Abstract: 8040 Background: Passive monitoring using wearables can objectively measure sleep over extended time periods. MM patients (PTs) are susceptible to fluctuating sleep patterns due to pain and dexamethasone (dex) treatment. In this prospective study, we remotely monitored sleep patterns on 40 newly diagnosed MM (NDMM) PTs while administering electronic PT reported outcome (ePRO) surveys. The study aim was to establish sleep bioprofiles during therapy and correlate with ePROs. Methods: Eligible PTs for the study had untreated NDMM and assigned to either Cohort A – PTs 〈 65 years or Cohort B – PTs ≥ 65 years. PTs were remotely monitored for sleep 1-7 days at baseline [BL] and continuously up to 6 therapy cycles. PTs completed ePRO surveys (EORTC - QLQC30 and MY20) at BL and after each cycle. Sleep data and completed ePRO surveys were synced to Medidata Rave through Sensorlink technology. Associations between sleep measurement trends and QLQC30 scores were estimated using a linear mixed model with a random intercept. Results: Between Feb 2017 - Sep 2019, 40 PTs (21 M and 19 F) were enrolled with 20 in cohort A (mean 54 yrs, 41-64) and 20 in cohort B (mean 71 yrs, 65-82). Regimens included KRd 14(35%), RVd 12(30%), Dara-KRd 8(20%), VCd 5(12.5%), and Rd 1(2.5%). Sleep data was compiled among 23/40 (57.5%) PTs. BL mean sleep was 578.9 min/24 hr for Cohort A vs. 544.9 min/24 hr for Cohort B (p = 0.41, 95% CI -51.5, 119.5). Overall median sleep trends changed for cohort A by -6.3 min/24 hr per cycle (p = 0.09) and for cohort B by +0.8 min/24 hr per cycle (p = 0.88). EPRO data trends include global health +1.5 score/cycle (p = 0.01, 95% CI 0.31, 3.1), physical +2.16 score/cycle (p 〈 0.001, 95% CI 1.26, 3.07), insomnia -1.6 score/cycle (p = 0.09, 95% CI [-3.47, 0.26]), role functioning +2.8 score/cycle (p = 0.001, 95% CI 1.15, 4.46), emotional +0.3 score/cycle (p = 0.6, 95% CI -0.73, 1.32), cognitive -0.36 score/cycle (p = 0.44, 95% CI -1.29,0.56), and fatigue -0.36 score/cycle (p = 0.4, 95% CI -1.65, 0.93). No association between sleep measurements and ePRO were detected. Difference in sleep on dex days compared to all other days during the sample cycle period for cohort A was 81.4 min/24 hr (p = 0.004, 95% CI 26, 135) and for cohort B was 37.4 min/24 hr (p = 0.35, 95% CI -41, 115). Conclusions: Our study provides insight into wearable sleep monitoring in NDMM. Overall sleep trends in both cohorts do not demonstrate significant gains or losses, and these trends fit with HRQOL ePRO insomnia responses. Upon further examination, we demonstrate objective differences (younger PTs) in intra-cyclic sleep measurements on dex days compared to other cycle days (less sleep by 〉 1 hr). For older patients, less variation in sleep profiles was detected during dex days, possibly due to higher levels of fatigue or longer sleep duration. Sleep is an integral part of well-being in the cancer patient. Future studies should continue to characterize sleep patterns as it relates to HRQOL.

