Cancer-related loneliness mediates the relationships between social constraints and symptoms among cancer patients

Cancer patients have high rates of persistent and disabling symptoms. Evidence suggests that social constraints (e.g., avoidance and criticism) negatively impact symptoms, but pathways linking these variables have yet to be identified. This study examined whether cancer-related loneliness (i.e., feeling socially disconnected related to having cancer) mediated the relationships between social constraints and symptoms (i.e., pain interference, fatigue, sleep disturbance, and cognitive complaints) in patients with various cancers (N = 182). Patients (51% female, mean age = 59) were recruited from the Indiana Cancer Registry and completed questionnaires assessing social constraints, cancer-related loneliness, and symptoms. Structural equation modeling was used to evaluate the hypothesized relationships among variables. The model demonstrated good fit. Consistent with our hypothesis, cancer-related loneliness mediated the relationships between social constraints and each symptom. Findings suggest that addressing cancer-related loneliness in symptom management interventions may mitigate the negative impact of social constraints on outcomes

The Cancer Loneliness Scale and Cancer-related Negative Social Expectations Scale: development and validation

PURPOSE: Loneliness is a known risk factor for poor mental and physical health outcomes and quality of life in the general population, and preliminary research suggests that loneliness is linked to poorer health outcomes in cancer patients as well. Various aspects of the cancer experience contribute to patients feeling alone and misunderstood. Furthermore, loneliness theory suggests that negative social expectations, which may specifically relate to the cancer experience, precipitate and sustain loneliness. Cancer-specific tools are needed to assess key constructs of this theory. In the current study, we developed and tested measures of (1) loneliness attributed to cancer (i.e., cancer-related loneliness) and (2) negative social expectations related to cancer. METHODS: First, we developed the items for the measures based on theory, prior research, and expert feedback. Next, we assessed the measures' psychometric properties (i.e., internal consistency and construct validity) in a diverse sample of cancer patients. RESULTS: The final products included a 7-item unidimensional Cancer Loneliness Scale and a 5-item unidimensional Cancer-related Negative Social Expectations Scale. Evidence of excellent reliability and validity was found for both measures. CONCLUSIONS: The resulting measures have both clinical and research utility

Recognition of early mortality in multiple myeloma by a prediction matrix

Early mortality (EM; death ≤ 6 months from diagnosis) has been reported in several newly diagnosed multiple myeloma (NDMM) trials. Before the era of novel agents, the incidence was 10%-14%. Causes of death included infections/pneumonia, renal failure, refractory disease, and cardiac events. Staging systems, such as the revised International Staging System (r-ISS), and prognostic factors including cytogenetics, lactate dehydrogenase levels, and myeloma-specific factors, are useful to assess overall prognosis; however, they cannot predict EM. We evaluated patients treated with novel agents in the Connect MM® Registry and identified risk factors of the EM cohort. Eligible patients were enrolled in the registry within 60 days of diagnosis. Univariate and multivariate analyses were conducted to evaluate associations between baseline characteristics and EM. Prediction matrices for EM were constructed from a logistic model. Between September 2009 and December 2011, 1493 patients were enrolled in the registry and had adequate follow-up. Of these patients, 102 (6.8%) had EM and 1391 (93.2%) survived for > 180 days. Baseline factors significantly associated with increased EM risk included age > 75 years, higher Eastern Cooperative Oncology Group performance status, lower EQ-5D mobility score, higher ISS stage, lower platelet count, and prior hypertension. Renal insufficiency trended toward increased EM risk. These risk factors were incorporated into a prediction matrix for EM. The EM prediction matrix uses differential weighting of risk factors to calculate EM risk in patients with NDMM. Identifying patients at risk for EM may provide new opportunities to implement patient-specific treatment strategies to improve outcomes

In Vivo Effects of Myeloablative Alkylator Therapy on Survival and Differentiation of MGMTP140K-Transduced Human G-CSF-Mobilized Peripheral Blood Cells

