Dispenzieri, Angela

Abstract We describe a series of 102 patients diagnosed from January 1, 1990 to December 31, 2015 with Type 1 monoclonal cryoglobulinemia (MoC). Symptoms were seen in 89 (87%) patients, including: cutaneous symptoms in 64 (63%) patients, with purpura (n = 43, 42%) and ulcers/gangrene (n = 35, 34%) being most common; neurological findings in 33 (32%) patients, most frequently sensory neuropathy (n = 24, 24%); vasomotor symptoms, mainly Raynaud's phenomenon in 25 (25%); arthralgias in 24 (24%); and renal manifestations, primarily glomerulonephritis in 14 (14%) patients. An underlying lymphoproliferative disorder was identified in 94 (92%) subjects; MGUS—39, myeloma—20, lymphoplasmacytic lymphoma—21 and others—14. Treatment was initiated in 73 (72%) patients, primarily for cryoglobulinemia‐related symptoms in 57. Treatment regimens consisted of: steroids ± alkylating agents in 29 (40%), novel myeloma therapies in 16 (22%), rituximab with alkylating agents in 12 (16%) and rituximab ± steroids in 11 (15%) patients; 22 patients received plasmapheresis. Six patients underwent autologous stem cell transplant. Cryocrit at treatment initiation, change in cryocrit and time to nadir cryocrit were predictive of symptom improvement. Treatment directed toward the underlying clonal disorder resulted in improvement (n = 47) or stabilization (n = 16) of symptoms in the majority of patients and disappearance of cryoglobulin in over one‐half.

AbstractWe analyzed the outcomes following initial relapse or refractory disease in systemic light chain amyloidosis (AL) and the impact of type of therapy employed.A total of 1327 patients with AL seen at Mayo Clinic within 90 days of diagnosis, between 2006 and 2015, were reviewed. The study included 366 patients experiencing a documented hematological or organ relapse or refractory disease requiring start of second line therapy. Overall survival (OS) and time to next treatment (TTNT) were calculated from start of second line treatment.The median time to require second line treatment was 16.2 months (1‐93) from the start of first line therapy. At relapse, patients received proteasome inhibitors (PI; 45.1%), immunomodulators (IMiD; 22.7%), alkylators (9%), PI and IMiD combination (4.1%), autologous transplant (3.8%), steroids and other therapies (4.9%). Among these, 124 (33.9%) required change or reinstitution of therapy. The median time to require third line treatment was 31 months (95% CI; 24, 40.5) and the median overall survival (OS) was 38.8 months (95% CI; 29.6, 52.6) from the start of second line treatment. Retreatment with same therapy at relapse significantly reduced TTNT (22 m vs 32.3 m; P = .01) as compared to different therapy; but did not have any impact OS (30.8 m vs 51.1 m; P = .5). In conclusion, this study provides important information about outcomes of patients with AL who require second line treatment for relapsed/refractory disease . Treatment with a different therapy at relapse improves time to next therapy but does not impact OS.

AbstractImmunoglobulin light chain (AL) amyloidosis is a fatal complication of B‐cell proliferation secondary to deposition of amyloid fibrils in various organs. Urinary exosomes (UEX) are the smallest of the microvesicles excreted in the urine. Previously, we found UEX of patients with AL amyloidosis contained immunoglobulin light chain (LC) oligomers that patients with multiple myeloma did not have. To further explore the role of the LC oligomers, UEX was isolated from an AL amyloidosis patient with progressive renal disease despite achieving a complete response. LC oligomers were identified. Mass spectrometry (MS) of the UEX and serum identified two monoclonal lambda LCs. Proteomics of the trypsin digested amyloid fragments in the kidney by laser microdissection and MS analysis identified a λ6 LC. The cDNA from plasma cell clone was from the IGLV‐ 6‐57 family and it matched the amino acid sequences of the amyloid peptides. The predicted mass of the peptide product of the cDNA matched the mass of one of the two LCs identified in the UEX and serum. UEX combined with MS were able to identify 2 monoclonal lambda LCs that current clinical methods could not. It also identified the amyloidogenic LC which holds potential for response assessment in the future.