Abstract: Background: The total therapy 3 protocol for multiple myeloma (MM) introduced the use of intensive induction with VDT-PACE, a combination of bortezomib, dexamethasone, thalidomide, cisplatin, adriamycin, cyclophosphamide, and etoposide for newly diagnosed MM patients. This regimen, which demonstrated rapid responses in the first-line setting, has also been used in relapsed disease, to rescue induction failures or for stem cell mobilization. We evaluated the efficacy and toxicity of using VDT-PACE in these clinical settings. Patients and Methods: We identified 84 patients through pharmacy profile review who received at least one cycle of VDT-PACE for the treatment of MM between 1/2007 and 8/2013 at our institution. Patients were grouped into a stem cell collection cohort (C) if stem cell pheresis was performed following VDT-PACE. Remaining patients were analyzed in the relapsed cohort (RR). The primary objective of this study was to determine the overall response rate with combination VDT-PACE. Secondary Objectives include progression-free survival (PFS), overall survival (OS), stem cell collection in patients that underwent chemomobilization, and the extent of toxicity. Results: In the RR group, 45 patients received VDT-PACE after a median of 4 prior therapies (range 1-8) including autologous stem cell transplantation (ASCT) in 79%. The median time between diagnosis and first cycle of VDT-PACE treatment was 35.4 months (range 1.3-163.4). 47% of patients had adverse cytogenetics defined as presence of complex karyotype or FISH with del 17p, t4;14, or t14;16. Patients received a median of 2 cycles of VDT-PACE (range 1-4) with a response rate after all cycles of 51% (2% CR, 22% VGPR, 27% PR). Additional therapy was administered in 82% within 6 months (18% allogeneic SCT, 35% ASCT, 29% chemotherapy regimens). 18% of patients died without additional therapy (13% from disease progression, 5% from toxicity), all within 5 months of their last VDT-PACE cycle. PFS and OS for the RR group was 8.8 months (95% CI 4.6, 13.1) and 10.3 months (95% CI 8.8, 17.4), respectively. Patients that received subsequent lines of therapy following VDT-PACE achieved a median PFS and OS of 9.5 months (95% CI 5.6, 13.3) and 9.5 months (95% CI 7.5, 32.1), respectively, measured from the time of next therapy. In the C group, 39 patients received a median of 2 prior regimens (range 1-4) before starting VDT-PACE and 31% of patients had adverse cytogenetics. Reasons for using VDT-PACE for mobilization included residual or progressive disease (64%), provider discretion (33%), and failure of a prior attempt at collection (3%). The median time between diagnosis and first cycle of VDT-PACE treatment was 7 months (range 2.3-122.7). Patients received a median of 2 cycles (range 1-4) of VDT-PACE. The median number of cells collected was 12.3x106CD34 cells/kg (range 0.21-43.74) and the median number of collection session required was 2 (range 1-6), with 21% of patients requiring plexirafor. Two patients (5%) from this group failed collection. The response rate after all cycles of VDT-PACE was 59% (3% CR, 13% VGPR, 44% PR). 35 out of the 39 patients went to transplant following VDT-PACE (34 ASCT, 1 allogeneic SCT). Of the 4 patients who did not receive transplant, 2 were for toxicity attributed to VDT-PACE, 1 for failure to mobilize, and 1 for personal reasons. The post-transplant response rate was 91% (17% CR, 34% VGPR, 40% PR) with 1 patient (3%) experiencing disease progression immediately after transplant. Median PFS and OS for the C group patients was 34.5 months (95% CI 20.2, n.r.) and 64.8 months (95% CI 26.0, n.r.), respectively. Reported toxicities following treatment included infection (20%), fatigue (19%), nausea (17%), renal complications (6%), thrombosis (4%), and edema (4%), which were seen in 67% and 62% of the RR and C groups, respectively. Hospital readmission for management of side effects occurred in 30% of patients. Conclusions: VDT-PACE is an effective therapy for RR patients and for stem cell mobilization in patients with residual or progressive disease following initial therapy. Importantly, it is also associated with significant morbidity and requires careful monitoring. VDT-PACE does not appear to adversely affect stem cell collection or SCT outcomes. At our institution, this regimen is commonly used for stem cell collection in patients with unfavorable outcomes following initial therapy. Disclosures No relevant conflicts of interest to declare.

