ALBERT

Description: Introduction- High dose chemotherapy followed by autologous hematopoietic stem cell transplantation (ASCT) remains the standard treatment for multiple myeloma (MM) for eligible patients. While ASCT in most centers is performed on an inpatient basis, we and others have shown its feasibility in an outpatient setting. Due to improved supportive care, enhanced patient and caregiver education and preference, the majority of MM patients at our center will initiate outpatient ASCT. However, a part of these patients will require hospital admission pre-emptively due to co-morbid conditions or related to therapy-associated toxicity. To elucidate clinical characteristics and markers predicting for hospital admission in an ambulatory setting, we investigated a total of 1446 MM patients receiving ASCT at UAMS from 2015-2019. Methods- Of the 1446 MM patients, 550 initiated their ASCT as inpatients, 280 started as outpatients but required subsequent hospital admission and 616 completed ASCT in an ambulatory setting. The decision to initiate ASCT as in- or outpatient was based on clinical and social factors. In most cases, Pptients received high dose Melphalan conditioning (74%) followed by dose-reduced Melphalan in combination with Cisplatin, Adriamycin, Cyclophosphamide and Etoposide (PACE, 15%) and BEAM conditioning (9.2%). For comparison between the transplant groups, we used analysis of variance (for continuous-like variables) and Pearson's chi-squared test (for categorical variables). Multivariable logistic regression model was used to examine the combined effects of various clinical variables on the probability of hospitalization after receiving an outpatient autologous transplant. Results- 62% (896/1446) of all patients initiated ASCT on an outpatient basis. Of those, 31% (280/896) required hospital admission within 15 days post-transplant. Main reasons for hospital admission were neutropenic fever (45%), intractable nausea/diarrhea/poor oral intake (29%, n=81/280) followed by more uncommon events such as cardiac problems (6%) and MM related pain (4%, n=12/280) and 16% other reasons (45/280). Median day of admission was D+7 after ASCT (range: D+1 to D+15) with a median length of stay of 8 days (range: 2-49 days). Median age of patients who completed outpatient ASCT (60.4 years) was significantly lower (p