PurposeTo evaluate if cardiac magnetic resonance elastography (MRE) can measure increased stiffness in patients with cardiac amyloidosis. Myocardial tissue stiffness plays an important role in cardiac function. A noninvasive quantitative imaging technique capable of measuring myocardial stiffness could aid in disease diagnosis, therapy monitoring, and disease prognostic strategies. We recently developed a high‐frequency cardiac MRE technique capable of making noninvasive stiffness measurements.Materials and MethodsIn all, 16 volunteers and 22 patients with cardiac amyloidosis were enrolled in this study after Institutional Review Board approval and obtaining formal written consent. All subjects were imaged head‐first in the supine position in a 1.5T closed‐bore MR imager. 3D MRE was performed using 5 mm isotropic resolution oblique short‐axis slices and a vibration frequency of 140 Hz to obtain global quantitativein vivoleft ventricular stiffness measurements. The median stiffness was compared between the two cohorts. An octahedral shear strain signal‐to‐noise ratio (OSS‐SNR) threshold of 1.17 was used to exclude exams with insufficient motion amplitude.ResultsFive volunteers and six patients had to be excluded from the study because they fell below the 1.17 OSS‐SNR threshold. The myocardial stiffness of cardiac amyloid patients (median: 11.4 kPa, min: 9.2, max: 15.7) was significantly higher (P = 0.0008) than normal controls (median: 8.2 kPa, min: 7.2, max: 11.8).ConclusionThis study demonstrates the feasibility of 3D high‐frequency cardiac MRE as a contrast‐agent‐free diagnostic imaging technique for cardiac amyloidosis.Level of Evidence:2Technical Efficacy:Stage 2J. Magn. Reson. Imaging 2017;46:1361–1367.

229 Background: Modern clinical practice places time restrictions on the amount of information and processing that can be done in a typical office visit. Meeting patient needs within the healthcare system is often inefficient and ineffective, contributing to patient and clinician dissatisfaction and suboptimal outcomes. We developed a point-of-care case management system for oncology clinical practices adapted from an algorithm initially designed for patients with diabetes. The system’s goal is to obtain patient-reported quality of life (QOL) outcomes and provide clinicians with information regarding QOL issues to address. Methods: Literature review and focus groups of oncology patients were used to identify key patient concerns. The program was adapted for cancer patients to collect the identified patient concern including QOL, fatigue, pain and other cancer-specific issues scored on a scale of 0-10. Suggested actions and available resources were identified for the patient/clinician based on the issue selected. We performed a pilot study involving 20 cancer patients to assess feasibility, and administered a “was it worth it survey” (WIWI). Results: The resultant hematology/oncology electronic system includes a set of eight primary “buttons”: Personal Relationships, Emotional health, Physical healthy, Cancer diagnosis and treatment, Health behaviors, Money, Care planning and Something else. Every “button” was selected, most commonly Cancer diagnosis and treatment 6/20 (30%). The median (range) reported QOL, fatigue and pain were 7 (1-10), 4 (0-8), 2 (0-8), respectively. The average completion of the tool took 4 minutes. One hundred percent of patients who took the survey thought it was worth it, would participate again and recommend it to others. Conclusions: The system was quick and easy to utilize in a small pilot of patients. All of the identified categories were chosen and relevant to our patient population. This tool has the potential to improve patient well-being and clinical outcomes, reduce the burden on clinicians and distribute case management activities to the most appropriate providers. Next steps include initiating a larger prospective protocol to assess if this tool improves QOL over time.

