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Background: Hematopoietic stem cell transplant (SCT) is a high-intensity treatment that can cause psychological distress. Pre-transplant psychosocial screening is commonly used to assess mental health, social support, compliance, and health behaviors in HCT centers. However, the optimal standardized approach to psychosocial screening is still being defined. Some studies have shown that pre-transplant psychosocial assessments can predict overall survival (OS) after SCT, while others have found associations with non-relapse mortality (NRM) but not with OS. Single-institution reports consistently indicate that pre-HCT psychosocial assessments are associated with the length of SCT hospitalization and readmission rate.

Background:Multiple myeloma (MM) remains a highly treatable but generally incurable plasma cell dyscrasia. These plasma cells synthesize massive amounts of paraprotein relying heavily on the ubiquitin proteasome system to maintain homeostasis and are exquisitely sensitive to proteasome inhibition to avoid terminal ER stress. We postulated that increased expression of clinically relevant proteasome subunits would correlate with reduced overall survival in MM patients treated with proteasome inhibitors.

Evasion of immune destruction is a hallmark of cancer that thwarts the efficacy of immunotherapy and reduces patient benefit. The development of immunotherapies has sparked a revolution in oncology by releasing the power of the human immune system, but the identity of novel, actionable antigens exclusively presented on cancer cells remains elusive. Proteasomes are multi-subunit proteolytic complexes that selectively degrade intracellular proteins. Proteasomes play a critical in controlling myriad cellular processes including metabolism, cell cycle progression, signal transduction, protein quality control and differentiation. Importantly, proteasomes are also the source of most antigenic peptides presented to the immune system on major histocompatibility complex (MHC)-class I molecules. In this process, intracellular and viral proteins are degraded in the cytosol to 8 and 9-amino acid peptides, which are then transported into the endoplasmic reticulum, where they associate with MHC-class I molecules and are presented to the cell surface. Immune cells contain a highly specialized, cytokine-inducible proteasome variant, known as the immunoproteasome, in which the three constitutive catalytic subunits are replaced by homologous catalytic subunits. Immunoproteasomes are specially adapted for a role in MHC class I antigen processing and presentation to CD8 +T-cells. Here, we performed a high-through screen (HTS) to detect novel molecular entities that activated immuno-proteasomal catalytic activity. We identified a curated panel of molecules which not only enhanced hydrolysis of the cell-permeable substrate LLVY-R110 but also enhanced the presentation of MHC class I antigens. E.G7-Ova is a mouse lymphoma cell line derived by electroporation of EL4 cells (C57BL/6, H-2b, T lymphoma) with chicken ovalbumin ( OVA) cDNA. Proteasomes degrade OVA to generate the peptide SIINFEKL that is presented by murine MHC-class I H-2Kb molecules. E.G7-Ova cells were pretreated with compound A and co-cultured with the T-cell hybridoma B3Z that had been genetically-engineered to express a SIINFEKL-restricted t-cell receptor (TCR). Pretreatment of E.G7-Ova cells with compound A significantly increased tumor cell lysis by B3Z cells. The treatment of multiple myeloma (MM) cells with compound A also dramatically enhanced the expression of pan-MHC class I antigens. Treatment of MM cells with compound A increased the intracellular level of the proteasome activator PA28α/β, which is expressed by PSME1/2. Compound A treatment also enhanced hydrolysis of the fluorogenic peptide substrate Ac-ANW-AMC, which is selectively cleaved by the immunoproteasome β5-associated catalytic activity. Treatment of MM cells with compound A followed by mass spectrometry (MS) revealed that immunoproteasome activation modulated the relative presentation of individual antigenic peptides bound to MHC class I molecules. Pre-treatment of MM cells with compound A also significantly enhanced the anti-myeloma activity of human cytotoxic T-cells. Taken together, our results demonstrate that immunoproteasome activation has the potential to overcome immune escape and promote host immunity. In addition, our model systems now allows us to identify actionable tumor antigens on patient tumor cells as an indispensable tool for the development of cancer immunotherapies, e.g., T cell receptor (TCR)-transduced T-cells and patient-specific mRNA and peptide vaccines. Finally, immunoproteasome activators have the potential to contribute not only to cytotoxic T-cell mediated tumor lysis but also the treatment of intracellular infections and autoimmune and neurodegenerative proteinopathies characterized by the pathologic accumulation of toxic, proteinaceous aggregates.