High-intensity alkylator-based chemotherapy is required to eradicate tumors expressing high levels of O6-methylguanine DNA methyltransferase (MGMT). This treatment, however, can lead to life-threatening myelosuppression. We investigated a gene therapy strategy to protect human granulocyte colony-stimulating factor-mobilized peripheral blood CD34+ cells (MPB) from a high-intensity alkylator-based regimen. We transduced MPB with an oncoretroviral vector that coexpresses MGMTP140K and the enhanced green fluorescent protein (EGFP) (n = 5 donors). At 4 weeks posttransplantation into nonobese diabetic/severe combined immunodeficient (NOD/SCID) mice, cohorts were not treated or were treated with low- or high-intensity alkylating chemotherapy. In the high-intensity-treated cohort, it was necessary to infuse NOD/SCID bone marrow (BM) to alleviate hematopoietic toxicity. At 8 weeks posttreatment, human CD45+ cells in the BM of mice treated with either regimen were EGFP+ and contained MGMT-specific DNA repair activity. In cohorts receiving low-intensity therapy, both primitive and mature hematopoietic cells were present in the BM. Although B-lymphoid and myeloid cells were resistant to in vivo drug treatment in cohorts that received high-intensity therapy, no human CD34+ cells or B-cell precursors were detected. These data suggest that improved strategies to optimize repair of DNA damage in primitive human hematopoietic cells are needed when using high-intensity anti-cancer therapy

Cell adhesion molecule CD166 drives malignant progression and osteolytic disease in multiple myeloma

Multiple myeloma (MM) is incurable once osteolytic lesions have seeded at skeletal sites, but factors mediating this deadly pathogenic advance remain poorly understood. Here we report evidence of a major role for the cell adhesion molecule CD166, which we discovered to be highly expressed in MM cell lines and primary bone marrow (BM) cells from patients. CD166+ MM cells homed more efficiently than CD166− cells to the BM of engrafted immunodeficient NSG mice. CD166 silencing in MM cells enabled longer survival, a smaller tumor burden and less osteolytic lesions, as compared to mice bearing control cells. CD166 deficiency in MM cell lines or CD138+ BM cells from MM patients compromised their ability to induce bone resorption in an ex vivo organ culture system. Further, CD166 deficiency in MM cells also reduced formation of osteolytic disease in vivo after intra-tibial engraftment. Mechanistic investigation revealed that CD166 expression in MM cells inhibited osteoblastogenesis of BM-derived osteoblast progenitors by suppressing RUNX2 gene expression. Conversely, CD166 expression in MM cells promoted osteoclastogenesis by activating TRAF6-dependent signaling pathways in osteoclast progenitors. Overall, our results define CD166 as a pivotal director in MM cell homing to the BM and MM progression, rationalizing its further study as a candidate therapeutic target for MM treatment

Impact of post-transplantation maintenance therapy on health-related quality of life in patients with multiple myeloma: data from the Connect® MM Registry

Maintenance therapy after autologous stem cell transplantation (ASCT) is recommended for use in multiple myeloma (MM); however, more data are needed on its impact on health-related quality of life (HRQoL). Presented here is an analysis of HRQoL in a Connect MM registry cohort of patients who received ASCT ± maintenance therapy. The Connect MM Registry is one of the earliest and largest, active, observational, prospective US registry of patients with symptomatic newly diagnosed MM. Patients completed the Functional Assessment of Cancer Therapy-MM (FACT-MM) version 4, EuroQol-5D (EQ-5D) questionnaire, and Brief Pain Inventory (BPI) at study entry and quarterly thereafter until death or study discontinuation. Patients in three groups were analyzed: any maintenance therapy (n = 244), lenalidomide-only maintenance therapy (n = 169), and no maintenance therapy (n = 137); any maintenance and lenalidomide-only maintenance groups were not mutually exclusive. There were no significant differences in change from pre-ASCT baseline between any maintenance (P = 0.60) and lenalidomide-only maintenance (P = 0.72) versus no maintenance for the FACT-MM total score. There were also no significant differences in change from pre-ASCT baseline between any maintenance and lenalidomide-only maintenance versus no maintenance for EQ-5D overall index, BPI, FACT-MM Trial Outcomes Index, and myeloma subscale scores. In all three groups, FACT-MM, EQ-5D Index, and BPI scores improved after ASCT; FACT-MM and BPI scores deteriorated at disease progression. These data suggest that post-ASCT any maintenance or lenalidomide-only maintenance does not negatively impact patients' HRQoL. Additional research is needed to verify these findings

