Search

Abstract: We sought a regimen that incorporates optimal novel agents and balances efficacy with toxicity in transplant‐ineligible multiple myeloma (MM) patients. Our study evaluated modified lenalidomide‐bortezomib‐dexamethasone (RVD lite) in this population and was administered over a 35‐day cycle. Lenalidomide 15 mg was given orally on days 1–21; bortezomib 1·3 mg/m2 weekly subcutaneously on days 1, 8, 15 and 22; and dexamethasone 20 mg orally was given on the day of and day after bortezomib for 9 cycles followed by 6 cycles of consolidation with lenalidomide and bortezomib. The primary objective was to evaluate the overall response rate (ORR); secondary objectives included safety, progression‐free survival (PFS) and overall survival (OS). Fifty‐three eligible patients were screened between April 2013 and May 2015; 50 received at least one dose of therapy. Median age at study entry was 73 years (range 65–91). The ORR was 86% and 66% of patients achieved a very good partial response or better. Median PFS was 35·1 months (95% confidence interval 30·9–not reached) and median OS was not reached at a median follow‐up of 30 months. Peripheral neuropathy was reported in 31 (62%) patients with only 1 patient experiencing grade 3 symptoms. RVD lite is a well‐tolerated and highly effective regimen, with robust PFS and OS, in the transplant‐ineligible MM population. [ABSTRACT FROM AUTHOR]

Summary: The phase 3 PANORAMA‐1 trial led to regulatory approvals of panobinostat (PAN) in combination with bortezomib (BTZ) and dexamethasone (DEX) for the treatment of multiple myeloma after ≥2 prior regimens, including BTZ and an immunomodulatory drug. Patient‐reported outcomes (PROs) were assessed in PANORAMA‐1, with data available for 73 patients in the PAN + BTZ + DEX arm and 74 patients in the placebo (PBO) + BTZ + DEX arm. Per the European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire‐Core 30 (EORTC QLQ‐C30), global health status/quality of life (QoL) scores initially declined with PAN + BTZ + DEX during the first 24 weeks before approaching baseline scores and remaining steady during the next 24 weeks, with no difference between arms at Week 48. The EORTC QLQ‐Myeloma module (EORTC QLQ‐MY20) demonstrated initial improvements and subsequent stabilization of disease symptom scores in both arms and initial worsening and subsequent improvement of side effects of treatment scores, with the initial worsening more pronounced and recovery less pronounced with PAN + BTZ + DEX. Functional Assessment of Cancer Therapy/Gynecologic Oncology Group‐Neurotoxicity scores remained relatively stable and similar between the arms. Overall, these PRO findings support the addition of PAN to the BTZ+DEX regimen as an efficacious treatment option, with limited symptomatology and impact on patients’ QoL. The reported results are based on a descriptive analysis of the data. No formal statistical tests have been performed. [ABSTRACT FROM AUTHOR]

Panobinostat in combination with bortezomib and dexamethasone demonstrated a significant and clinically meaningful progression-free survival benefit compared with placebo, bortezomib and dexamethasone in the phase 3 PANORAMA 1 (Panobinostat Oral in Multiple Myeloma 1) trial. Despite this benefit, patients in the panobinostat arm experienced higher rates of adverse events ( AEs) and higher rates of discontinuation due to AEs. This PANORAMA 1 subanalysis examined AEs between 2 treatment phases of the study ( TP1 and TP2), in which administration frequency of bortezomib and dexamethasone differed per protocol. The incidences of several key AEs were lower in both arms following the planned reduction of bortezomib dosing frequency in TP2. In the panobinostat arm, rates of thrombocytopenia (grade 3/4: TP1, 56·7%; TP2, 6·0%), diarrhoea (grade 3/4: TP1, 24·1%; TP2, 7·1%), and fatigue (grade 3/4: TP1, 16·3%; TP2, 1·8%) were lower in TP2 compared with TP1. Dose intensity analysis of panobinostat and bortezomib by cycle in the panobinostat arm showed reductions of both agent doses during cycles 1-4 due to dose adjustments for AEs. Exposure-adjusted analysis demonstrated a reduction in thrombocytopenia frequency in TP1 following dose adjustment. These results suggest that optimization of dosing with this regimen could improve tolerability, potentially leading to improved patient outcomes. [ABSTRACT FROM AUTHOR]