PURPOSE: Based on the success of hematopoietic stem-cell transplantation (HSCT) for multiple myeloma, HSCT is being used to treat patients with primary systemic amyloidosis (AL). This article addresses the extent to which eligibility to undergo HSCT is a favorable prognostic feature and explores prognostic factors within the subset of eligible patients. PATIENTS AND METHODS: The Mayo Clinic amyloid database was queried for all patients with AL seen at the Mayo Clinic from 1983 through 1997 who would have been eligible for peripheral-blood stem-cell transplantation. Inclusion criteria included biopsy-proven amyloid, symptomatic disease, absence of a clinical diagnosis of multiple myeloma, age ≤ 70 years, cardiac interventricular septal thickness ≤ 15 mm, cardiac ejection fraction more than 55%, serum creatinine ≤ 2 mg/dL, and direct bilirubin ≤ 2.0 mg/dL. RESULTS: Median age was 56 years (range, 25 to 70) with 79 (34%) older than 60 years. One hundred patients had early cardiac involvement; 41, hepatic involvement; 167, renal involvement; and 39, nerve involvement. The 229 patients have had a median follow-up of 52 months, and 151 have died. The median survival was 42 months with 5- and 10-year survival rates of 36% and 15%, respectively. Important predictors of survival were size of M-component in 24-hour urine, number of involved organs, alkaline phosphatase, performance score, and weight loss. CONCLUSION: The same patients who are eligible for HSCT are a good-risk population who do relatively well with chemotherapy (median survival, 42 months), substantially better than the expected median survival of 18 months for all patients with AL. A randomized trial is needed to assess the true effect of HSCT.

PURPOSE: Samarium-153 ethylene diamine tetramethylene phosphonate (153Sm-EDTMP), a bone-seeking radiopharmaceutical, provides therapeutic irradiation to osteoblastic bone metastases. Because the dose-limiting toxicity of 153Sm-EDTMP is thrombocytopenia, a dose-escalation trial using peripheral-blood progenitor cells (PBPCs) or marrow support was conducted to treat metastatic bone cancer. PATIENTS AND METHODS: Patients with locally recurrent or metastatic osteosarcoma or skeletal metastases avid on bone scan were treated with 1, 3, 4.5, 6, 12, 19, or 30 mCi/kg of 153Sm-EDTMP. RESULTS: Thirty patients were treated with 153Sm-EDTMP. Transient symptoms of hypocalcemia were seen at 30 mCi/kg. Estimates of radioisotope bound to bone surfaces and marrow radiation dose were linear with injected amount of 153Sm-EDTMP. Cytopenias also occurred in all subjects and were dose-related. At day +13 after 153Sm-EDTMP, residual whole-body radioactivity was 1% to 65% of whole-body radioactivity considered safe for PBPC infusion, 3.6 mCi. After PBPC or marrow infusion on day +14 after 153Sm-EDTMP, recovery of hematopoiesis was problematic in two patients at the 30 mCi/kg dose infused with less than 2 × 106 CD34+/kg on day +14, but not in other patients. Reduction or elimination of opiates for pain was seen in all patients. Patients had no adverse changes in appetite or performance status. CONCLUSION: 153Sm-EDTMP with PBPC support can provide bone-specific therapeutic irradiation (estimates of 39 to 241 Gy). Hematologic toxicity at 30 mCi 153Sm-EDTMP/kg requires PBPC grafts with more than 2 × 106 CD34+/kg to overcome myeloablative effects of skeletal irradiation. Nonhematologic side effects are minimal.

Attenuated Edmonston lineage measles virus (MV-Edm) vaccine strains can preferentially infect and lyse a wide variety of cancer cells. Oncolytic MV-Edm derivatives are genetically engineered to express the human carcinoembryonic antigen (MV-CEA virus) or the human sodium iodide symporter (MV-NIS virus) and are currently being tested in clinical trials against ovarian cancer, glioblastoma multiforme, multiple myeloma, mesothelioma, head and neck cancer, breast cancer and malignant peripheral nerve sheath tumors. This review describes the basic and preclinical data that facilitated the clinical translation of MV-Edm strains, and summarizes the clinical results of this oncolytic platform to date. Furthermore, we discuss the latest clinically relevant MV-Edm vector developments and creative strategies for future translational steps.