Newly Diagnosed Multiple Myeloma Patients Research Articles

A Systematic Review of Daratumumab Based Four Drug Regimen for Newly Diagnosed Multiple Myeloma in Phase III Clinical Trials

Introduction: Daratumumab (Dara) is a human an IgG1k monoclonal antibody that targets the CD38 which is overexpressed in the malignant cells of multiple myeloma (MM). Its use has been approved for use as a single agent as well as in combination therapy for the treatment of both newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). This review highlights the efficacy and safety of Dara in the four-drug regimen in NDMM patients (pts). Methods: We conducted a literature search using four databases (PubMed, Embase, Cochrane, and Clinicaltrials.gov). Our search strategy included Medical Subject Headings (MeSH terms) and keywords for multiple myeloma and daratumumab including trade names and generic names from the date of inception to June 2020. After excluding review articles, duplicates, and non-relevant articles, we included three phase III trials out of 588 articles reporting Dara addition to the standard of care four drug regimens for NDMM pts. Results: A total of 1998 patients were enrolled and evaluated in three-phase III randomized controlled trials. A total of 997 patients were evaluated in the Dara group and 1001 patients were evaluated in the control group. Total 1292 were transplant eligible and 706 patients were transplant ineligible. Transplant eligible Moreau et al. (2019) studied the efficacy of Dara + bortezomib (V) + thalidomide (T) + dexamethasone (d) vs VTd in newly diagnosed MM (NDMM) pts (n=1085) in CASSIOPEIA phase III trial. Addition of Dara to VTd group showed marked improvement in progression-free survival (PFS): 93% vs 85% at 18 months (hazard ratio (HR) 0.42 [0.34-0.51]; p<0.0001), and overall response rate (ORR) of 92.6% in Dara + VTd group as compared to 89.9% in VTd group (CI: 95%, P<0.0001). Minimal residual disease (MRD) negative status (10-⁵ sensitivity threshold, assessed by multiparametric flow cytometry) in bone marrow was 64% in Dara using VTd vs 44% in the VTd group (P<0.0001). Vorhees et al. (2020) reported addition of Dara to lenolidamide (R), and Vd in GRIFFIN study in NDMM patients (n= 207). Addition of Dara to VRd resulted in improved PFS: 95.8% ((95% CI, 89.2- 98.4) vs 89.8% ((95% CI, 77.1-95.7) at 24 months), and ORR of 99% (Odd's ratio (OR) 8.75 with 95% CI: 1.08-71.01; p=0.0160) in Dara + VRd group vs VRd group (91.8%). MRD status in bone marrow was also higher in Dara group as compared to control group (51% vs 20.4%) (p<0.0001). Transplant ineligible Mateos et al. (2018) reported the role of Dara + V + melphalan (M) + prednisone (P) vs VMP in NDMM pts (n=706) in a phase III trial (Alcyone). Addition of Dara to VMP group showed marked improvement in PFS: 63% vs 36 at 24 months (HR: 0.47, 95% CI 0.33-0.67, p<0.0001), and ORR: 90.9% vs 73.9%, respectively. MRD negative status in bone marrow was observed higher with Dara compared to without Dara using VMP (28% vs 7%) (p<0.0001). Significant toxicities in phase III trials mainly included pancytopenias and opportunistic infections (Table 2). Conclusion: NDMM treatment with Dara in four-drug regimens (VTd, VMP, VRd) has shown promising outcomes with improved efficacy and higher negative MRD status, providing a benchmark for future studies. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

On-Demand Plerixafor with Cyclophosphamide and G-CSF for Hematopoietic Stem-Cell Mobilization in Multiple Myeloma Patients: Preliminary Results of a Prospective Observational Study (MOZOBL06877)

On-Demand Plerixafor with Cyclophosphamide and G-CSF for Hematopoietic Stem-Cell Mobilization in Multiple Myeloma Patients: Preliminary Results of a Prospective Observational Study (MOZOBL06877)

Assessment of Minimal Residual Disease in a Phase 1b Study of Once-Weekly Carfilzomib Combined with Lenalidomide and Dexamethasone in Patients with Multiple Myeloma

Assessment of Minimal Residual Disease in a Phase 1b Study of Once-Weekly Carfilzomib Combined with Lenalidomide and Dexamethasone in Patients with Multiple Myeloma

Use of Anti-Infective Prophylaxis in Newly Diagnosed and Relapsed/Refractory Multiple Myeloma Patients Initiating Treatment with Daratumumab

Introduction: Infections continue to be one of the main causes of morbidity and mortality in multiple myeloma (MM) patients. Compared to the general population, MM patients have a 7-fold increased risk of bacterial infections and 10-fold risk of viral infections. The recent National Comprehensive Cancer Network (NCCN) guideline has provided guidance for prevention of cancer-related infections; however, utilization of anti-infective prophylaxis among MM patients in real-world practice has not been fully established. Daratumumab, a human IgGκ monoclonal antibody targeting CD38, is approved as monotherapy and in combination with standard-of-care regimens for newly diagnosed MM (NDMM) and relapsed/refractory MM (RRMM). The primary objective of the study was to describe the proportion of MM patients who received anti-infective prophylaxis when initiating a daratumumab-based treatment regimen. Methods: Medical and pharmacy claims from the Optum's de-identified Clinformatics® Data Mart Database were obtained for a cohort of US patients with NDMM or RRMM who initiated treatment with daratumumab (in combination with other antimyeloma agents or monotherapy) between 1/1/2017 and 12/24/2019. The index date was defined as the first daratumumab treatment date in the study period. Two steps were applied to identify anti-infective prophylaxis. First, use of anti-infective prophylaxis was assessed during the period between the week prior to and the week after the date of daratumumab initiation, including anti-virals for preventing herpesviruses (i.e., herpes zoster, herpes simplex, and cytomegalovirus), systemic anti-bacterials, systemic anti-fungals, Pneumocystis jiroveci pneumonia (PJP) prophylaxis, and intravenous/subcutaneous immune globulin (IVIG/SCIG). Second, use of an anti-infective drug was defined as prophylactic if there was no diagnosis for an infection treated by the anti-infective drug (i.e., patients with infection events one week prior to and one day after the start of drug prescription were excluded). Receipt of vaccines for seasonal influenza (in the year prior to daratumumab initiation) and herpes zoster and pneumococcal infections (at any time prior in the patient's claims history) were also assessed. Results: 929 newly daratumumab-treated patients were eligible for study inclusion; 92 had NDMM (median age 74 years; 48.9% female) and 837 had RRMM (median age 72 years; 46.0% female). At the time of daratumumab initiation, antibacterial prophylaxis was administered to 12.0% of NDMM and 17.0% of RRMM patients; antifungal prophylaxis to 1.1% of NDMM and 1.3% of RRMM patients; and PJP prophylaxis to 4.4% of NDMM and 10.5% of RRMM patients (Table 1). IVIG/SCIG prophylaxis was given to 1.1% of NDMM patients and 2.5% of RRMM patients. Herpesvirus prophylaxis was administered to 57.6% of NDMM and 69.4% of RRMM patients, and 17.4% of NDMM and 11.5% of RRMM patients received vaccination for herpes zoster. Seasonal influenza and pneumococcal vaccinations were given to 56.5% and 47.8% of NDMM patients and 62.5% and 51.3% of RRMM patients, respectively. Conclusion: Use of herpesvirus prophylaxis was approximately 70% in RRMM and 60% in NDMM patients at time of daratumumab initiation, with limited use of herpes zoster vaccination, suggesting that a meaningful minority of patients may not be protected against herpesvirus as recommended by NCCN guidelines for patients treated for MM. While rates of influenza and pneumococcal vaccination were higher than for herpes zoster, nearly half of patients did not have evidence of vaccination for these two pathogens in their claims data. These results indicate that a significant percentage of MM patients are not receiving care to optimally prevent potential viral infections. Further studies are needed to understand the potential benefit of infectious prophylaxis in the clinical management of MM patients. Disclosures Tai: Janssen Scientific Affairs: Current Employment. Ammann:Janssen Scientific Affairs: Current Employment, Current equity holder in publicly-traded company. Kaila:Janssen Scientific Affairs: Current Employment. Pericone:Janssen Scientific Affairs: Current Employment, Current equity holder in publicly-traded company. Singh:Mu Sigma: Current Employment, Other: Mu Sigma was contracted by Janssen Scientific Affairs to conduct the analyses for the present study. Lin:Janssen Scientific Affairs: Current Employment, Current equity holder in publicly-traded company. Davies:Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotech: Honoraria; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Roche: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Oncopeptides: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene/BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