Abstract: We previously described clinically relevant reductions in fecal microbiota diversity in patients undergoing allogeneic hematopoietic cell transplantation (allo-HCT). Recipients of high-dose chemotherapy and autologous HCT (auto-HCT) incur similar antibiotic exposures and nutritional alterations. To characterize the fecal microbiota in the auto-HCT population, we analyzed 1161 fecal samples collected from 534 adult recipients of auto-HCT for lymphoma, myeloma, and amyloidosis in an observational study conducted at 2 transplantation centers in the United States. By using 16S ribosomal gene sequencing, we assessed fecal microbiota composition and diversity, as measured by the inverse Simpson index. At both centers, the diversity of early pretransplant fecal microbiota was lower in patients than in healthy controls and decreased further during the course of transplantation. Loss of diversity and domination by specific bacterial taxa occurred during auto-HCT in patterns similar to those with allo-HCT. Above-median fecal intestinal diversity in the periengraftment period was associated with decreased risk of death or progression (progression-free survival hazard ratio, 0.46; 95% confidence interval, 0.26-0.82; P = .008), adjusting for disease and disease status. This suggests that further investigation into the health of the intestinal microbiota in auto-HCT patients and posttransplant outcomes should be undertaken.

Abstract: Background: The aggressive approach to first-line treatment of multiple myeloma (MM) incorporating autologous stem cell transplantation (ASCT) remains widely prevalent, although it is not without controversy in the current era of novel effective agents. Some trials and meta-analysis comparing ASCT to non-myeloabaltive standard therapy or delayed ASCT have failed to show an overall survival (OS) difference between the two arms [Fermand et al. Blood 92:3131-3136 (1998); Koreth et al. BBMT 13:183-196 (2007); Kumar, et al. Cancer 118(6):1585-92 (2012)]. On the other hand, analysis of transplant-eligible patients receiving lenalidomide and dexamethasone induction on the E4A03 trial and then either undergoing ASCT or continuing lenalidomide and dexamethasone showed that ASCT conferred improved OS (Blood 2010;116:38a). This controversy lead us to design a phase II clinical trial comparing continuous lenalidomide and dexamethasone (Ld) versus ASCT followed by lenalidomide maintenance, in patients responding to four cycles of Ld. Methods: Patients with newly diagnosed symptomatic MM as defined by IMWG criteria were enrolled. Patients deemed to be in urgent need of aggressive therapy (e. g. symptomatic bone disease, acute renal failure, hyperviscosity syndrome, etc) were not eligible. Patients received induction with lenalidomide (L) 25 mg PO daily on days 1-21, and dexamethasone (d) 40 mg PO daily on days 1,8,15, and 22 of a 28-day cycle with standard prophylaxis. Patients with POD during induction or SD after four cycles of Ld were taken off study. All other patients had stem cells harvested after four cycles of Ld and were randomized to either the continuous (Ld) arm (L at the last tolerated dose during induction, continued indefinitely until progression or toxicity; and d at 20mg weekly for one year) or the ASCT arm (using melphalan conditioning followed by L maintenance started three months post-ASCT at 10mg daily, escalated to 15 mg daily six months post-ASCT and continued indefinitely until progression or toxicity). Results: Fifty seven patients have been registered to the trial. Two patients did not initiate therapy, one because of a concurrent diagnosis of amyloidosis and the other due to aggressive disease mandating alternative therapy according to the treating physician. At this time, four patients are still receiving induction therapy and are not available for response assessments. Among the 51 remaining patients, the response to initial induction therapy includes 12% CR (n=6), 2% uCR (n=1), 4% nCR (n=2), 14% VGPR (n=7), 51% PR (n=26), 6% SD (n= 3), 4% POD (n=2), and 8 % inevaluable (n = 4 who did not receive at least two cycles of Ld). Thirteen patients were removed from the trial prior to randomization due to POD (n=2), SD after four cycles (n=3), toxicity (n=4), physician discretion (n=2), and withdrawal of consent (n=2). Among these 13 patients, one was lost to follow-up, two continued lenalidomide therapy off protocol (one patient refused ASCT, and one patient had inadequate stem cell collection), and 10 proceeded to alternative induction. All 12 patients achieved a response [25 % CR (n=3), 42 % VGPR (n=5), and 33 % PR (n=4)]; 10 patients proceeded to ASCT without event. Thirty-eight patients were randomized, 20 to Ld and 18 to ASCT. Improvement of response by at least one level occurred in 45% and 65% of patients on the Ld and ASCT arms, respectively. The median follow-up for all surviving patients from time of randomization is 38.3 months. The 1- and 3-year PFS in the Ld arm were 100% and 66%, respectively. The 1- and 3-year PFS in the ASCT arm were 89% and 68%, respectively. The 2- and 3-year OS in the Ld arm were 100% and 92%, respectively. The 2- and 3-year OS in the ASCT arm were 100% and 85%, respectively. Considering the entire population of 51 patients, with a median follow-up of 38 months, the median PFS has not been reached. Conclusions: This interim analysis, with relatively short follow-up, suggests that in transplant-eligible patients responsive to Ld during induction, continuous Ld results in similar PFS and OS compared to patients who undergo ASCT followed by L maintenance. Furthermore, this overall approach based on response-adapted treatment results in 100% of patients reaching at least PR at completion of first-line therapy. The trial remains ongoing. Figure 1 Figure 1. Figure 2 Figure 2. Disclosures No relevant conflicts of interest to declare.

