Faculty Bibliography

INTRODUCTION: This study evaluated the safety and efficacy of radiotherapy (RT) with concurrent novel agents (NAs), cytotoxic therapy (CTx), or both in the management of osteolytic bone lesions in multiple myeloma (MM). PATIENTS AND METHODS: A total of 39 patients with MM received RT to 64 different bone sites during the 2007-2012 period, with a dose of 8 to 37.5 Gy (mean, 26.8 Gy) delivered in 1 to 15 fractions (median, 10 fractions). Of these patients, 21 also received concurrent NAs or CTx. Pain response, M protein and kappa light chain response, and adverse events were evaluated. RESULTS: RT was completed in 35 of 39 patients (89.7%) in this study. Pain relief was observed in 30 of 31 patients (96.7%). Hematologic toxicity (grade 3 or 4 by the Radiation Therapy Oncology Group system) was seen in 43.2% of treated patients, and NA therapy was stopped in 2 patients owing to grade 4 toxicity. RT adverse effects resolved at 4 to 6 weeks posttreatment. Changes in pre- and posttreatment levels of M protein trended toward significance in patients treated with RT + systemic therapy (ST) versus. RT alone (DeltaM ProteinRT+ST = 5.6 g/L; DeltaM ProteinRT = 0 g/L; P = .089). CONCLUSION: Treating MM with RT concurrently with CTx including NAs was safe and well tolerated in the majority of patients (14 of 16 [87.5%] for those taking NAs and 19 of 21 [90.5%] for all patients). Excellent clinical pain response (> 95%) was also seen in patients regardless if they were treated with RT + ST or RT alone.

Disruption of protein processing in the secretory pathway is a measurable hallmark of endoplasmic reticulum (ER) stress. Activation of ER stress-mediated pathways has been implicated in numerous diseases, including cancer. To identify agents that induce ER stress, we established a screen for compounds that reduce secretion of the reporter protein Gaussia luciferase (GLUC). Given the clinically validated importance of targeting ER stress-mediated pathways in the treatment of multiple myeloma (MM), we used this hematological malignancy as a model for validating our screening system. From a screen of 2000 marketed drugs and natural compounds in KMS11 and ARP1 MM cells, we identified 97 agents that reduced GLUC secretion in both cell lines by at least 30%. To confirm inducers of ER stress, we applied a secondary screen that assessed splicing of the unfolded protein response (UPR) transcription factor XBP1. One agent, theaflavin-3,3'-digallate (TF-3), was chosen based on its history of safe human consumption and further validated through studies of ER stress-related pathways, including the UPR and apoptosis. Given these promising results, this screen could be a useful tool to identify agents targeting ER stress-related mechanisms in other cellular systems wherein ER stress plays a role in disease etiology.

INTRODUCTION: The evaluation of myeloma cells in multiple myeloma (MM) patients has generally been limited to the assessment of bone marrow involvement because of the sensitivity limitations of traditional minimal-residual-disease-detection methods. MATERIALS AND METHODS: We developed a sequencing-based method to identify myeloma cells in bone marrow (BM) and peripheral blood (PB) samples, based on their unique immunoglobulin gene rearrangements, that can detect cancer clones at levels well below 1 in 1 million leukocytes (0.0001%). In this multisite study, we used this sequencing method to determine the fraction of patients with myeloma cells in their PB at diagnosis and posttreatment time points. RESULTS: Using this sequencing approach, we detected myeloma cells in the PB in the vast majority of MM patients (44/46, 96%). We demonstrated a clear correlation (R(2) = 0.57) between myeloma clone levels in paired BM and PB samples, and noted that PB clone levels were approximately 100-fold lower than levels in BM samples. The sequencing assay demonstrated a clear sensitivity advantage in the BM compartment and at least equivalent sensitivity in the PB compared with that of monoclonal-protein results. CONCLUSION: This study highlights the promise of a blood-based, sequencing minimal-residual-disease assay that can be used to measure MM disease burden at different time points and various disease stages.

In this prospective, multicenter, phase 2 study, 64 patients with relapsed or relapsed and refractory multiple myeloma (MM) received up to 8 21-day cycles of bortezomib 1.0 mg/m(2) (days 1, 4, 8, and 11), lenalidomide 15 mg/day (days 1-14), and dexamethasone 40/20 mg/day (cycles 1-4) and 20/10 mg/day (cycles 5-8) (days of/after bortezomib dosing). Responding patients could receive maintenance therapy. Median age was 65 years; 66% were male, 58% had relapsed and 42% had relapsed and refractory MM, and 53%, 75%, and 6% had received prior bortezomib, thalidomide, and lenalidomide, respectively. Forty-eight of 64 patients (75%; 90% confidence interval, 65-84) were alive without progressive disease at 6 months (primary end point). The rate of partial response or better was 64%; median duration of response was 8.7 months. Median progression-free and overall survivals were 9.5 and 30 months, respectively (median follow-up: 44 months). Common treatment-related toxicities included sensory neuropathy (53%), fatigue (50%), and neutropenia (42%); common grade 3/4 treatment-related toxicities included neutropenia (30%), thrombocytopenia (22%), and lymphopenia (11%). Grade 3 motor neuropathy was reported in 2 patients. Lenalidomide-bortezomib-dexamethasone appears effective and tolerable in patients with relapsed or relapsed and refractory MM, demonstrating substantial activity among patients with diverse prior therapies and adverse prognostic characteristics. This trial is registered with www.clinicaltrials.gov as #NCT00378209.

BACKGROUND:Emerging interest on three-dimensional (3D) cell culture models to replace two-dimensional cultures of cancer cells and their xenografts in immunocompromised animal hosts prompted us to investigate the use of new biodegradable gels to recapitulate the physiological conditions of the microenvironment of multiple myeloma (MM) cells. MATERIALS AND METHODS/METHODS:In the present study, for the first time, we used a new 3D model of hyaluronic acid (HA)-based hydrogels with difference in their matrix composition and stiffness. RESULTS:We demonstrated that hyaluronic acid (HA)-based hydrogels perfectly accommodate MM cells; confirmed by cell survival, migration, colony forming units and expression of cell adhesion proteins of the Wnt signaling pathways over a period of time. CONCLUSION/CONCLUSIONS:This study provides the first 3D microenvironment data that HA-based hydrogels could provide with a suitable 3D substratum for MM cells to comprehensively analyze phenotypic changes and the influence of bone marrow stromal stem cells on Wnt/β catenin signaling in response to targeted drug treatments.