Description: Introduction Novel agents are incorporated into a backbone of multi-agent chemotherapy and tandem transplantation in successive Total Therapy (TT) protocols for multiple myeloma (MM) patients. The TT protocols extend the duration of remission with a significant proportion of patients achieving long-term disease control. However, a small percentage of patients have documented late relapse and we theorize that these relapses are indolent with overall good clinical outcome. While even a late relapse is seemingly an undesirable outcome, defining the clinical implications is imperative to understanding the impact on long-term prognosis and management. Methods Our MM database was interrogated to identify patients that presented with relapsing disease ≥ 10 years from diagnosis and were treated on TT protocols. All patients had myeloma markers every 2 to 3 months and bone marrows with either PET-CT or MRI at least once a year. In the group of patients with documented relapse, we obtained the pattern of relapse, clinical and laboratory markers, cytogenetics, FISH, gene expression profile (GEP), bone marrow (BM) minimal residual disease (MRD), imaging (PET-CT and MRI, use of salvage transplant, and response assessment including best response to treatment. Patterns of relapses were evaluated based on elevated serum myeloma markers, BM plasmacytosis and presence of macrofocal relapse/extramedullary disease. Clinical relapses were classified based on the International Myeloma Working Group criteria. Indolent relapse was defined as a biochemical relapse with a rising M-protein or free light chains, less than 30% bone marrow plasmacytosis involvement, absence of focal lesion on imaging and of CRAB criteria, low riskGEP70 signature at relapse or no abnormal metaphase cytogenetics. Results A total of 2055 patients were enrolled and treated on successive TT protocols (TT1 to TT7) of which 658 patients had ≥10 years follow up from initial study enrollment. Among these 658 patients, 8% (53/658) had a clinical relapse ≥ 10 years from diagnosis. The median time to clinical relapse was 11. 8 years (range, 9.8 - 17.6). Median age at the time of relapse was 67.7 years with 28% being females. Gene expression profiling showed that 45% (24/53) belonged to the molecular CD2 and LB subgroups. The most common pattern of relapse is with BM plasmacytosis in 49% (26/53) with 36% (19/53) presenting with CRAB clinical features. Focal lesions by MRI and/or CT-PET were present in 35.8% (19/53). Overall, 56.6% (30/53) of patients had indolent relapses; of these 9 and 7 belonged to the CD2 and LB molecular subgroups, respectively. BM MRD assessment by 8-color flow cytometry was available in 17 patients and MRD positivity preceded clinical relapse by a median 17.9 months (range: 0 - 60.8). Forty-one patients required treatment for disease relapse with 11 patients managed expectantly without treatment. While most patients (73.1%, 30/41) received initial treatment with either PI/IMiD/PI IMiD combinations, 8 patients later underwent salvage ASCT. A response of ≥ VGPR was attained in 70% (31/47) of the treated patients with the large majority (87%) achieving a sCR/CR. The overall survival from relapse at 5 years was 73.3% (95% CI: 55.0% to 85.1%). A total of 14/53 patients died during follow-up;7 patients died to progressive disease; 6 of these 7 presented with focal lesions detected on imaging and had an aggressive relapse. Three patients died to treatment related complications, 1 had an unrelated pneumonia, the cause of death was indeterminate in 2 and unknown in 1. Overall, in these 14 patients, median time to death from initial diagnosis was 15.4 years (range: 11.8 - 18.0) and a median time to death from relapse was 3.2 years (range: 0.3 - 6.0). Conclusions Late relapses (〉10 years) in MM are a rare event occurring in 8% of long-term survivors and accounting for 2.6% of all patients treated on the TT protocols. Intriguingly, most patients with late relapsing MM belong to the GEP subtype LB and CD2 and accounted for 51% of the indolent relapses. These findings have clinical implications and emphasizes the importance of extended and close follow-up even in patients with prolonged clinical remission. Disclosures van Rhee: Karyopharm: Consultancy; Adaptive Biotech: Consultancy; Takeda: Consultancy; EUSA: Consultancy; CDCN: Consultancy.

Description: Bone destruction is a major complication of multiple myeloma (MM). Healthy bone is constantly remodeled through bone resorption by osteoclasts and bone formation by osteoblasts. New bone formation in MM is virtually non-existent, because differentiation of osteoblasts is inhibited by DKK1, a Wnt-β-catenin signaling inhibitor secreted by MM cells, reported by our group in NEJM, 2003. MM in its early stages is totally dependent on its microenvironment and for the hyperdiploid type MM this dependence is perpetual. Based on concordant gene expression signatures, predominantly driven by recurrent translocations and hyperdiploidy, we have classified MM into 7 distinct molecular entities. One subgroup, with significantly less bone disease and superior event-free and overall survival following high-dose therapy and stem cell transplantation than the other subgroups, defined as the Low Bone (LB) disease subgroup. Consistent with the LB phenotype, we have observed a strong inverse correlation between DKK1 and CST6 expression and by analyzing gene expression profiling (GEP) and RNA-sequencing data of more than 1,000 myeloma patients, we identified CST6 as the most upregulated gene in the LB subgroup. The aim of the present study was to determine the role of Cystatin E/M (CST6) in MM biology and to apply this knowledge to prevent both bone disease and MM cell growth. CST6, a 14-17 kD secretory protein, is a lysosomal protease inhibitor and suggested tumor suppressor gene. We showed that overexpression of CST6 in human MM cell lines prevents MM cell growth in vitro and in vivo. Also, purified CST6 protein from conditioned media of CST6-overexpressing MM cells significantly inhibits MM cell growth (p