Abstract: Background: High-dose chemotherapy followed by ASCT remains the standard of care for patients aged ≤75 years with NDMM. The ability of novel agents, such as lenalidomide and bortezomib, to produce treatment response rates comparable to those seen with ASCT has raised questions about the necessity for upfront ASCT in transplant-eligible NDMM patients. This analysis aimed to compare the efficacy and safety of continuous Ld versus Ld+ASCT in patients with NDMM. Methods: Data were pooled from two randomized clinical trials (NCT01731886 and NCT00807599) that compared Ld alone versus Ld+ASCT in NDMM patients aged ≤75 years. Patients received four 28-day cycles of Ld (lenalidomide 25mg daily on days 1-21; dexamethasone 40mg on days 1, 8, 15, and 22) followed by stem-cell mobilization and collection, and either a) Arm A: continuous Ld (an additional 4 cycles +/- lenalidomide maintenance in NCT01731886, or continuous lenalidomide at the last tolerated dose until disease progression plus dexamethasone 20mg for 1 year following treatment initiation in NCT00807599); or b) Arm B: ASCT conditioned with high-dose melphalan, and followed by lenalidomide maintenance therapy. In both trials, patients were withdrawn if they developed progressive disease (PD) at any time, or had stable disease (SD) after cycle 4 of Ld induction. We evaluated overall response rate (ORR; defined as a partial response or better), progression-free survival (PFS), overall survival (OS), and adverse event (AE) incidence rates, focusing on those randomized patients who responded to 4 cycles of Ld induction. Results: Sixty patients were enrolled into NCT01731886, and 63 into NCT00807599. The analysis included a total of 85 patients who had been randomized and achieved a response to 4 cycles of Ld induction: 41 in Arm A, and 44 in Arm B. Mean ages in Arm A versus Arm B were 61.8 versus 61.7 years; median (range) follow-up times were 3.97 (0.27-6.19) versus 3.71 (0.16-5.66) years. Baseline cytogenetic risk profiles were similar overall, although Arm A contained a higher percentage of intermediate-risk patients (17.1% versus 11.4%). More than half of all patients included in the analysis had International Staging System stage 1 disease: 63.4% of patients in Arm A, and 47.7% of those in Arm B. Median PFS was similar with the two treatment approaches: 4.3 versus 4.4 years (Figure 1; p = 0.9107). OS also did not differ significantly between the two arms (Figure 2). As expected, both treatment regimens were well tolerated. Clinically significant grade 3 and 4 AEs occurring outside of the transplant period included the following: anemia (17.1% Arm A versus 15.9% Arm B); neutropenia (36.6% versus 38.6%); thrombocytopenia (17.1% versus 18.4%); infectious complications (14.6% versus 27.3%); thromboembolic events (7.3% versus 6.8%); and secondary malignancies (7.3% versus 4.5%). Conclusions: The findings of this pooled analysis suggest that, in transplant-eligible patients responsive to Ld induction, continuous Ld results in similar PFS and OS to Ld+ASCT. Larger phase III trials addressing this question are awaited. Figure 1. Figure 1. Figure 2. Figure 2. Disclosures Lentzsch: Celgene: Consultancy; BMS: Consultancy; Novartis: Consultancy; Janssen: Consultancy; Axiom: Honoraria. Landau:Janssen: Consultancy; Spectrum Pharmaceuticals: Honoraria; Prothena: Consultancy, Honoraria; Janssen: Consultancy; Onyx: Honoraria, Research Funding; Takeda: Research Funding. Lesokhin:Efranat: Consultancy; Genentech: Research Funding; Aduro: Consultancy; Janssen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding. Kewalramani:Celgene: Consultancy; Abbvie: Consultancy; Getchell v Doon East Community Hospital, Alfred Wakeman et al.: Consultancy. Comenzo:Karyopharm: Research Funding; Prothena: Membership on an entity's Board of Directors or advisory committees; Janssen: Research Funding; Prothena: Research Funding; Takeda Millennium: Research Funding; Takeda Millennium: Membership on an entity's Board of Directors or advisory committees. Landgren:Celgene: Honoraria; Bristol-Myers Squibb: Honoraria; Medscape: Honoraria; Onyx: Honoraria; International Myeloma Foundation: Research Funding; Onyx: Research Funding; BMJ Publishing: Consultancy; BMJ Publishing: Honoraria; Medscape: Consultancy; Bristol-Myers Squibb: Consultancy; Celgene: Consultancy; Onyx: Consultancy. Hassoun:Novartis: Consultancy; Celgene: Membership on an entity's Board of Directors or advisory committees; Celgene: Research Funding; Takeda: 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: INTRODUCTION. Bortezomib, lenalidomide and dexamethasone (VRd) is considered a standard of care combination therapy for newly diagnosed multiple myeloma patients. Prior studies show that ~25% of patients treated with 8 cycles of VRd achieve minimal residual disease (MRD) negativity. Recently, 42% stringent complete response (sCR) rates were reported with the use of VRd combined with the CD38-targeted monoclonal antibody daratumumab (VRd-D). Prior studies using 8 cycles of bi-weekly carfilzomib 36 mg/m2 with lenalidomide and dexamethasone (bKRd) combination therapy in newly diagnosed multiple myeloma show ~40% MRD negativity rates. We were motivated to develop a phase 2 study (total N=82) using weekly dosing of carfilzomib 56 mg/m2 with lenalidomide and dexamethasone (wKRd) in combination with daratumumab (wKRd-D). Our study also included a parallel cohort of bi-weekly dosing of carfilzomib 36 mg/m2 with lenalidomide and dexamethasone (bKRd) in combination with daratumumab (bKRd-D). Primary end-point of our study was to rule out 60% and to target up to 80% MRD negativity rate. METHODS. This is a two-arm, Phase II clinical trial based on Simon's optimal two-stage design. The once-a-week carfilzomib (wKRd) (N=41) has the following treatment schedule: 8 cycles of treatment; 28-day cycles with carfilzomib 20/56 mg/m2 days 1, 8, and 15; 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 bi-weekly carfilzomib (bKRd) (N=41): 8 cycles of treatment; 28-day cycles with carfilzomib 20/36 mg/m2 days 1, 2, 8, 9, 15 and 16; lenalidomide, dexamethasone, and daratumumab are given at the same doses/schedules as the weekly cohort. For fit patients, stem cell 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 MRD assays (10-color single tube flowcytometry and invivoscribe IGHV sequencing); per IMWG guidelines both MRD assays allow detection of 1 myeloma cell in 100,000 bone marrow cells (10^-5). Baseline bone marrow samples are evaluated with targeted DNA sequencing for FISH-Seq and somatic mutational characteristics (myTYPE). RESULTS. The first stage of the weekly cohort (wKRd-D) is fully enrolled (N=28) and the second stage of the cohort (N=13) is anticipated to complete enrollment shortly (total N=41). Currently, 29 patients meeting eligibility criteria were enrolled (14 males, 15 females) between October 2018 and August 2019. Baseline characteristics include; median age 59 years (range 36-70 years); 12 (41%) 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, 28 patients have completed one or more cycles wKRd-D; among these, 10 patients have completed therapy. The median number of cycles delivered is currently 6 (range 1-8). Seven of the 10 patients who have completed study treatment are MRD negative. So far, additional 8 patients have become MRD negative while on therapy. Thus, among patients treated on the weekly cohort (wKRd-D) and who were evaluable for the MRD primary end-point at this analysis, we found 15/18 (83%) to be MRD negative. We further show no added major clinical toxicities with wKRd-D compared to our institution standard of care bKRd. The bi-weekly carfilzomib cohort (bKRd-D) shows similar results to the weekly cohort (wKRd-D). With a comparable efficacy and safety profile coupled with a substantial reduction of the number of infusions (total of 51 vs 27 infusions with bKRd-D vs wKRd-D, respectively), we conclude that the weekly dosing (wKRd-D) may offer an attractive treatment modality for newly diagnosed multiple myeloma patients. CONCLUSIONS. Among patients evaluable for the MRD primary end-point, in the absence of an autologous bone marrow transplant, we show an unprecedented 15/18 (83%) MRD