Ixazomib Based Regimens in Patients with Newly Diagnosed Multiple Myeloma: A Systematic Review and Meta-Analysis of Clinical Trials

Introduction: Multiple myeloma (MM) is an incurable malignancy, and clinical trials with newer agents have shown improved patient outcomes. Ixazomib (Ixa) is a proteasome inhibitor and induces apoptosis in cancer cells. It is commonly used with immunomodulators for the treatment of MM. We conducted a systematic review and meta-analysis to assess the efficacy of Ixazomib alone and in combination with other drugs for the treatment of newly diagnosed multiple myeloma (NDMM). Methods: A literature search was performed on PubMed, Cochrane, Embase, Web of Science, and clinicaltrials.gov. We used the following MeSH and Emtree terms; "ixazomib" AND "Multiple Myeloma" from inception till 06/05/2020. We screened 1,558 articles and included 3 randomized clinical trials (RCTs) (N=901) and 12 non-randomized clinical trials (NRCT) (N=632). We excluded case reports, case series, preclinical trials, review articles, observational studies, meta-analysis, and ongoing clinical trials that did not report interim efficacy outcomes. We used the R programming language (version 4.0.2) to conduct a meta-analysis. Results: In 15 clinical trials (N=1533), Ixa based regimens were used in patients with age range of 39-92 years. (Table 1) In 3 clinical trials (N=170), Ixa with Lenalidomide (Len) and dexamethasone (Dex) yielded a pooled overall response rate (ORR) of 90% (95% CI=0.82-0.94, I2=32%), a pooled complete response (CR) of 23% (95% CI=0.16-0.32, I2=24%) and a pooled ≥very good partial response and better (≥VGPR) of 39% (95% CI=0.24-0.57, I2 =76%) when used as induction therapy for NDMM patients. As consolidation therapy (N=88), pooled ORR was 91% (95% CI=0.79-0.97, I2=0), pooled CR was 36% (95% CI=0.27-0.47, I2=0) and pooled ≥VGPR was 70% (95% CI=0.53-0.84, I2=60%). (Fig 1-3) In 5 clinical trials (N=233), Ixa + cyclophosphamide (Cyc) + Dex yielded a pooled ORR, CR, and ≥VGPR of 76% (95% CI=0.70-0.81, I2 =0), 12% (95% CI=0.07-0.20, I2=44%), and 25% (95% CI=0.14-0.39, I2=78%), respectively. (Fig 1-3) The lower dose of Cyc 300mg/m2 had similar efficacy as 400mg/m2 with better safety profile in elderly patients. In a RCT (N=175) of Ixa with multiple combinations, Ixa + Dex yielded ORR 55% (95% CI=0.40-0.69), CR 14% (95% CI=0.07-0.28) and ≥VGPR 24% (95% CI=0.13-0.39). Ixa+ thalidomide (Thal) + Dex fostered ORR 82% (95% CI=0.70-0.90), CR 15% (95% CI=0.08-0.26), and VGPR 43% (95% CI=0.31-0.55). Ixa + bendamustine + Dex yielded ORR of 73% (95% CI=0.41-0.91), CR 9% (95% CI=0.01-0.44), and ≥VGPR 27% (95% CI=0.09-0.59). In one clinical trial (N=53), Ixa + melphalan (Mel) + prednisone (Pred) combination yielded pooled ORR, CR, and ≥VGPR of 66% (95% CI=0.52-0.77), 13% (95% CI=0.06-0.25), and 30% (95% CI=0.19-0.44), respectively. In a phase II trial (N=40), Ixa + daratumumab (Dara) + Len + Dex yielded an ORR, CR and ≥VGPR of 97% (95% CI=0.84-1), 15% (95% CI=0.07-0.28), and 35% (95% CI=0.22-0.51) respectively. (Fig 1-3) In a phase III RCT by Dimopholous et al. (N=656), Ixa maintenance therapy after stem cell transplant (SCT) yielded an ORR, CR, and ≥VGPR of 76%, 15%, and 54%, respectively. They observed 28% reduction in the risk of progression or death with Ixa vs. placebo, median progression free survival (mPFS) was 26.5 months (95% CI 23·7-33·8) vs 21·3 months [18·0-24·7]; hazard ratio 0·72, 95% CI 0·58-0·89; p=0·0023). Second malignancies were 3% in both ixazomib and placebo group. 27% of the patients in ixazomib group and 20% patients in placebo group experienced serious adverse events. In a clinical trial on unfit and frail patients (N=46) treated with Ixa + daratumumab (Dara) + Dex, pooled ORR and ≥VGPR were 83% (95% CI=0.69-0.91, I2=0), and 33% (95% CI=0.21-0.47, I2=0), respectively. (Fig 1-3) In the phase II trial, ORR, CR, and VGPR with ixazomib and lenalidomide were 64%, 26%, and 53%, respectively. Conclusion: Ixa in combination with Len, Dex, Cyc, Dara, Mel, Pred is effective in the treatment of NDMM patients. In early phase trials, Ixa with Dara, Len, and Dexa showed the highest overall response as induction therapy. Ixazomib maintainance therapy prolongs PFS after SCT as compared to placebo and represents an additional option for post SCT maintainace therapy in NDMM patiens. The safety profile of Ixa was acceptable with most commonly encountered adverse events were hematological including neutropenia and thrombocytopenia. Additional multicenter, double-blind, randomized clinical trials are needed to confirm these results. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Genome-Wide Transcriptome Analysis Identifies Molecular Patterns of FDG-PET/CT Biomarkers in MM Patients from the Cassiopet Study