Description: Background Iron is an essential element for cell growth, including cancer cells, and is present in the microenvironment. We have shown that multiple myeloma (MM) cells have abnormal iron metabolism and harbor increased intracellular iron. However, the mechanism by which MM cells retain iron has remained largely elusive. Methods Expression and clinical relevance of the transferrin receptor in MM samples were analyzed in publicly available microarray and RNA-sequencing databases. Macrophages were isolated from C57BL/6J mice and were induced to specific subtypes by cytokines or culturing with MM cells. The 5TGM1-KaLwRij MM mice were used to confirm whether MM cells induce macrophage polarization in vivo. Specific subtypes of macrophage and transferrin receptor expression in MM cells were assessed by flow cytometry. Expression of ferroportin (FPN1) and ferritin in MM cells and/or macrophages were analyzed by Western blots. Single-cell RNA-sequencing (scRNA-seq), RNA-seq, and gene expression profiles (GEPs) were employed to identify ferroportin-signaling pathways in both tumor cells and macrophages of primary human MM samples. Results MM cells induced polarization with a significant increase of CD38+CD206- M1 macrophages both in vitro and in vivo. We also confirmed that the tumor associated macrophages (TAMs) were increased in the 5TGM1-KaLwRij MM mice. MM cells upregulated ferroportin expression in macrophages to provide iron to MM cells in co-culture studies and in vivo models. The transferrin receptor antibody treatment prevented MM cells from taking up iron from macrophages. scRNA-seq identified a subset of FPN1+ TAMs in human bone marrow aspirates, which are assumed to provide iron to MM cells. Using RNA-seq and GEPs analyses in primary human samples, multiple signaling pathways were differentially modulated in FPN1+ versus FPN1- TAMs, including those related to inflammation and apoptosis Conclusions Increased expression of the transferrin receptor in MM cells strongly suggests that tumor cells take up iron from its environment. MM cells promote intracellular iron mobilization in macrophages, which provide iron to MM cells in a transferrin-dependent manner. Blockade of iron trafficking between MM cells and macrophages might be a promising approach to MM therapy. Disclosures van Rhee: EUSA: Consultancy; CDCN: Consultancy; Karyopharm: Consultancy; Adaptive Biotech: Consultancy; Takeda: Consultancy.

Description: Introduction - Despite improvement in Multiple Myeloma (MM) therapy, most patients will eventually experience disease relapse. The course of relapsed MM can be quite heterogeneous with some patients achieving long-term disease control while others experience rapid successive relapses with short survival. Other than genetic features, there is currently a lack of prognostic markers to guide intensity and duration of therapy in relapsed MM. In the present study, we elucidate the prognostic value of minimal residual disease (MRD) and focal lesion assessment by PET-CT in relapsed patients. Methods- We investigated 120 MM patients that were diagnosed between 2000-2016 and treated on our Total Therapy (TT) 2-6 protocols, which incorporated multi-agent chemotherapy and tandem transplantation. All 120 patients had achieved a complete remission (CR) after TT and relapsed subsequently after a median of 5 years (0.9-18). Focal lesions were assessed with PET-CT in 112 patients at diagnosis and relapse. Other features investigated included gene expression analysis (GEP) defined by the UAMS GEP70 at diagnosis and relapse (n=75) and FISH at diagnosis (n=84). Once treatment for relapsed disease was initiated, response to therapy, including sequential measurement of MRD by conventional 8 color flow cytometry with a sensitivity of 10-5 was assessed at least every 6-12 months. MM therapy after progression was directed by the treating physician and consisted mostly of combination therapy of a Proteasome Inhibitor with an IMiD and Dexamethasone (62%) or a Daratumumab combination (25%) or other (13%). Results- Median age at first progression was 65 years and median follow up time was post-relapse was 19 months (range 2.2-65 months). High risk FISH features, including deletion 17p, 1q amplification, t(4;14) and t(14;16) were present in 29% (25/84) of the patients, but were limited in predicting worse PFS post-relapse (p=0.3) and OS (p= 0.5); 75 patients had GEP performed at diagnosis and relapse showing a significant increase (p