Cryopreservation Preserves Cell-Type Composition and Gene Expression Profiles in Bone Marrow Aspirates From Multiple Myeloma Patients

Single-cell RNA sequencing reveals gene expression differences between individual cells and also identifies different cell populations that are present in the bulk starting material. To obtain an accurate assessment of patient samples, single-cell suspensions need to be generated as soon as possible once the tissue or sample has been collected. However, this requirement poses logistical challenges for experimental designs involving multiple samples from the same subject since these samples would ideally be processed at the same time to minimize technical variation in data analysis. Although cryopreservation has been shown to largely preserve the transcriptome, it is unclear whether the freeze-thaw process might alter gene expression profiles in a cell-type specific manner or whether changes in cell-type proportions might also occur. To address these questions in the context of multiple myeloma clinical studies, we performed single-cell RNA sequencing (scRNA-seq) to compare fresh and frozen cells isolated from bone marrow aspirates of six multiple myeloma patients, analyzing both myeloma cells (CD138+) and cells constituting the microenvironment (CD138-). We found that cryopreservation using 90% fetal calf serum and 10% dimethyl sulfoxide resulted in highly consistent gene expression profiles when comparing fresh and frozen samples from the same patient for both CD138+ myeloma cells (R ≥ 0.96) and for CD138- cells (R ≥ 0.9). We also demonstrate that CD138- cell-type proportions showed minimal alterations, which were mainly related to small differences in immune cell subtype sensitivity to the freeze-thaw procedures. Therefore, when processing fresh multiple myeloma samples is not feasible, cryopreservation is a useful option in single-cell profiling studies

MGP Panel is a comprehensive targeted genomics panel for molecular profiling of multiple myeloma patients

PURPOSE: We designed a comprehensive multiple myeloma (MM) targeted sequencing panel to identify common genomic abnormalities in a single assay and validated it against known standards. EXPERIMENTAL DESIGN: The panel comprised 228 genes/exons for mutations, 6 regions for translocations, and 56 regions for copy number abnormalities (CNAs). Toward panel validation, targeted sequencing was conducted on 233 patient samples and further validated using clinical fluorescence in situ hybridization (FISH) (translocations), multiplex ligation probe analysis (MLPA) (CNAs), whole genome sequencing (WGS) (CNAs, mutations, translocations) or droplet digital PCR (ddPCR) of known standards (mutations). RESULTS: Canonical IgH translocations were detected in 43.2% of patients by sequencing, and aligned with FISH except for one patient. CNAs determined by sequencing and MLPA for 22 regions were comparable in 103 samples and concordance between platforms was R2=0.969. VAFs for 74 mutations were compared between sequencing and ddPCR with concordance of R2=0.9849. CONCLUSIONS: In summary, we have developed a targeted sequencing panel that is as robust or superior to FISH and WGS. This molecular panel is cost effective, comprehensive, clinically actionable and can be routinely deployed to assist risk stratification at diagnosis or post-treatment to guide sequencing of therapies

Effect of initial treatment on health-related quality of life in patients with newly diagnosed multiple myeloma without immediate stem cell transplant intent: results from the Connect ® MM Registry

Although new multiple myeloma (MM) therapies are effective in alleviating some disease-associated symptoms (e.g. bone pain, fatigue, functional decline), they can result in additional toxicities, further impacting health-related quality of life (HRQoL). Here, we compared HRQoL and safety of lenalidomide-bortezomib-dexamethasone [RVd (n = 445)], bortezomib-melphalan-prednisone [VMP (n = 77)] and Vd or VMP (n = 588) in patients with newly diagnosed MM (NDMM) from the Connect® MM Registry, a large, USA, multicentre, prospective observational cohort study. Functional Assessment of Cancer Therapy-Multiple Myeloma subscale, EuroQol-5D overall score and Bone Pain Inventory HRQoL scores were significantly improved with RVd versus Vd/VMP. Serious adverse event rates were similar in all groups. Treatment with RVd maintained HRQoL in this real-world, largely community-based population of patients with NDMM