Background Positron emission tomography (PET) using 18Fluorodeoxyglucose (FDG) provides independent prognostic informations in newly diagnosed multiple myeloma (NDMM) patients (Moreau et al, ASH 2019; Moreau et al, JCO 2017; Zamagni et al, Blood 2011). At baseline, FDG-PET/CT characteristics such as maximum standardized uptake value (SUVmax), presence of extramedullary disease (EMD), and paramedullary disease (PMD) define high-risk NDMM patients. Similarly, the presence of negative FDG-PET/CT at baseline has been associated with favorable outcome in NDMM patients (Abe et al, EJNMMI 2019; Moreau et al, ASH 2019). The aim of the present study was to identify MM molecular features associated with these functional imaging biomarkers. Methods A group of 136 patients from CASSIOPET, a companion study of the CASSIOPEIA cohort (ClinicalTrials.gov, number NCT02541383) were subjected to whole genome expression profiling using RNA sequencing (RNA-seq) on sorted bone marrow plasma cells in addition to FDG-PET/CT imaging at baseline. RNA-seq reads were aligned to hg38 reference genome with STAR and subjected to differential expression testing with DESeq2 with sample purity treated as a model covariate. High risk group with the GEP70 signature and classification from the seven molecular subgroups (CD-1, CD-2, HY, LB, MF, MS, and PR) were determined by weighted mean value of gene expression (Zhan et al, Blood 2006). Special attention was paid to genes associated with glucose metabolism and related to plasma cells proliferation. On FDG-PET/CT, SUVmax of areas of focally increased tracer uptake on bone was determined and the presence of EMD or PMD identified. Results FDG-PET/CT was positive in 108 patients out of 136 (79,4%), with 19 (14%) and 15 (11%) of them presenting PMD and EMD disease respectively. Expression level of glucose transporter GLUT1 was independent of these three imaging biomarkers (FDG-PET/CT positivity, EMD and PMD), while HK2 was downregulated in negative scans only (Fold Change = 2.1, padj=0.02). GLUT5 expression was associated with positive FDG-PET/CT (Fold Change = 3.5, padj = 8E-4). Both GLUT1 and HK2 weakly correlated with SUVmax (r=0.26 and 0.36, respectively). Of note, negative FDG-PET/CT were enriched for the LB group of patients, consistent with the lower incidence of MRI-defined bone lesions reported in this subgroup, and it remained independent of the GEP70 signature. Furthermore, high risk GEP70 signature was associated with a SUVmax ≥ 4, and correlated with the presence of PMD (OR=3.2, CI=[0.95-10.6], p=0.03), but not with EMD (p=0.7).Conversely, there was no patient from the LB group with detected PMD on imaging, but 25% (2/8) showed EMD, suggesting that different biological features support both disease patterns. Finally, positive PET/CT profiles seemed to display two distinct signatures with either high expression of proliferation genes (MKI67, PCNA, TOP2A, STMN1), or high expression of GLUT5 and lymphocyte antigens (CD19, CD30L, and CCR2), suggesting a different phenotype for this subgroup. This finding was independent of a high SUVmax. Conclusion Our study confirmed that negative FDG-PET/CT at baseline is associated with low HK2 expression while positive exams showed increased GLUT5 expression and proliferation markers. We describe a strong correlation between two imaging biomarkers (baseline SUVmax and PMD) and high risk signature and molecular subgroup with highly proliferative disease. On the contrary, EMD appeared independent of high risk signature or molecular subgroups. Additional studies will confirm and extend the correlation between imaging and clinical features of the disease and molecular characteristics of malignant plasma cells. Disclosures Touzeau: Sanofi: Honoraria, Research Funding; Abbvie: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses, Research Funding; Amgen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses; GlaxoSmithKline: Honoraria, Research Funding; Takeda: Consultancy, Honoraria, Other: Travel, Accommodations, Expenses. Moreau:Amgen: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria; Abbvie: Consultancy, Honoraria; Novartis: Honoraria; Celgene/Bristol-Myers Squibb: Consultancy, Honoraria; Janssen: Consultancy, Honoraria; Takeda: Honoraria.

Prognostic Impact of Hyperdiploidy on Multiple Myeloma in the Era of New Agents

Introduction Multiple myeloma (MM) is a kind of hematological malignancy which is characterized by high genetic heterogeneity. It has been proved that the existence and even the coexistence of numerical and structural cytogenetic abnormalities (CAs) play a critical role in the development and progression of MM. Hyperdiploidy (HD), as one of the two primary CAs of MM, can be observed in around half of the patients and is considered as a favorable prognostic factor. Nevertheless, its role in overcoming the negative effect of concomitant high-risk CAs remains controversial. Although the outbreak of novel drugs by the last decades, such as proteasome inhibitors (PIs) and Immunomodulatory drugs (IMiDs), has significantly improved the survival of patients, MM is still incurable and can relapse recurrently. The prognostic impact of HD in the era of novel agents and its impact on other CAs are unclear and under to be explored. Here, we report our results based on the Chinese population to provide some evidence for the above questions. Methods A total of 213 patients between January 2013 to November 2017 were included in this study. All of the participants were from our database consisting of patients with newly diagnosed MM (NDMM) enrolled into the prospective, nonrandomized clinical trial (BDH 2008/02 or BDH 2014/03, all informed consents were obtained) approved by Institute of Hematology & Blood Diseases Hospital, Chinese Academy of Medical Science & Peking Union Medical College. According to patients' willingness and specific conditions, they were assigned to either PI- or IMiD-based inductive treatment and maintenance, with or without autologous stem cell transplantation (ASCT) as consolidation therapy. Bone marrow aspirate samples were collected before the initiation of therapy and MM cells were enriched by CD138 magnetic beads. Then fluorescence in situ hybridization (FISH) was performed. Specifically, if patients possessed at least an extra copy of probes for any two of chromosomes 5, 9, or 15 concurrently in more than 10% cells, they would be classified into HD subgroup; otherwise, they would be divided into NHD (non-hyperdiploidy) subgroup. Clinical and biological baseline characteristics were compared. Progression-free survival (PFS) and overall survival (OS) were measured using the log-rank test. Significant variables from the univariate analysis were selected for the cox stepwise regression analysis. Results In our cohort, HD was identified in 34% (72/213) NDMM patients. HD was more common among older people (p=0.007). Patients with HD often had a lower level of serum albumin (p=0.037), but NHD patients had a higher frequency of elevated lactate dehydrogenase (LDH). Moreover, immunoglobulin isotype distribution was not similarly (p<0.001), in which patients with NHD were more often IgD or light chain isotype. As to the genetics aspect, 99.1% (211/213) patients harbored at least one CA, and NHD patients appeared to be more genetic instability. 14q32 (IGH) translocation(p<0.001), del(13q) (p<0.001) and del(17p) (p=0.012) were likely to be detected in patients with NHD. However, there were no significant differences in the ratio of 1q21 gain/amplification and complex karyotype. Among patients with IGH translocation, t(14;undefined) [could not find partner genes by t(4;14), t(11;14), t(14;16) or t(14;20) probes] and t(11;14) were the most common translocation type in HD and NHD patients respectively. Median follow-up was 37 (4-82) months, Patients with HD showed a better median PFS (41 months vs. 27 months, p=0.047) and median OS (75 months vs. 55 months, p=0.024). Further subgroup analysis showed that the prolonged survival of HD was significant in patients who did not receive ASCT as part of the first-line therapy, but it could not overcome negative prognostic effects of other CAs except complex karyotype. Multivariate analysis confirmed that the state of ploidy was an independent prognostic factor for MM. Conclusions HD patients have specific differences in clinical and biological features. In the era of novel agents, MM patients with HD still have better survival than NHD. However, it may not ameliorate the adverse prognosis of concurrent high-risk CAs identified by FISH. Figure Disclosures No relevant conflicts of interest to declare.

