 cycles. The median number of cycles delivered is currently 4 (range 1-8). Full assessments with MRD assays have been completed in 3 patients: -Pt #1 obtained complete response (CR) after 3 cycles, and workup after the last cycle of therapy showed MRD-negativity (by 10-color single tube flowcytometry and V(D)J sequencing) in the bone marrow; and peripheral blood (serum) was negative by MALDI-TOF MS after completion of cycle 2. -Pt#2 obtained CR after 4 cycles, however, workup after cycle 5 showed MRD-positivity (by 10-color single tube flowcytometry and V(D)J sequencing) in the bone marrow; and peripheral blood (serum) was positive by MALDI-TOF MS throughout the end of the last cycle. -Pt#3 obtained CR after 4 cycles and after 6 cycles both 10-color single tube flowcytometry and V(D)J sequencing showed MRD-negativity in the bone marrow. However, MALDI-TOF MS detected small abnormal serum proteins in peripheral blood and remained positive throughout the end of cycle 8. Overall, the DKRd therapy is well tolerated and it has similar toxicity profile as KRd. Grade 〉3 adverse events were hypotension, musculoskeletal deformity, back pain, dyspnea, lung-infection, and febrile neutropenia. So far, 5 patients underwent dose reductions of lenalidomide. CONCLUSIONS In this pre-planned interim analysis of our phase II study, we show that DKRd is a highly effective and well tolerated combination therapy for newly diagnosed multiple myeloma patients. Based on small numbers of patients who have completed the planned DKRd cycles and been evaluated by bone marrow-based MRD and peripheral-blood based assays, we show that highly sensitive protein assays may allow longitudinal MRD tracking in peripheral-blood. At the meeting, we will present updated results using longitudinal testing with MALDI TOF-MS and QTOF-MS on the entire cohort. Disclosures 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; Amgen: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Pfizer: Consultancy; Karyopharm: Consultancy; Merck: Membership on an entity's Board of Directors or advisory committees. Lesokhin:Takeda: Consultancy, Honoraria; Janssen: Research Funding; Squibb: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Genentech: Research Funding; Serametrix, inc.: Patents & Royalties: Royalties. Mailankody:Juno: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding; Janssen: Research Funding. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Hassoun:Oncopeptides AB: Research Funding. Shah:Amgen: Research Funding; Janssen: Research Funding. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Korde:Amgen: Research Funding.

Description: Background: Taste disturbance, or dysgeusia, negatively affects quality of life and may lead to poorer nutritional status after high-dose melphalan and autologous stem cell transplantation (mel-AHCT) for patients with multiple myeloma (MM). Despite its frequency, dysgeusia has received limited prospective study. Here, we report the interim results of an on-going prospective clinical trial aimed at evaluating the feasibility of performing chemical gustometry, and quantifying the effects of dysgeusia on patient-reported symptom burden and nutritional status in MM patients undergoing mel-ASCT. We also sought to identify novel associations between mel serum and salivary pharmacokinetic (PK) levels and dysgeusia. Methods: For this study, chemical gustometry was considered feasible for use as an endpoint in a future clinical trial if 〉 60% of the patients could complete 〉 60% of the evaluations. Chemical gustometry was performed according to the Henkin method (Henkin et al., Am J Otolaryngol 2013) at baseline (pre-AHCT) and on days -1, +7, +14, and +30 to test the 5 basic flavors: sweet (sucrose), sour (citric acid), salty (sodium chloride), bitter (quinine), and umami (monosodium glutamate). These data were used to calculate a total gustometry score (maximum value of 30). At the above time-points as well as day +3 and +10, caloric intake (kcal) was calculated using the USDA 5-Step Multiple-Pass Approach with 24-hour recall, and patient-reported symptom burden was assessed using the MD Anderson Symptom Inventory-Myeloma Module (MDASI-MM). Serum PK levels were drawn at 6 times points after mel infusion to calculate an area under the curve (AUC). Spearman rank-sum correlation was calculated for serum mel AUC and its association with total gustometry scores, caloric intake, and MDASI scores over time using a scaled 30-day AUC. A peak salivary mel level was measured at 75 minutes after infusion, and correlated with total gustometry scores, caloric intake, and MDASI scores. Results: To date, 22 patients with MM undergoing mel-AHCT have been enrolled and have follow-up data through day +30. Eighteen patients (82%) completed 〉 60% of all assessments. Median age was 62 (41-75), and 11 (50%) were female. Nineteen (86%) patients received mel 200 mg/m2 and 3 (14%) received mel 140 mg/m2. Median serum mel AUC was 12.6 mg*h/L (range 5.8-17.5), and median salivary mel was 119 ng/ml (range 25-662). Higher serum mel AUC correlated with higher salivary mel levels [Spearman correlation 0.59, p=0.004] as shown in Figure 1. Higher serum mel AUC was associated with poorer caloric intake from pre-ASCT to day +30 [Spearman correlation -0.45, p=0.04] as shown in Figure 2. Higher serum melphalan AUC was also associated with higher total MDASI scores (worse symptom burden) from pre-ASCT to day +30 [Spearman correlation 0.57, p=0.005], but was not significantly associated with total gustometry scores. A higher peak salivary mel level was associated poorer caloric intake from pre-ASCT to day +30 [Spearman correlation -0.49, p=0.02]. Among all patients, MDASI scores appeared highest on day +10, and total gustometry scores and caloric intake appeared lowest on days +7 and +10, respectively. At days +7, +14, and +30, 9 of 16 patients (56%), 8 of 17 patients (47%), and 9 of 19 (47%) had a drop of at least 1 point in gustometry score compared to baseline, respectively. Overall, gustometry scores appeared to improve by day +30, but often did not return to baseline (Figure 3A-C). Conclusion: Chemical gustometry is feasible and comprehensively evaluates changes in taste function in MM patients after AHCT. The lowest gustometry scores were apparent on day +7 and often did not return to baseline by day +30, confirming the persistence of dysgeusia after AHCT. Moreover, higher serum and salivary mel levels are associated with poorer caloric intake and higher symptom burden scores within the first 30 days after AHCT. Preventing mel overexposure by targeted mel PK dosing may reduce dysgeusia, improve caloric intake, and limit symptom burden in MM patients after AHCT. Disclosures Shah: Janssen: Research Funding; Amgen: Research Funding. Peled:Seres Therapeutics: Research Funding.

Description: Background: Deep and durable hematologic remissions following RA-ASCT are associated with improved organ function and extended overall survival (OS) in AL amyloidosis. Achieving at least a very good partial response (VGPR) defined by a dFLC