Ashley E. Rosko

Multiple Myeloma in the Older Adult: Better Prospects, More Challenges

PURPOSE Multiple myeloma (MM) is disproportionately diagnosed in older adults; with the aging of the population, the number of older adults diagnosed with MM will increase by nearly 80% in the next two decades. Duration of survival has improved dramatically over the last 20 years, but the improvements in older adults have not been as great as those in younger adults with MM. METHODS In this article, we address treatment approaches in older adults who are eligible for and those ineligible for high-dose therapy with autologous stem-cell transplantation as well as supportive care considerations and the potential role for geriatric assessment in facilitating decision making for older adults with MM. RESULTS The evidence from recent studies demonstrates that combinations of novel and conventional antimyeloma agents result in improved response rates and, in some cases, improved progression-free and overall survival. However, some older adults are particularly vulnerable to toxicities of therapy and discontinuation of therapy and, consequently, they have poorer survival. In addition, older adults may prioritize other outcomes of therapy, such as quality of life, over more conventional end points such as disease response and duration of survival. Geriatric assessment can facilitate risk-stratification of older adults at greater risk for adverse events from therapy and aid in personalizing therapy for vulnerable or frail older adults. CONCLUSION Survival in older adults with MM is improving with novel therapeutics, but efficacy must be balanced with risk of toxicity of therapy and maintenance of quality of life. Novel instruments such as geriatric assessment tools may facilitate these aims.

A Phase I Trial of Single-Agent Reolysin in Patients with Relapsed Multiple Myeloma

Purpose: Reolysin, a proprietary isolate of reovirus type III dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase I-II trials; no clinical trials have been conducted in patients with hematologic malignancies. Experimental Design: A phase I trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by in situ-based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA, and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer upregulated gene 2 (CUG2) were evaluated in patient samples and multiple myeloma cell lines. Neutralizing anti-reovirus antibody assay was performed weekly during cycle 1. Results: There were no dose-limiting toxicities, patients reached the 3 × 1010 TCID50 daily on days 1 to 5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. ISH demonstrated reoviral genome confined in multiple myeloma cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA-positive cells. The longest durations of stable disease were 4, 5, and 8 months. Conclusions: Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within multiple myeloma cells. Our data support that in multiple myeloma cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers. Clin Cancer Res; 20(23); 5946–55. ©2014 AACR.

Proteomic characterization of circulating extracellular vesicles identifies novel serum myeloma associated markers.

UNLABELLED Multiple myeloma (MM) is a hematological malignancy of clonal plasma cells in the bone marrow (BM). The microenvironment plays a key role in MM cell survival and drug resistance through release of soluble factors, expression of adhesion molecules and release of extracellular vesicles (EVs). The aim of this manuscript is to use proteomic profiling of EVs as a tool to identify circulating tumor associated markers in MM patients. First, we characterized the EV protein content obtained from different MM cell lines. Then, we established differences in protein abundance among EVs isolated from MM patient serum and BM and the serum of healthy donors. These data show that the Major Histocompatibility Complex Class I is highly enriched in EVs of MM cell lines and MM patients serum. Next, we show that CD44 is highly expressed in the EVs isolated from the corticosteroid resistant MM cell line, MM.1R. Furthermore, CD44 was found to be differentially expressed in EVs isolated from newly diagnosed MM patients. Finally through ELISA analysis, we establish the potential of serum CD44 as a predictive biomarker of overall survival. These results support the analysis of EVs as an easily accessible source for MM biomarkers. BIOLOGICAL SIGNIFICANCE Extracellular vesicles are becoming a research focus due to their roles in cancer cell biology such as immune evasion, therapeutic resistance, proliferation and metastases. While numerous studies of vesicle characterization and biology have been conducted in many cancer models, the role of EV in MM remains relatively unstudied. Here we found that EVs isolated from MM cells are enriched in MHC-1 antigen presenting complex and its binding protein β2-MG, this observation is compatible with the enhanced proteasome activity of MM cells compared to other cancers and the ability of functional MHC-1 to bind and present peptides, generated from protein degradation by the proteasome. Additionally, our experiments show that CD44 is particularly enriched in the EV fraction of corticosteroid resistant MM.1R cells and is differentially expressed in the EV fraction of MM patients. This is of high significance due to the established role of CD44 in adhesion of MM cells to BMSC and induction of IL-6, the primary cytokine for MM cell survival, secretion by the BMSC. Furthermore, ELISA assays for CD44 content from the serum of 254 newly diagnosed MM patients enrolled in a Phase 3 randomized trial show highly variable CD44 levels and those patients with >280 ng/mL serum CD44 showing a reduced overall survival time. These results suggest the potential use of CD44 as a prognostic biomarker in MM.