Multiple Myeloma Cells Induce Lipolysis in Adipocytes and Uptake Fatty Acids through Fatty Acid Transporter Proteins

Multiple myeloma (MM) originates in the bone marrow where adipocytes occupy 65% of the cellular volume in a typical myeloma patient. Cancer associated adipocytes support the initiation, progression, and survival of solid tumors via mechanisms including adipokine secretion, modulation of the tumor microenvironment, and metabolic reprogramming of cancer cells. Although MM cells are surrounded by abundant bone marrow adipocytes (BMAd), the nature of their interaction remains unclear. Recent studies have elucidated the role of BMAds in supporting the survival of MM cells, in part, through secreted adiponectin. Increased fatty acid (FA) metabolism may result in metabolic reprogramming of cancer cells impacting their growth and survival. Here, we hypothesize that MM cells extract FA from adipocytes for their growth. We first characterized mesenchymal stem cells (MSCs) from MGUS, smoldering MM (SMM), and newly diagnosed MM (NDMM) patients by flow cytometry analysis. MSCs showed significant increase in Pref1, leptin receptor and perilipin A, suggesting increased adipogenic commitment. MSCs from healthy donors (HD), MGUS, SMM, and NDMM patients were induced to differentiate into adipocytes and then co-cultured with human MM MM.1S cells. After 72 hr of co-culture, CyQUANT assay demonstrated significant increase in proliferation of MM.1S cells in the presence of BMAd from HD; this was further increased in the presence of BMAd from MGUS/SMM and NDMM. These data suggest that the BMAd support the growth of MM cells and this effect is more pronounced in patient derived BMAd. A PCR-array targeting lipid metabolism on BM fat aspirates showed significant deregulation of genes involved in FA synthesis and lipolysis. Taken together, our data suggest that BMAd in MM patients are altered to further support the aggressive expansion of MM cells. The proliferative-supportive role of adipocytes was further validated in co-culture of OP9 murine BM stromal preadipocytes with 5TGM1 murine MM cells. To study the bidirectional interaction of MM/ BMAd, mature OP9 adipocytes were co-cultured with 5TGM1 or human OPM2 MM cells for 24 hr. Intracellular lipid droplets were labelled with Deep Red LipidTox stain. The lipid droplet sizes were significantly decreased in the presence of both 5TGM1 and OPM2 cells compared to OP9 alone. The decrease in lipid size suggested that MM cells may induce lipolysis in adipocytes. Indeed, 24hr co-culture of 5TGM1 cells with OP9 mature adipocytes significantly increased lipolysis 3-fold as measured by glycerol secretion in conditioned media. Co-culture of OP9 adipocytes with other MM cell lines of human origin, MM.1S, INA6, KMS-12 PE, and OPM2 also significantly increased the glycerol production as much as 4-fold. Taken together these data indicate that MM cells induce lipolysis in adipocytes. In contrast, treatment of 5TGM1 cells with synthetic catecholamine isoproterenol did not induce lipolysis, or glycerol production, indicating lack of triglyceride storage. Next, we hypothesized that the free FAs released from adipocytes are taken up by MM cells for various biological processes. To test this, 5TGM1, MM.1S and OPM2 cells were incubated with BODIPY-C12 and BODIPY-C16, the BODIPY-fluorophore labelled 12-carbon and 16-carbon long chain FA. All MM cells showed saturated uptake of the FA within 10 minutes suggesting that MM cells have efficient FA transporters. To confirm this uptake, unstained 5TGM1, OPM2 and KMS12 PE cells were co-cultured with the LipidTox-labelled OP9 mature adipocytes. After 24 hours, flow cytometric analysis showed LipidTox signal in MM cells. These data demonstrate that FAs released by MM induced adipocyte lipolysis are taken up by MM cells. Long-chain FAs such as BODIPY-C12 and BODIPY-C16 are transported into cells through FA transporter protein (FATP) family of lipid transporters. We therefore analyzed patient samples which showed that CD138+ plasmacells and myeloma cells expressed high levels of FATP1 and FATP4 whereas, their expression was absent in lineage-sibling T-cells. Moreover, pretreatment with Lipofermata, a FATP inhibitor, was able to decrease the uptake of BODIPY-C12 and -C16 in 5TGM1 cells. Taken together, our data show that myeloma cells induce lipolysis in adipocytes and the released free FAs are then uptaken by myeloma cells through FATPs. Inhibiting myeloma cell induced lipolysis or uptake of FA through FATPs may be a potential anti-tumor strategy. Disclosures Fulzele: FORMA Therapeutics, Inc: Current Employment, Other: Shareholder of Forma Therapeutics. Raje:Amgen: Consultancy; bluebird bio: Consultancy, Research Funding; Caribou: Consultancy, Membership on an entity's Board of Directors or advisory committees; Immuneel: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy; Celgene: Consultancy; Immuneel: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Takeda: Consultancy.

Upfront Autologous Hematopoietic Stem-Cell Transplantation Improves Overall Survival in Comparison with Bortezomib-Based Intensification Therapy in Newly Diagnosed Multiple Myeloma: Long-Term Follow-up Analysis of the Randomized Phase 3 EMN02/HO95 Study

Upfront Autologous Hematopoietic Stem-Cell Transplantation Improves Overall Survival in Comparison with Bortezomib-Based Intensification Therapy in Newly Diagnosed Multiple Myeloma: Long-Term Follow-up Analysis of the Randomized Phase 3 EMN02/HO95 Study

Efficacy of Ixazomib and Bortezomib with Lenalidomide Combination Regimens for Multiple Myeloma: A Systematic Review

Introduction: Three drug regimen using bortezomib (V), lenalidomide (R), and dexamethasone (d) is a standard first-line treatment modality for multiple myeloma (MM). If compared to bortezomib that can cause neurotoxicity, ixazomib is an oral proteasome inhibitor (PI) with markedly lower chances of neurotoxicity. Ixazomib (I) use showed favorable results in both newly diagnosed MM (NDMM) and relapsed refractory MM (RRMM). This systemic review compares the efficacy and safety outcomes of IRd with VRd in MM patients. Methods: We performed a comprehensive literature search on PubMed, Cochrane Library, and ClinicalTrials.gov on June 9, 2020. We used the MeSH terms for 'multiple myeloma', 'ixazomib', 'bortezomib', 'dexamethasone', 'lenalidomide', and their associated keywords. The search yielded 1117 articles. Screening and data extraction were done following PRISMA guidelines. After excluding case reports, case series, observational studies, review articles, meta-analysis, and retrospective studies, 18 clinical trials (n=2295) were shortlisted of which six assessed IRd and twelve assessed VRd. Results: No direct comparison trial between IRd and VRd was found. Total 1007 patients were evaluable who received IRd (Table 1). Among them 892 had RRMM and 115 had NDMM. Moreover, total 1288 evaluable patients received VRd where 977 had NDMM and 311 had RRMM (Table 3). IRd arm results Among 892 RRMM patients received IRd, Gupta et al. (2015, n=43) reported an overall response rate (ORR) of 65% with 23% achieving a very good partial response (VGPR) and 9% achieving complete response (CR). In TOURMALINE-MM1 Study by Moreau et al. (2016, n=722), authors reported the median progression-free survival (mPFS) as 20.6 months with IRd. The ORR was 78% (95% CI 74-83). Hou et al. (2017, n=115) reported mPFS of 6.7 with IRd. After a median follow-up of 20.2 months, the median overall survival (mOS) was reported to be 25.8 months. The ORR was 56% (95% CI 42-69). 115 NDMM patients received IRd in two clinical tials. Richardson et al. (2018, n=50) in a phase II trial reported an ORR of 94% (95% CI 83-99) with 29% CR and 37% VGPR. The mPFS was 24.9 months (95% CI 17.4-40.5) and 3-year OS was 90% in the intention-to-treat analysis. Kumar et al. (2019, n=65) reported ORR of 88% (CR=23%, VGPR=34%, PR=64%). The mPFS of 35.4 months (95% CI 17.8-44.12) slightly better than the previous study. The mOS was not reached in either of the trials. Any drug-related grade ≥ 3 adverse events were reported in 50% to 80% of participants receiving IRd but were manageable with prompt intervention. VRd arm results NDMM patients, in a phase III trial by Durie et al. (2016, n=471) achieved ORR of 82% (PR=38%, VGPR=28% and CR=16%) with VRd. The mPFS was 43 months and mOS was 75 months, both significantly better than control. Stadtmauer et al. (2019, n=254) results were similar as well with 3-year PFS and OS as 58% and 85% respectively. Kumar et al. (2012, n=42) had a 1-year OS of 100% and PFS of 83%. O'Donnel et al. (2018, n=50) achieved mPFS of 35 months while mOS could not be reached. Luoma et al. (2019, n=78) achieved a 3-year PFS of 52% while OS of 83%. Among the 311 patients who had RRMM, Brojil et al. (2015, n=64) in phase I/II study showed ORR of 89% but mPFS and mOS were limited to 19 and 42 months respectively. In Richardson et al. (2014, n=64) 2-year PFS=36% and OS=65%. Mori et al. (2020, n=68) reported ORR=71% largely driven by PR of 43%. 1-year PFS and OS were 14% and 37% respectively. The toxicity profile with VRd was mostly mild and manageable except for severe neurotoxicity. Conclusion: Based on the data, IRd and VRd combinations have shown comparable efficacy and safety outcomes in MM patients. IRd based all-oral regimen is showing favorable outcomes, especially in RRMM patients. Future trials to compare IRd vs VRd are recommended for NDMM and RDMM patients. Disclosures Anwer: Incyte, Seattle Genetics, Acetylon Pharmaceuticals, AbbVie Pharma, Astellas Pharma, Celegene, Millennium Pharmaceuticals.: Honoraria, Research Funding, Speakers Bureau.

