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: 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. Prior studies consistently show that the use of maintenance therapy after completion of combination therapy translates into longer progression-free survival (PFS) in patients with multiple myeloma. Some studies show that maintenance therapy prolongs overall survival (OS). Typically, maintenance therapy is used in the setting of newly diagnosed multiple myeloma; however, emerging data suggest that (at least a subset of) patients in the early relapse setting, for example those who achieve MRD negativity, may also be candidates for maintenance therapy integrated with careful disease monitoring. Currently, lenalidomide is considered the standard of care for maintenance; however, there is only limited published data on long-term use, with respect to the ability to sustain MRD negativity, mechanisms of relapse, and late toxicities. We were motivated to develop a study focusing on long-term lenalidomide maintenance therapy and to study clinical and correlative data. Here, we report on sustained MRD negativity and clinical tolerability. Methods. This single arm, phase 2 was designed to enroll 100 evaluable patients. Per protocol, maintenance therapy with lenalidomide 10 mg is given days 1-21 on a 28-day cycle. The initial study design had a total duration of 36 months; it was subsequently extended with additional 24 months (i.e., total of 60 months). Per standard procedures for protocol amendments, patients were offered to re-consent for the extension. Per protocol, patients underwent bone marrow biopsies and aspirates as well as PET/CT exams at baseline, annually, at progression/end of treatment; blood work was done every 3 months. Bone marrow and blood samples were banked longitudinally per the research protocols. Based on practical considerations, the study was statistically powered for the primary end-point progression-free survival, which provided sufficient numbers of samples for the planned correlative assays focusing on MRD testing, genomic characterization of detectable disease, and profiling of the bone marrow microenvironment. All these assays were conducted in serial samples collected over time and assessed in relation to clinical outcomes. Results. A total of 100 evaluable patients meeting eligibility criteria were enrolled (63% males) between September 2015 and January 2019. Baseline characteristics include median age 63 years (range 38-86 years) and median ECOG score 1 (range 0-1). At the submission of this abstract, the median number of cycles delivered is currently 26 (range 1 to 48); 86 patients have completed 12 or more cycles, 57 patients have completed 24 or more cycles, and 29 patients have completed 36 or more cycles. MRD testing had been completed at least once in all patients. Thirty-four patients were MRD negative at enrollment. At median followup time of 28 months (range 3.4 to 45.6), 15/100 (15%) patients have progressed. Considering the entire follow-up time from initial MRD negativity to last follow-up on study, we found 39 (of 85 tested; 46%) and 25 (of 57 tested; 44%) to have evidence of 1 and 2 years sustained MRD negativity, respectively. Only 19 patients were tested for MRD at 3 years and 16 (84%) had sustained MRD negativity. Toxicities (grade 3) include neutrophil count decrease (N=9), hypertension (N=3), diarrhea (N=2), lung infection (N=2), and rash maculo-papular (N=2), and toxicities (grade 4) include sepsis (N=2) and platelet count decrease (N=1). The most common 1/2 toxicities were diarrhea (N=51), fatigue (N=33), and upper respiratory infection (N=23). Among evaluable patients, dose reductions of lenalidomide due to toxicities and tolerability issues were done in 6 (6%) patient. Conclusions. Among evaluable patients who were treated with lenalidomide 10 mg maintenance therapy days 1-21 on a 28-day cycle on this study, at a median followup of 28 months, we found 46% and 44% to have evidence of 1 and 2 years sustained MRD negativity, respectively. Currently, 19 patients have been tested for MRD at 3 years; 16 (84%) show evidence of 3 years sustained MRD negativity. The toxicity profile was in accord with prior studies and tolerability was quite good reflected in only 6 patients requiring dose reductions due to toxicities. Correlative assays focusing on mechanisms of sustained MRD negativity in this study are presented in a separate abstract at this meeting. Disclosures Landgren: Adaptive: Honoraria, 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; Theradex: Other: IDMC; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; 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; 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; Merck: Other: IDMC. Lesokhin:Genentech: Research Funding; GenMab: Consultancy, Honoraria; Janssen: Research Funding; Serametrix Inc.: Patents & Royalties; Juno: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria. Smith:Celgene: Consultancy, Patents & Royalties, Research Funding; Fate Therapeutics and Precision Biosciences: Consultancy. Mailankody:Juno: Research Funding; Celgene: Research Funding; Janssen: Research Funding; Takeda Oncology: Research Funding; CME activity by Physician Education Resource: Honoraria. Hassoun:Janssen: Research Funding; Celgene: Research Funding; Novartis: Consultancy. Landau:Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Karyopharm: Consultancy, Honoraria; 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; Caelum: Membership on an entity's Board of Directors or advisory committees; Prothena: Membership on an entity's Board of Directors or advisory committees; Pfizer: 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:Physicians' Education Resource: Other: Provision of services; Celgene: Other: Provision of Services; Auron Therapeutics: Equity Ownership, Other: Provision of services. Dogan:Roche: Consultancy, Research Funding; Corvus Pharmaceuticals: Consultancy; Seattle Genetics: Consultancy; Celgene: Consultancy; Takeda: Consultancy; Novartis: Consultancy.

Abstract: Multiple myeloma (MM) progression is characterized by the seeding of cancer cells in different anatomic sites. To characterize this evolutionary process, we interrogated, by whole genome sequencing, 25 samples collected at autopsy from 4 patients with relapsed MM and an additional set of 125 whole exomes collected from 51 patients. Mutational signatures analysis showed how cytotoxic agents introduce hundreds of unique mutations in each surviving cancer cell, detectable by bulk sequencing only in cases of clonal expansion of a single cancer cell bearing the mutational signature. Thus, a unique, single-cell genomic barcode can link chemotherapy exposure to a discrete time window in a patient′s life. We leveraged this concept to show that MM systemic seeding is accelerated at relapse and appears to be driven by the survival and subsequent expansion of a single myeloma cell following treatment with high-dose melphalan therapy and autologous stem cell transplant.

Abstract: A Correction to this paper has been published: https://doi.org/10.1038/s41467-021-20978-y.

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.