Reduced intensity conditioned allograft yields favorable survival for older adults with B-cell acute lymphoblastic leukemia

Older adults with B‐cell acute lymphoblastic leukemia (B‐ALL) have poor survival. We examined the effectiveness of reduced intensity conditioning (RIC) hematopoietic cell transplant (HCT) in adults with B‐ALL age 55 years and older and explored prognostic factors associated with long‐term outcomes. Using CIBMTR registry data, we evaluated 273 patients (median age 61, range 55–72) with B‐ALL with disease status in CR1 (71%), >CR2 (17%) and Primary Induction Failure (PIF)/Relapse (11%), who underwent RIC HCT between 2001 and 2012 using mostly unrelated donor (59%) or HLA‐matched sibling (32%). Among patients with available cytogenetic data, the Philadelphia chromosome (Ph+) was present in 50%. The 3‐year cumulative incidences of nonrelapse mortality (NRM) and relapse were 25% (95% confidence intervals (CI): 20–31%) and 47% (95% CI: 41–53%), respectively. Three‐year overall survival (OS) was 38% (95% CI: 33–44%). Relapse remained the leading cause of death accounting for 49% of all deaths. In univariate analysis, 3 year risk of NRM was significantly higher with reduced Karnofsky performance status (KPS <90: 34% (95% CI: 25–43%) versus KPS ≥90 (18%; 95% CI: 12–24%, P = 0.006). Mortality was increased in older adults (66+ vs. 55–60: Relative Risk [RR] 1.51 95% CI: 1.00–2.29, P = 0.05) and those with advanced disease (RR 2.13; 95% CI: 1.36–3.34, P = 0.001). Survival of patients in CR1 yields 45% (95% CI: 38–52%) at 3 years and no relapse occurred after 2 years. We report promising OS and acceptable NRM using RIC HCT in older patients with B‐ALL. Disease status in CR1 and good performance status are associated with improved outcomes. Am. J. Hematol. 92:42–49, 2017.

Autologous hematopoietic stem cell transplant induces the molecular aging of T-cells in multiple myeloma

Multiple myeloma (MM) is an incurable hematologic malignancy diagnosed primarily in older adults. As the population ages, myeloma incidence is expected to increase at a higher rate than many other malignancies.1 Approved chemotherapy and targeted regimens for older adults with MM are numerous and exhibit distinct toxicities. The physiological heterogeneity of older adults makes it challenging for physicians to identify the most effective, yet best tolerated regimen, for each MM patient. As such, use of a two-drug regimen, three-drug regimen, or intensive autologous hematopoietic stem cell transplant (AHSCT) is often subjective. Consequently, AHSCT eligibility is subjectively applied and more objective measures are warranted to better understand health status in older adults. We believe that objective markers of physiological age will improve treatment stratification and will be an additional tool in understanding how treatment and transplant have an impact on health status.