Copy Number Signatures Predict Chromothripsis and Poor Clinical Outcome in Newly Diagnosed Multiple Myeloma Patients

Copy Number Signatures Predict Chromothripsis and Poor Clinical Outcome in Newly Diagnosed Multiple Myeloma Patients

Risk of Early Severe Infections in Newly Diagnosed Multiple Myeloma Patients Treated with Novel Agents: A Pooled Analysis

Risk of Early Severe Infections in Newly Diagnosed Multiple Myeloma Patients Treated with Novel Agents: A Pooled Analysis

In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy Increases the Feasibility of Long-Term PI Treatment and Benefit for Newly Diagnosed Multiple Myeloma (NDMM) Patients in an Outpatient Setting: Updated Real-World Results from the Community-Based United States (US) MM-6 Study

In-Class Transition (iCT) from Parenteral Bortezomib to Oral Ixazomib Proteasome Inhibitor (PI) Therapy Increases the Feasibility of Long-Term PI Treatment and Benefit for Newly Diagnosed Multiple Myeloma (NDMM) Patients in an Outpatient Setting: Updated Real-World Results from the Community-Based United States (US) MM-6 Study

Sequential Intravenous to Oral Proteasome Inhibitor Based Regimens for the Treatment of Newly Diagnosed Multiple Myeloma Patients: A Real-World Study

Objective To assess in-class transition (iCT) from intravenous bortezomib-based induction to all-oral ixazomib-based treatment improving proteasome inhibitor-based continuous therapy with efficiency, safety and convenience in clinical practice. Methods In this real-world retrospective study from Chinese seven hospitals during Oct, 2017-Jul, 2020, we analysed newly diagnosed multiple myeloma (NDMM) patients without transplantation, who achieved at least partial response of bortezomib-based introduction, and then received ixazomib-based regimen for 2 years or until progression/intolerant toxicity. Primary endpoint: progression-free survival (PFS). Key endpoints included response rate, therapy duration and adverse event (AE). Results 96 patients were enrolled in this study (median age 61 years; 25% ≥ 65 years; 7% ≥ 75 years; 61% male; ISS stage I/II/III 10%/35%/55%; IgG/IgA/IgD/IgE/light chain /double clonal /non-secretory 50%/18%/2%/1%/26%/1%/2%). R-ISS stage was estimated in 85 patients (stage I/II/III 6%/78%/16%). 35% high risk(HR) (27/78) and 65% standard risk (SR)(51/78) were tested by metaphase fluorescence in situ hybridization (M-FISH) according to Mayo clinic risk stratification. 96 patients received median 5 cycles (2-12) of bortezomib-based regimen including VD1/VRD1/VTD1/VCD1/PAD1/PD2D1, and median 6 cycles (1-17) of iCT regimen including ID1/IRD1/ITD1/ICD1 (30/96,43/96,10/96,13/96), three-drug ixazomib-based regimens account for the majority (66/96). Median duration of total PI therapy was 11.3 months and of ixazomib-based regimen was 5.3 months. With 13 months median follow-up, 18-month progression free survival (PFS) rate was 87% (95% confidence interval,78-95) from the start of bortezomib-based induction and 82% (95% confidence interval,70-94) from the start of ixazomib-based treatment(Figure 1A), 79% patients remain on therapy at data cutoff. After bortezomib-based induction, overall response(ORR) rate was 100% (strict complete response [sCR], 10/96, 10%; complete response [CR], 31/96, 32%; very good partial response [VGPR], 24/96, 26%; partial response [PR], 31/96, 32%) and 88% (sCR 22/96, 23%; CR, 28/96, 29%; VGPR, 16/96, 17%; PR, 18/96, 19%) at data cutoff. There were 3 PR improved to VGPR, 4 VGPR improved to CR, 1 PR, 4 VGPR and 5 CR improved to sCR (Figure 1B). ORR of HR patients were 100% and 85%(23/27), 1 PR improved to VGPR, 1PR improved to CR, 4CR improved to sCR; ORR of SR patients were 100% and 85% (45/51), 2PR improved to VGPR, 5VGPR improved to CR, 4VGPR and 3CR improved to sCR, before and after ixazomib-based regimen, respectively. Among 66 patients who transited to IRD1/ITD1/ICD1 regimen, medium duration of total PI therapy was 11.0 months and of ixazomib-based regimen was 5.4 months, 77% patients remain on therapy. ORR rate was 100% (sCR, 7/66, 11%; CR, 16/66, 24 %; VGPR, 16/66, 24%; PR, 27/66, 41%) and 91% (sCR 15/66, 23%; CR, 18/66, 27%; VGPR, 9/66, 14%; PR, 18/66, 27%) at data cutoff, 3 PR improved to VGPR, 4PR and 6 VGPR improved to CR, 4 VGPR and 3 CR improved to sCR. ORR of HR (23/52) patients were 100% and 96%, ORR of SR patients (29/52)were 100% and 86% before and after ixazomib-based regimen, respectively. The ixazomib-safety profile was consistent with previous clinical trial data. In our study, 59% (57/96) of patients had any grade adverse events AE. In which, the most frequent grade <=2 AEs were peripheral neuropathy(PN) (31%, 31/96, PN of 23 patients began after bortezomib-based induction), nausea and vomiting (33%), diarrhea (5%), constipation (4%), incomplete intestinal obstruction (3%), fatigue (2%), edema (1%), abdominal distension (1%) , anorexia (1%), rash(1%) , weakness of lower limbs (1%). The most frequent grade 3/4 AEs were agranulocytosis (2%) , rash (2%), PN (2%, occurred after bortezomib-based induction). Treatment discontinued of ixazomib-based regimen are PN (6/96), incomplete intestinal obstruction (1/96), agranulocytosis (1/96), rash (2/96). Conclusion In real-world China MM population, NDMM patients are sensitive to PI-based continuous therapy with satisfied response rate; iCT can permit prolonged PI-based therapy with promising efficacy and tolerated adverse events. Note: VD1, VRD1, VTD1, VCD1, PAD1, PD2D1, IRD1, ITD1, ICD1 : I: ixazomib, R: lenalidomide, T: thalidomide, C: cyclophosphamide, V: bortezomib, D1: dexamethasone P: bortezomib, A: adriamycin D2: liposome doxorubicin Disclosures No relevant conflicts of interest to declare.