Everolimus, an oral mammalian target of rapamycin ( mTOR) inhibitor, has been studied in multiple myeloma (MM) but lacks significant single agent activity. Based on preclinical studies showing synergistic activity of mTOR inhibitors with lenalidomide, we studied the combination of lenalidomide and everolimus in relapsed or refractory MM in a phase I clinical trial. We assessed patient samples using gene expression, Western blotting and immunohistochemistry to probe the mTOR pathway. Twenty-six patients were evaluable for toxicity. Dose-limiting toxicities included grade 4 neutropenia and thrombocytopenia. The maximum tolerated dose was lenalidomide 15 mg and everolimus 5 mg for 21 d with a 7 d rest period. Grade 3/4 adverse events included thrombocytopenia (35%) and neutropenia (42%). The overall response rate was 65% (1 complete response + 4 partial response + 10 minimal response). The median progression-free survival was 5·5 months and median overall survival was 29·5 months. Biomarker data demonstrated downregulation of phosphorylated p70S6K. Gene expression profiling suggested activation of mTOR in responders versus non-responders. The combination of lenalidomide and everolimus was well tolerated with predictable toxicities and showed responses in a heavily pretreated population. When confirmed with larger patient numbers, this analysis may guide patient selection for future clinical trials of mTOR inhibition in MM. [ABSTRACT FROM AUTHOR]

We present the case of a woman with relapsed multiple myeloma (MM) who received combination lenalidomide and bortezomib therapy for 90 cycles followed by continuous lenalidomide monotherapy and has completed over 100 cycles of treatment to date. The patient was diagnosed with advanced-stage, symptomatic MM in 2001. Following a partial response (PR) to dexamethasone in combination with pamidronate and thalidomide, the patient underwent protocol-directed non-myeloablative allogeneic bone marrow transplantation from her matched sibling donor the following year. In 2004, the patient relapsed and was enrolled in a phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and refractory MM. After eight cycles of study treatment, the patient achieved a minimal response. The patient received a total of 90 cycles of treatment with lenalidomide 5 mg given for 14 d every 21 d, and 1 mg/m2 of bortezomib initially given on days 1, 4, 8, and 11 for the first 20 cycles, and then weekly thereafter on days 1 and 8. Bortezomib was discontinued after 90 cycles, and the patient continued to receive lenalidomide monotherapy. As of cycle 100, the patient achieved a PR. Currently, she is clinically stable with response sustained for over 7 yrs. Therapy has been well tolerated with no significant long-term toxicity; no dose reductions of lenalidomide and bortezomib were required. The excellent tolerability of this steroid-free approach and the durable response seen underscore the potential benefits of participating in early-phase clinical trials evaluating novel therapies and new drug combinations. This case further supports that combination treatment with lenalidomide and bortezomib is an effective therapy in the management of patients with relapsed and refractory MM. [ABSTRACT FROM AUTHOR]