Acidosis Sensing Receptor GPR65 Correlates with Anti-Apoptotic Bcl-2 Family Member Expression in CLL Cells: Potential Implications for the CLL Microenvironment

The tumor microenvironment is generally an acidic environment, yet the effect of extracellular acidosis on chronic lymphocytic leukemia (CLL) is not well established. Here we are the first to report that the extracellular acid sensing G-protein coupled receptor, GPR65, is expressed in primary CLL cells where its level correlate strongly with anti-apoptotic Bcl-2 family member levels. GPR65 expression is found normally within the lymphoid lineage and has not been previously reported in CLL. We demonstrate a wide range of GPR65 mRNA expression among CLL 87 patient samples. The correlation between GPR65 mRNA levels and Bcl-2 mRNA levels is particularly strong (r=0.8063, p= <0.001). The correlation extends to other anti-apoptotic Bcl-2 family members, Mcl-1 (r=0.4847, p=0.0010) and Bcl-xl (r=0.3411, p=0.0252), although at lower levels of significance. No correlation is detected between GPR65 and levels of the pro-apoptotic proteins BIM, PUMA or NOXA. GPR65 expression also correlates with the favorable prognostic marker of 13q deletion. The present findings suggest the acid sensing receptor GPR65 may be of significance to allow CLL tolerance of extracellular acidosis. The correlation of GPR65 with Bcl-2 suggests a novel cytoprotective mechanism that enables CLL cell adaptation to acidic extracellular conditions. These findings suggest the potential value of targeting GPR65 therapeutically.

Aging: Treating the Older Patient

• Despite the greater use of autologous transplant for multiple myeloma and allogeneic transplant for AML, significant underuse persists.

Associations of high‐dose melphalan pharmacokinetics and outcomes in the setting of a randomized cryotherapy trial

High‐dose melphalan followed by autologous stem cell transplantation remains the standard of care for eligible patients with multiple myeloma, but disease response and toxicity, including severe mucositis, varies among patients. Our randomized trial investigated duration of cryotherapy (2 and 6 h) for reduction of mucositis prevalence and severity and explored factors associated with variability in pharmacokinetics and outcomes from melphalan therapy. The results demonstrate that 2‐h is at least as effective as 6‐h cryotherapy in decreasing severe mucositis. From a population pharmacokinetic model, we identified that fat‐free mass, hematocrit, and creatinine clearance were significant covariates, as reported previously. Furthermore, we observed the rs4240803 SLC7A5 polymorphism was significantly associated with pharmacokinetic variability, and pharmacokinetics was associated with both mucositis and neutropenia. However, melphalan exposure was not associated with progression‐free or overall survival in our dataset. These findings contribute to ongoing efforts to personalize melphalan dosing in transplant patients.

Vancomycin-resistant enterococci infection: not just for the transplanted

Abstract Vancomycin-resistant enterococcal (VRE) blood stream infections (BSIs) pose significant hazards to patients with hematologic malignancy. We compared and examined VRE BSI rates, patient characteristics and clinical outcomes for two cohorts of patients: those who did and did not undergo hematopoietic cell transplant (HCT). In this single institution study, we retrospectively analyzed records of consecutive patients from 1998 through 2011. Over this 14-year period, VRE was identified in 14% of all BSIs in patients with HCT with a cumulative rate of 1.9% (48/2581 BSIs/patients). VRE was identified in 10% of all BSIs in non-HCT patients with a cumulative rate of 1.1% (35/3154 BSIs/patients). Transplant patients who developed VRE BSI tended to be younger, hospitalized more frequently, were exposed to vancomycin therapy frequently, and were more likely to have had a central venous catheter removed. VRE remains a significant cause of morbidity and mortality, as 22 deaths were directly or indirectly attributed to this infection. Both HCT and non-HCT patients are susceptible to VRE infection and are equally at risk for adverse outcomes related to VRE BSI.

A call to action in hematologic disorders: A report from the ASH scientific workshop on hematology and aging

The American Society of Hematology (ASH) has recently promoted efforts to advance the intersection of hematology and aging by sponsoring an annual Scientific Friday Workshop on Hematology and Aging [1]. Hematologic disorders, both malignant and benign, are highly prevalent among older adults [2–4]. Despite the disproportionate burden of hematologic disease among older adults [2–5], research studying the implications of age across the translational spectrum remains limited older adults understudied [6–8]. The lack of pre-clinical aging models, dearth of translational efforts across diseases, and under-enrollment of older adults in clinical trials result in substantial gaps in knowledge. Understanding the interface of human aging and hematologic disorders in a growing population of older adults is warranted. Here we outline the progress to date spearheaded by the ASH community dedicated to hematology and aging.