VRd Versus KRd Safety Profiles in Newly Diagnosed Multiple Myeloma Patients Using Real-World Evidence Data from a Single Institution: VRd Has High Rates of Chronic Neuropathy, and KRd Has Low Rates of Cardiopulmonary or Renal Toxicities When Using Optimized IV Fluid Management Coupled with Baseline Cardiac Workup

VRd Versus KRd Safety Profiles in Newly Diagnosed Multiple Myeloma Patients Using Real-World Evidence Data from a Single Institution: VRd Has High Rates of Chronic Neuropathy, and KRd Has Low Rates of Cardiopulmonary or Renal Toxicities When Using Optimized IV Fluid Management Coupled with Baseline Cardiac Workup

Identifying the Genomic Profile of Functional High-Risk Multiple Myeloma Patients

Background: Multiple myeloma (MM) patients with suboptimal response to induction therapy or early relapse, classified as the functional high-risk (FHR) patients, have been shown to have poor outcomes. However, the current risk stratification at diagnosis has not been able to accurately identify these patients. In clinical practice, we saw patients who were not identified as being high-risk at diagnosis having refractory disease or early relapse. The aim of our study is to evaluate the genomic profile of FHR MM patients at diagnosis. Method: We evaluated newly-diagnosed MM patients in the CoMMpass dataset and divided them into 3 groups: genomic high-risk (GHR) group for patients with t(4;14) or t(14;16) or del17p13 and TP53 mutation or 1q gain and International Staging System (ISS) stage 3; FHR group for patients who were refractory to induction therapy or had early relapse within 12 months and without the markers of GHR group; and standard-risk (SR) group for patients who did not fulfil both criteria. We evaluated the genomic profile based on the differentially expressed genes (DEG), copy number aberrations (CNA), mutational signatures (MS), and gene set enrichment analysis (GSEA). Results: Of 512 evaluable patients, there were 345 patients in the SR group, 106 patients in the GHR group, and 61 patients in the FHR group. On the survival analysis, both FHR and GHR groups had significantly poorer outcomes as compared with the SR group, with FHR group being the worst (FHR: HR=5.19, p=3.42x10-11;GHR: HR=3.55, p=3.5x10-8) (Fig A) The DEGs in FHR and GHR groups were distinct. FHR patients were enriched for genes linked to centromeres, mitosis, DNA repair, C2H2-type zinc finger proteins, and proteasome complex. On the other hand, GHR patients were enriched for genes linked to ribosomal proteins, immunoglobulin proteins, and cell-cell junctions. As FHR patients could not be identified at diagnosis by clinical and genetic parameters, we applied established gene expression signatures of high-risk disease, including proliferation (PI), chromosomal instability (CIN70, CINSARC, CINGEC), centrosome (CI), cell death (HZDCD), and others (EMC92, HMCL7, IFM15, UAMS70, and UAMS80), to see if they could be used. Interestingly, none of these could identify all FHR patients. The best amongst these signatures was able to identify one-third of these patients. Indeed, about one-third of patients were not classified as high-risk by any of these signatures (Fig B). We next explored the use of machine learning methods on the 453 DEGs to identify a predictive model for the FHR group. Our predictive model based on random forest technique resulted in 19 significant genes with accuracy of 0.88, specificity of 0.94, sensitivity of 0.47, AUC - ROC of 0.70, F1 score of 0.48, and Matthews correlation coefficient of 0.42 (Fig C). In terms of CNA, FHR group was predominantly hyperdiploid. On the other hand, GHR group was mostly non-hyperdiploid with fewer gains of odd-numbered chromosomes, more pronounced 13q deletion, and increased 1q gain, as compared with FHR (p=1.45×10-10) and SR groups (p<2.2×10-16). Mutation analysis revealed that IL6-JAK-STAT3 pathway had more mutated genes per patient in FHR group, while estrogen response, KRAS, and WNT β catenin signaling pathways had more mutated genes per patient in GHR group. GHR also had higher mutational load (p=0.00331), and FGFR3 (p=1.63×10-11), PRKD2 (p=2.82×10-7), and TP53 (p=8.7×10-6) were predominantly mutated in GHR group as compared with others. MS analysis using SigProfiler with Catalogue Of Somatic Mutations in Cancer (COSMIC) reference catalogue (version 3.1) showed that as compared with SR group, FHR group had increased activity in the defective homologous recombination-based DNA damage repair signature (SBS3), while GHR group had increased activity in the AID/APOBEC family of cytidine deaminase signatures (SBS2, SBS13). Interestingly, GSEA showed enrichment in cell cycle related gene sets (G2M, E2F) in FHR group and estrogen response gene sets in GHR group (Fig D). Conclusion: Identifying FHR MM patients at diagnosis represents an unmet clinical need and in this study, we report preliminary results in developing a high-specificity classifier. Our study also shows that FHR patients have specific MS and deregulate genes in unique pathways and biological processes as compared with GHR patients. This may provide insights into the biology and potential therapeutics of this group. Figure 1 Disclosures Chng: Amgen: Honoraria, Research Funding; Janssen: Honoraria, Research Funding; Celgene: Honoraria, Research Funding; Novartis: Honoraria; Abbvie: Honoraria.

Minimal Residual Disease in Autografts and Bone Marrow of Patients with Multiple Myeloma: 8-Color Multiparameter Flow Cytometry (EuroFlow-NGF) Vs. Next-Generation Sequencing