The introduction of CD38-targeting monoclonal antibodies (CD38 MoABs), daratumumab and isatuximab, has significantly impacted the management of patients with multiple myeloma (MM). Outcomes of patients with MM refractory to CD38 MoABs have not been described. We analyzed outcomes of 275 MM patients at 14 academic centers with disease refractory to CD38 MoABs. Median interval between MM diagnosis and refractoriness to CD38 MoAB (T0) was 50.1 months. The median overall survival (OS) from T0for the entire cohort was 8.6 [95% C.I. 7.5–9.9] months, ranging from 11.2 months for patients not simultaneously refractory to an immunomodulatory (IMiD) agent and a proteasome inhibitor (PI) to 5.6 months for “penta-refractory” patients (refractory to CD38 MoAB, 2 PIs and 2 IMiDs). At least one subsequent treatment regimen was employed after T0in 249 (90%) patients. Overall response rate to first regimen after T0was 31% with median progression-free survival (PFS) and OS of 3.4 and 9.3 months, respectively. PFS was best achieved with combinations of carfilzomib and alkylator (median 5.7 months), and daratumumab and IMiD (median 4.5 months). Patients with MM refractory to CD38 MoAB have poor prognosis and this study provides benchmark for new therapies to be tested in this population.

Manjappa: Pfizer: Research Funding. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Celgene: Speakers Bureau; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding. de Lima:BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding. Malek:Clegene: Other: Advisory board , Speakers Bureau; Janssen: Other: Advisory board, Speakers Bureau; Sanofi: Other: Advisory board; Amgen: Honoraria; Medpacto: Research Funding; Cumberland: Research Funding; Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau.

Monoclonal gammopathy of undetermined significance (MGUS) is a premalignant, clonal plasma cell disorder, characterized by the presence of a monoclonal (M) protein in serum, <10% clonal plasma cells in the bone marrow, and absence of end-organ damage attributable to multiple myeloma (MM). MGUS incidence is estimated as 0.3% and 3% among those <50 years and >50 years, respectively. Although renal failure is a defining feature of MM, frequently patients (pts) with a variety of renal pathologies have less than 10% plasma cell burden in the bone marrow, therefore they cannot be categorized as MM to be eligible for an anti-myeloma therapy. However, it is clear that there is a causative relationship between MGUS and the pathologic process in kidneys in at least a subset patient and starting anti-myeloma therapy potentially can reverse or slow down the renal insult caused by MGUS. This led to the creation of the new entity and term, “monoclonal gammopathy of renal significance” (MGRS), to properly convey the nature of these relationship. Therefore, MGRS depicts a subset of MGUS and ascertains that the significance of the monoclonal gammopathy is no longer undetermined.

Multiple Myeloma (MM) is a cancer of terminally-differentiated plasma cells residing in the bone marrow. Myeloma cells frequently secrete monoclonal proteins that can be used to assess tumor volume and patient response to therapy. Monoclonal proteins are measured by gel electrophoresis and subsequent immunofixation of the observed M-spike for protein typing. However, this a time-consuming process that may take up to 3-5 days that delays physician-patient decision-making, determining response to treatment and can be a significant psychological stressor for patients. Hence, there is an unmet need to develop a more rapid, point-of-care method to determine M-spike levels. Gamma gap is the difference between total serum protein and albumin and includes a variety metabolic proteins, i.e., transferrin, as well as immunologic proteins, e.g., non-involved immunoglobulins, in addition to the M-spike. Since estimation of the non-M-spike portion of the gamma gap cannot be achieved on routine patient care, the gamma gap cannot serve as an accurate surrogate for M-spike protein levels. Here, we hypothesized that an artificial intelligence (AI) algorithm utilizing readily available clinical and laboratory data along with previous and same-day lab variables can accurately predict M-spike levels without the need for serum electrophoresis.