negativity rate among newly diagnosed multiple myeloma patients treated on the weekly cohort (wKRd-D) using carfilzomib 56 mg/m2 dosing. Our promising results have prompted the development of a large randomized multi-center study ("ADVANCE") evaluating wKRd-D in relation to established standard of care, which is anticipated to start enrollment in Q3/Q4 of 2019. Disclosures Landgren: Amgen: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: 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; Adaptive: Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Merck: Other: IDMC; Theradex: Other: IDMC; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees. Lesokhin:GenMab: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Juno: Consultancy, Honoraria; Janssen: Research Funding; Genentech: Research Funding; Takeda: Consultancy, Honoraria; Serametrix Inc.: Patents & Royalties. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Hassoun:Novartis: Consultancy; Celgene: Research Funding; Janssen: Research Funding. Smith:Fate Therapeutics and Precision Biosciences: Consultancy; Celgene: Consultancy, Patents & Royalties, Research Funding. Shah:Physicians' Education Resource: Honoraria. Landau: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; Amgen: Research Funding; Karyopharm: Consultancy, Honoraria; Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Pfizer: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees. Scordo:Angiocrine Bioscience, Inc.: Consultancy; McKinsey & Company: Consultancy. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Roshal:Auron Therapeutics: Equity Ownership, Other: Provision of services; Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services. Dogan:Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy; Roche: Consultancy, Research Funding. OffLabel Disclosure: Dara-KRd is not an FDA approved combination therapy for newly diagnosed multiple myeloma.

Abstract: Background: Monoclonal immunoglobulin deposition disease (MIDD) is a rare complication of plasma cell dyscrasias in which deposition of immunoglobulin light and/or heavy chains results in organ dysfunction, most commonly affecting the kidneys. MIDD can present with new onset hypertension, hematuria, renal insufficiency and proteinuria. The rarity of MIDD contributes to the uncertainty regarding optimal therapy (typically targeting the clonal plasma cells), and the relationship between hematologic response and renal outcome. We report here the experience at Memorial Sloan Kettering Cancer Center and New York Presbyterian Hospital/Weill Cornell Medical Center. Methods: An electronic query of pathology records was performed to identify patients with a biopsy-proven diagnosis of MIDD. Patients were eligible for inclusion in this analysis if they had received treatment and had been subsequently followed at either institution. A retrospective review of clinical records extracted patients' baseline characteristics and treatment history. Hematologic responses were assessed according to International Myeloma Working Group uniform response criteria (Kumar, S. et al 2016 Lancet Oncol 17(8): e328-346) and renal organ responses were evaluated based on changes in serum creatinine (SCr), and proteinuria, a modification of criteria previously reported (Kourelis, T. V., et al 2016, Am J Hematol 91(11): 1123-1128.; Nasr, S.H. et al. 2009, J Am Soc Nephrol 20(9): 2055-2064. The primary objective was to determine the rate of hematologic response after initial therapy. Secondary objectives included: (i) Estimation of renal response rate; (ii) Identification of risk factors associated with renal response using the Wilcoxon Rank Sum and Fisher's Exact Tests. Results: Among 54 patients identified who were diagnosed and started treatment between 1/1999 and 1/2016, 29 met criteria for inclusion. Baseline characteristics at diagnosis included: Median age of 50 (range, 32-79); 17 (59%) were male; 22 (75%) had hypertension. Renal parameters at diagnosis: median SCr of 2.4 mg/dl (range, 0.4-19), median CrCl 23 ml/min (range, 4-131), median proteinuria 2383.7mg/24h (range 4.7-13,000), nephrotic-range