Background: Autologous stem cell transplantation (ASCT) in conjunction with novel therapeutic drugs can dramatically improve response rates and the prognoses of patients with multiple myeloma (MM). However, most patients with MM ultimately relapse due to minimal residual disease (MRD). Next-generation multiparameter flow cytometry (MFC) (EuroFlow-NGF) and next-generation sequencing (NGS) are currently the standard methods to assess MRD. Aims: To compare the prognostic value of MRD detection in autografts and bone marrow (BM) cells using 8-color MFC (EuroFlow-NGF) and NGS (Adaptive Biotechnologies), and also MRD levels between fresh and cryopreserved autografts using NGF. Methods: The study enrolled 52 newly-diagnosed MM patients who underwent ASCT. The median age ASCT was 61 (range 41-69) years and included 29 males and 23 females at ISS I (n = 17), II (n = 23), and III (n = 12). Of these, 18 patients harbored high-risk chromosomal abnormalities including t(4;14) (n = 15), del17p and t(4;14) (n = 2), and complex (n = 1). Bortezomib-based chemotherapy was used for induction together with melphalan at 140 mg/m2 (n = 1) and 200 mg/m2 (n = 51) for conditioning before ASCT. 39 of 52 (75%) patients received maintenance therapy until progressive disease. The best responses achieved post-ASCT included 30 sCR, 4 CR, 15 VGPR, and 3 PR. Forty autografts, one from each MM patient, were analyzed using NGF and NGS protocols, and BM cells at pre/post-ASCT and autografts derived from 16 patients were analyzed using NGS. The EuroFlow-NGF method uses standard sample preparation; large numbers of cells are evaluated using an optimized 8-color antibody panel that facilitates accurate identification of discrimination between phenotypically aberrant plasma cells (aPCs) and their normal counterparts (Flores-Montero et al., Leukemia 2017). NGS-based MRD assessment was performed using Adaptive's standardized NGS-MRD Assay (Seattle, WA) (Martinez-Lopez et al., Blood 2014). Eight additional autografts were used to assess MRD in both fresh and cryopreserved samples by NGF. Results: MRD was evaluated in 48 of 52 autografts (92%) using NGF and in 44 of 52 autografts (85%) using NGS. We identified aPCs in autografts based on multivariate analysis of individual cell populations (e.g., CD56+, CD19−, CyIgκ+, and CD117+). As the results of NGF revealed a strong correlation with respect to MRD in fresh vs. thawed autografts (r = 0.999, P < 0.0001), MRD was subsequently evaluated in thawed autografts. The sensitivity of NGF was 1 × 10−5-2 × 10−6; the sensitivity of NGS was 1 × 10−6. 28 of 48 (58%) of the autografts were MRD-positive by NGF; 30 of 44 (68%) of the autografts were MRD-positive by NGS. MRD levels in autografts using NGF and NGS correlated with one another (r = 0.69, P < 0.0001; Fig. 1A). MRD negative in autografts by NGF cases (MRDNGF (-)) and MRDNGS (-) tended to show better progression-free survival (PFS) than MRDNGF (+) (P = 0.195) and MRDNGS (+) (P = 0.156), respectively. Furthermore, MRDNGS (-) showed significantly better overall survival (OS) than MRDNGS (+) (P = 0.03) (Fig. 1C) while MRDNGF (-) showed better OS than MRDNGF (+) (P = 0.09) (Fig. 1B). Our data revealed only a minimal correlation between MRD in the autografts (median 1.1 × 10−5,range 0-7.29 × 10−4) and in the BM cells at pre-ASCT (median 5.05 × 10−3,range 6 × 10−6-2.64 × 10−1; r = 0.09, P = 0.7) or at post-ASCT (median 2.11 × 10−4,range 0-9.09 × 10−3; r = 0.14, P = 0.6); MRD detected in the autografts was > 27 times lower than that detected in pre-ASCT BM cells, and MRD detected in the post-ASCT BM cells was > 3 times lower than that detected in pre-ASCT BM cells except for one case in which the ratio was increased by two times. Interestingly, while MRD was detected in all BM cells at pre-ASCT (n = 16), 4 of 16 (25%) of these autografts were MRDNGS-negative. The median of MRD levels of the 4 cases in pre-ASCT and post-ASCT BM cells were 4.14 × 10−4 (range 6-583 × 10−6)and 1.8 × 10−5 (range 0-27 × 10−6), respectively. Conclusion: Although EuroFlow-NGF is a rapid and accurate method for detecting MRD, NGS was more sensitive and provided greater prognostic value than EuroFlow-NGF. Disclosures Takamatsu: Adaptive Biotechnologies: Honoraria; Bristol-Myers Squibb: Honoraria, Research Funding; Janssen Pharmaceutical: Consultancy, Honoraria, Research Funding; Ono pharmaceutical: Honoraria, Research Funding; SRL: Consultancy, Research Funding. Takezako:Bristol-Myers Squibb: Honoraria, Research Funding; Takeda: Honoraria, Research Funding; Janssen: Research Funding; Abbvie: Research Funding. Nakao:Symbio: Consultancy; Kyowa Kirin: Honoraria; Alexion: Research Funding; Novartis: Honoraria.

Real-World Use of Maintenance Therapy and Associated Outcomes Following Autologous Stem Cell Transplant in US Patients with Newly Diagnosed Multiple Myeloma

Background: In patients with newly-diagnosed multiple myeloma (NDMM) who receive frontline autologous stem cell transplantation (ASCT), maintenance therapy (MT) following ASCT has been shown to delay disease progression and death. Current National Comprehensive Cancer Network (NCCN) guidelines also recommend MT for patients with MM, including the use of lenalidomide, bortezomib-based regimens, or ixazomib. However, there is limited evidence on the use and outcomes associated with MT in contemporary real-world patients. The present study assessed MT treatment patterns and clinical outcomes in a real-world US cohort of patients with NDMM following ASCT. Methods: This retrospective, observational cohort study included NDMM patients initially diagnosed from 2011-2018 who received frontline ASCT. Patients were selected from the US Flatiron Health (FH) deidentified electronic health record (EHR)-derived database, which includes longitudinal patient-level data from over 265 community-based and academic cancer clinics across the US. To ensure capture of post-ASCT consolidation and MT, the study sample was restricted to patients who resumed contact within the FH network within 60 days following ASCT. Patients were excluded if they received treatment within the context of a clinical trial or had a second transplant within 180 days of their initial ASCT. Patients were classified as receiving MT if (during the 180-day post-transplant period) they initiated treatment with an NCCN-recommended MT regimen or continued to receive a subset of the antimyeloma agents used as induction regimen following ASCT and consolidation (if any). Key measures included baseline demographic and clinical characteristics, antimyeloma treatments (frontline induction, consolidation, and MT, if any), and clinical outcomes (time to next myeloma treatment [TTNT] and overall survival [OS]). Treatment duration and clinical outcomes were analyzed using Kaplan-Meier estimators and Cox regression to account for right-censoring. For TTNT and OS, follow-up began on the earlier of the ASCT date + 90 days or start of MT and continued through the dataset cut-off date (May 30, 2020) or loss to follow-up; TTNT and OS were estimated for patients receiving lenalidomide maintenance [R-MT], bortezomib maintenance [V-MT], or no MT, but was not estimated for other MT regimens due to sample size considerations. Results: 528 NDMM patients (median age 61 years, interquartile range [IQR]: 55, 68; 45.3% female) underwent ASCT and met study inclusion criteria. The most common induction regimens were bortezomib-lenalidomide-dexamethasone (VRd; 60.0%), lenalidomide-dexamethasone (Rd; 16.3%), and cyclophosphamide-bortezomib-dexamethasone (CyBorD; 10.2%). Following ASCT, 7.2% of patients received consolidation therapy and 74.2% received MT (lenalidomide monotherapy [R-MT]: 58.7%; bortezomib monotherapy [V-MT]: 7.6%; other MT: 7.8%). Median duration of MT was 18.0 months (IQR: 8.7, 29.1), and was similar for R-MT and V-MT (median 18.9 and 18.6 months, respectively). MT use increased from 69.3% to 79.0% from 2011-2013 to 2017-2018 (P=0.04); in addition, patients were more likely to have received VRd as induction across different MT (Table 1). R-MT and V-MT were both associated with longer TTNT relative to no MT (unadjusted hazard ratios [HRs]: 0.29 [95% CI: 0.22, 0.38] and 0.39 [95% CI: 0.25, 0.61], respectively) (Figure 1A). Improvements in OS were marginally significant with R-MT (HR: 0.58 [95% CI: 0.33, 1.00]) and nonsignificant with V-MT (HR: 0.86 [95% CI: 0.35, 2.11]) relative to no MT (Figure 1B); however, the OS estimates are characterized by low precision due to the relatively small number of events observed. Limitations included lack of documentation of reasons for treatment in the FH database, and use of consolidation and MT were inferred from observed treatment patterns; therefore, misclassification of MT was possible. Conclusions: This analysis demonstrates that MT use following ASCT has increased in routine clinical practice in the US since 2011-2013, with R-MT being the most common regimen followed by V-MT. However, a substantial proportion of patients did not receive MT. MT use in real-world settings was associated with longer TTNT and a trend toward longer OS. Exploration of additional maintenance regimens to improve clinical outcomes is warranted in this patient population. Disclosures Ammann: Janssen Scientific Affairs: Current Employment, Current equity holder in publicly-traded company. Lam:Janssen: Current Employment. Tang:Janssen: Current Employment. Kampfenkel:Janssen: Current Employment. Sharma:Mu Sigma: Current Employment; Janssen: Other: Contractor. Lee:Janssen: Current Employment. Kaila:Janssen Scientific Affairs: Current Employment. Fu:Janssen: Current Employment. Gray:Janssen: Current Employment. He:Janssen: Current Employment.