proteinuria syndrome in 13 (45%), hematuria in 4/25 pts (16%; 4 unknown), 7 were on hemodialysis (HD) prior to initiation of therapy, and 26 (90%) patients had monoclonal kappa light chain deposits. Hematologic parameters included median free light chain ratio of 67.9 (2.8-1179.0), detectable M-spike in 11 pts with a mean level of 0.6 g/dL and median bone marrow plasmacytosis of 20% (range, 0-90%). Induction treatment regimens included bortezomib in 18 (62%), lenalidomide in 6 (21%), cyclophosphamide in 8 (28%), and 21 (73%) underwent autologous stem cell transplant (ASCT) during the course of their treatment. Outcomes are shown in Table 1. Hematologic response among the 29 pts at completion of first line therapy included an overall response rate (ORR) of 93% with sCR (N=14, 48%); CR (N=5, 17%), VGPR (N=6, 20%), PR (N=2, 6.9%), Not available (N=2, 7%). Renal response (Table 1) among 29 patients included CR (N=9, 31%), PR (N=14, 48%) and End Stage Renal Disease (ESRD) (N=6, 21%). Among 7 patients on HD at baseline, 3 remained on HD despite treatment, while 4 stopped HD after treatment, 2 as a result of the treatment and 2 after renal transplant. 3 patients progressed to ESRD and required HD during treatment. Baseline beta-2 microglobulin (B2M), SCr, and eGFR at diagnosis were factors associated with renal response (p 〈 0.05). Hematologic response (CR vs. non-CR) was not associated with renal response (p=0.68) in this cohort. Conclusions: In this cohort, we observed a high rate of hematologic response (65.5% reaching CR) to upfront treatment regimens. A majority of patients received bortezomib-based regimens and ASCT. We observed a large proportion of patients whose renal impairment from MIDD improved significantly after receiving therapy directed at the underlying clonal neoplasm, with 75.8% reaching PR or better, nearly a third of patients achieving a renal CR, and 2/7 patients on HD at diagnosis discontinuing HD after treatment. Our experience presented here serves to inform the treatment approach of patients with MIDD. Given the scarcity of outcome data in MIDD, especially in the era of novel anti-myeloma therapy, prospective studies to optimize the management of these patients are needed. Disclosures Rossi: Celgene: Consultancy. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Korde:Amgen: Research Funding. Mailankody:Janssen: Research Funding; Juno: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding. Lesokhin:Squibb: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Genentech: Research Funding; Janssen: Research Funding; Serametrix, inc.: Patents & Royalties: Royalties. Landgren: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; Pfizer: Consultancy; Celgene: Consultancy, Research Funding; Amgen: Consultancy, Research Funding; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Hassoun:Oncopeptides AB: Research Funding.

Abstract: Introduction Newly diagnosed multiple myeloma (NDMM) patients who achieve and maintain minimal residual disease (MRD) negativity demonstrate clinical benefit with prolonged progression-free survival and overall survival. Based on available data showing MRD negativity with standard dose KRD (36 mg/m2) approximating 40% (Korde JamaOnc 2015), we designed a MRD response-adapted treatment study for NDMM, where the number of treatment cycles is determined based on MRD status, instead of the traditional paradigm of fixed number of cycles followed by autologous hematopoietic cell transplantation (AHCT). We integrated a flow-based MRD driven platform in this phase I/II study evaluating higher doses of twice-weekly carfilzomib (Car) (45 and 56 mg/m2) in combination with lenalidomide (Len) and dexamethasone (Dex). Methods Eligible NDMM patients were given escalating doses of Car (45 and 56 mg/m2), Len, and Dex in a single arm, phase I standard 3+3 schema design, based on dose-limiting toxicities (DLTs) occurring in cycle 1. Treatment consisted of 28-day cycles with Car 20/45 mg/m2 or 20/56 mg/m2 - days 1, 2, 8, 9 15 and 16; Len 25 mg - days 1-21; and Dex 40 mg weekly cycles 1-4, 20 mg after cycle 4. AHCT eligible patients underwent stem cell collection after 6 cycles, and then continue with protocol therapy. Patients achieving MRD negative status (serum, urine, and bone marrow with 10-color flow) received 2 additional cycles from the time of conversion and then stop therapy. Patients with less than an MRD negative response after any cycle continued therapy until treatment completion (max 12 cycles), disease progression, or unacceptable toxicity. The primary endpoint of the phase II study was to determine the MRD negative rate at the MTD dose, using a Simon's optimal two-stage design. Herein, we have updated results on phase I and phase II portions of the study with a median follow-up of 20.7 months (1.4-31.1). For available data, we present MFC and NGS MRD platforms. Results Twenty-nine patients have enrolled onto study between October 2016 - June 2018, with 18 in phase 1 and stage I of phase II and 11 in stage II of phase II, thus completing target accrual. There were 16 males, 13 females, median age 61 (43-75) years. Baseline characteristics included 18(62%) ISS-I, 9(31%) ISS-II, and 2(7%) ISS-III, and 7(24%) patients high risk FISH (t(4,14), t(14,16), p53 deletion). There were no DLTs within the first cycle that met protocol criteria (0/3 patients in 20/45 mg/m2 cohort and 0/6 patients in 20/56 mg/m2). The MTD chosen was 20/56 mg/m2, and an additional 20 patients were enrolled. Three patients came off study (56 mg/m2 cohort): one due to MI (during C2); one due to intolerable rash (during C2); and one due to personal preference (during C2). Among all 29 patients, grade 3/4 non-hematologic toxicities included 6(21%) rash, 5(17%) electrolyte disturbances, 4(14%) infections, 3(10%) GI, 2(7%) cardiopulmonary, 2(7%) VTE, 2(7%) mood, 2(7%) cataract, and 1(3%) hyperglycemia, and grade 3/4 hematologic toxicities included 12(41%) lymphopenia, 2(7%) leukopenia, 1(3%) neutropenia, and 1(3%) thrombocytopenia. Ten patients had 13 SAEs. For the 15 patients completing protocol therapy, a median number of 11 (7-12) cycles were delivered, and best responses include 9(60%) sCR/CR MRD neg and 6(40%) obtaining VGPR. Among patients reaching sCR/CR MRD neg status, the median time to reach was 8 (5-9) cycles. Among the eleven patients currently remaining on study, 7 have received at least 1 cycle of therapy (response eligible) and best responses thus far, included 1(14%) sCR/CR MRD pending, 4(57%) VGPR, and 2(29%) PR with a median number of 4 (1-8) cycles delivered. Table comparison of MRD platforms shown in sCR/CR patients. Among patients that remain on study, median 20.7 months, no patients have progressed and all remain alive. One patient that came off study due to personal preference during cycle 2 achieved a PR, and has progressed since. Conclusion In this phase I/II clinical trial assessing higher doses of twice-weekly Car dosing in combination with Len and Dex, we established MTD 56 mg/m2 and demonstrated a MRD platform using multi-parametric flow cytometry can be successfully used to tailor individualized treatment plans. Higher doses of twice weekly Car (45 and 56 mg/m2) in combination with Len and Dex, resulted in rapid and deep responses with approximately 60% MRD negative rate, and a safety profile similar to KRD standard dose (Car 36 mg/m2). Table. Table. Disclosures Korde: Amgen: Research Funding. Mailankody:Janssen: Research Funding; Physician Education Resource: Honoraria; Takeda: Research Funding; Juno: Research Funding. Hassoun:Oncopeptides AB: Research Funding. Lesokhin:Janssen: Research Funding; Squibb: Consultancy, Honoraria; Genentech: Research Funding; Bristol-Myers Squibb: Consultancy, Honoraria, Research Funding; Serametrix, inc.: Patents & Royalties: Royalties; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties: CAR T cell therapies for MM, Research Funding. Arcila:Invivoscribe, Inc.: Consultancy, Honoraria. Ho:Invivoscribe, Inc.: Honoraria. Landgren:Janssen: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, 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; Amgen: Consultancy, Research Funding; Karyopharm: Consultancy; Pfizer: Consultancy.