Assessment of 1112 Newly Diagnosed Multiple Myeloma Patients According to Age and Year of Diagnosis at a Referral Cancer Center

Background Multiple Myeloma is the second more frequent hematological malignancy with a median age at diagnosis of 65 years old. However, this data is mainly of European countries and the United State of America. (1) The age is an important variable because the vast majority of cancer center use 65-70 years old as the cutoff for autologous transplantation. Two third of patients are considered not eligible for autologous transplant. The percentage of patients diagnosed at young age (<40 years) is relatively rare (2,2%)(1, 2) and even more rare is before 30 years (0.3%)(3). It is not available solid information of Latin American MM patients. The objective of this study was to determine the age at diagnosis according to the last 19 years. Also, to define the percentage of MM patients in a 5-year interval range of age. Methods We reviewed the database of the Department of Epidemiology at the National Institute of Neoplastic Diseases from 2000 to 2018 in Lima, Peru. We included all patients with Multiple Myeloma. Stratification was made based of age group, year of diagnosis and eligibility for hematopoietic stem cell transplant. Tables of relative and accumulative frequency were made. Results We found 1112 patients with newly diagnosed MM (NDMM), with a median age of 61 years and an average of 60.2 years. Male patients were 59% for the entire cohort. Patients under 40 years of age represented 4.6% (51), of which 72% (37) were male. Those under 30 years old were 0.9% (10%) of all cases of which 90% were male. Patients eligible for transplant were 63% in total, with a median age of 55 years, and the non-eligible group had a median age of 71 years. The median age for each year from 2000 to 2018 was 61 with a range of 56 to 65 years old (peak in 2010) with an oscillating trend, however with a slight downward slope. The median age from 2000 to 2008 was 61 and from 2009 to 2018 was 60 years. The most frequent affect group was 60 to 64 years (16.5%), nevertheless, in the last 10 years the age group of 55-59 was the most affected 16.05% vs 15.34%, respectively. Conclusion: Our study shows that NDMM patients in Peru have a lower median age compared to European or American countries with a tendency to have younger MM patients. In addition to having a higher percentage (4.6% vs 2%) of patients under 40 years old and 30 years old (0.9% vs 0.3%). This significantly younger population and specially those under 40 years of age deserve a comprehensive evaluation to determine if this impact their prognosis and survival.

TAK-169, a Novel Recombinant Immunotoxin Specific for CD38, Induces Powerful Preclinical Activity Against Patient-Derived Multiple Myeloma Cells

Monoclonal antibodies (daratumumab, anti-CD38; elotuzumab, anti-SLAMF7) and BCMA-targeting T-cell redirecting therapies are highly effective in a large proportion of multiple myeloma (MM) patients. Nonetheless, age, prior (chemo)therapy, and the tumor-microenvironment may impair immune effector cell function and therefore significantly reduce the efficacy of these immunotherapies. Alternatively, an appealing strategy would be the use of targeted therapies, such as immunoconjugates, that directly kill the tumor cells. TAK-169, a novel CD38-specific immunotoxin armed with a deimmunized (DI) Shiga-like toxin A subunit (SLTA) payload, has been designed with this idea. TAK-169 induces irreversible ribosome inactivation of target cells with no dependency on immune effector cells. Prior studies showed that TAK-169 exerts potent cytotoxic activity against CD38-positive human MM cell lines in vitro and in xenograft mouse models (Willert et al. AACR 2019 Abstract 2384). Also, TAK-169 was well tolerated in mice and non-human primates (Willert et al. AACR 2019 Abstract 2384), and deimmunizing the SLTA molecule significantly reduced the in vivo immunogenicity of the payload (Willert et al. AACR 2015 Abstract 2477; Rajagopalan et al. AACR 2016 Abstract 595; Robinson et al. AACR 2017 Abstract 2695). We now assessed the preclinical activity of TAK-169 on a large panel of primary MM cells present in bone marrow (BM) samples from newly diagnosed (ND) (n=13), daratumumab-naive relapsed/refractory (RR) (n=11), and daratumumab-refractory (DR) RR (n=12) patients in flow cytometry-based cytotoxicity assays. In these samples, we also tested the impact of TAK-169 on non-malignant CD38-expressing hematopoietic cells, to gain insight into its on-target off-tumor effects. TAK-169 effectively lysed MM cells present in 36/36 BM samples in a dose-dependent fashion (Figure 1A; median maximal lysis 89%; range 45-100%; EC50: 36pM). Of note, MM cells from ND and daratumumab-naïve RR patients were equally sensitive to TAK-169-mediated lysis (Figure 1B and 1C; median maximal lysis 90%; range 76-100% vs. median maximal lysis 91%; range 76-98%). While MM cells from DR RR patients were also effectively killed, a fraction of these samples was less sensitive to TAK-169-mediated lysis (Figure 1B and 1C; median maximal lysis 66%, range 45-99%). We are currently exploring the impact of several patient and tumor characteristics, such as previous therapies and surface CD38 expression levels on MM cells, on the cytotoxic activity of TAK-169, and results will be reported. In the BM samples, the cytotoxic activity of TAK-169 was mainly restricted to MM cells - except for limited lysis of NK cells (median maximal lysis: 18%) and monocytes (median maximal lysis: 21%), no other non-malignant hematopoietic cells were lysed (Figure 1D), indicating a favorable therapeutic window generated by targeting CD38 with TAK-169. In conclusion, we show that TAK-169 induces powerful lysis of primary MM cells from both ND and RR MM patients, including those refractory to daratumumab. Our findings support the ongoing phase 1 clinical trial evaluating TAK-169 monotherapy in heavily pretreated MM (NCT04017130), and encourage preclinical evaluation of TAK-169 in other CD38-positive malignancies such as AML and T-ALL. Disclosures Higgins: Molecular Templates, Inc.: Current Employment, Other: Stockholder. Willert:Molecular Templates, Inc.: Current Employment, Other: Stockholder. Newcomb:Takeda Pharmaceuticals International: Current Employment, Other: Stockholder. Dash:Millennium Pharmaceuticals, Inc., a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Current Employment, Other: Stockholder. Van De Donk:BMS: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Membership on an entity's Board of Directors or advisory committees; Roche: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Bayer: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; AMGEN: Membership on an entity's Board of Directors or advisory committees, Research Funding; Servier: Membership on an entity's Board of Directors or advisory committees. Zweegman:Takeda: Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding. Mutis:Gadeta: Research Funding; Onkimmune: Research Funding; Takeda: Research Funding; Janssen Pharmaceuticals: Research Funding; Genmab: Research Funding.