Osteolytic bone disease is a hallmark of symptomatic multiple myeloma. Bisphosphonates have been the mainstay of treatment to preserve skeletal integrity and prevent skeletal-related events in patients with myeloma-related bone disease. Recently, the MRC Myeloma IX trial demonstrated for the first time improved survival and delayed disease progression with the use of an intravenous amino-bisphosphonate, zoledronic acid, vs. an oral agent, clodronate, with intensive and non-intensive anti-myeloma treatment regimens in patients with newly diagnosed multiple myeloma. These results validate a large body of preclinical, translational and other clinical data suggesting anti-myeloma effects of amino-bisphosphonates. In addition, this trial also provided the first head-to-head evidence for superiority of one bisphosphonate over another (zoledronic acid vs. clodronate) for reducing skeletal morbidity in patients with multiple myeloma, as well as a prospective comparison of toxicities. Despite the use of non-bortezomib containing anti-myeloma treatment regimens in the MRC Myeloma IX trial, these results are encouraging and provide an impetus to continue to evaluate current treatment guidelines for myeloma-associated bone disease. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) cells express certain tumour-associated antigens (TAAs) that could serve as targets for active-specific immunotherapy. The aim of the present study was to test the MM/dendritic cell (DC) fusion as a vaccination strategy. We fused MM cells with DC to generate fusion cells (FCs) and tested their antigen presenting cell (APC) function in mixed lymphocyte reactions and cytotoxicity assays. First, the HS Sultan and SK0-007 HAT sensitive human MM cell lines and DCs generated from peripheral blood of normal donors were fused in the presence of 50% polyethylene glycol to form FCs. Next, tumour cells freshly isolated from patients were similarly fused with autologous DCs to generate FCs. The FCs demonstrated a biphenotypic profile, confirmed both by flow-cytometry and dual immunofluorescence microscopy. These FCs induced MM-specific cytotoxicity. FCs, but not MM cells or DCs alone, were potent stimulators of autologous patient T cells. More importantly, FC-primed autologous peripheral blood mononuclear cells demonstrated major histocompatibility complex-restricted MM-specific cytolysis. These studies therefore demonstrated that MM/DC FC can trigger an autologous immune response to MM cells and formed the framework for a clinical trial currently underway. [ABSTRACT FROM AUTHOR]

Summary. Multiple myeloma (MM) is associated with defects of humoral and cellular immunity, however, little is known about the frequency and function of antigen-specific CD8+ T cells. Such information might be critical for the development of immunotherapy for MM patients. As a model, we assessed the frequency and proliferation of CD8+ T cells specific for HLA-A*0201-restricted immunodominant epitopes from influenza A (Inf A) and Epstein–Barr virus (EBV). Experiments in identical twins demonstrated reduced numbers of antigen-specific T cells after ex-vivo antigenic challenge in the MM twin when compared with the healthy twin. Similarly, the proliferation and frequency of EBV- and Inf A-specific T cells was also significantly reduced in a cohort of 24 previously untreated or conventionally treated MM patients when compared with 19 healthy individuals. In contrast, MM patients studied after receiving an autologous stem cell transplantation showed strikingly higher frequencies of EBV-specific T cells with potential to proliferate ex vivo , suggesting that EBV-specific T cells are readily expandable under these circumstances. These data identify an impaired response of CD8+ T cells in MM patients, which might in part explain the relatively limited success of anti-MM immunisations. Prospective studies will determine whether such immune assessment strategies may identify patients more likely to benefit from cancer immunotherapy. [ABSTRACT FROM AUTHOR]

Multiple myeloma (MM) cells express certain tumour-associated antigens (TAAs) that could serve as targets for active-specific immunotherapy. The aim of the present study was to test the MM/dendritic cell (DC) fusion as a vaccination strategy. We fused MM cells with DC to generate fusion cells (FCs) and tested their antigen presenting cell (APC) function in mixed lymphocyte reactions and cytotoxicity assays. First, the HS Sultan and SK0-007 HAT sensitive human MM cell lines and DCs generated from peripheral blood of normal donors were fused in the presence of 50% polyethylene glycol to form FCs. Next, tumour cells freshly isolated from patients were similarly fused with autologous DCs to generate FCs. The FCs demonstrated a biphenotypic profile, confirmed both by flow-cytometry and dual immunofluorescence microscopy. These FCs induced MM-specific cytotoxicity. FCs, but not MM cells or DCs alone, were potent stimulators of autologous patient T cells. More importantly, FC-primed autologous peripheral blood mononuclear cells demonstrated major histocompatibility complex-restricted MM-specific cytolysis. These studies therefore demonstrated that MM/DC FC can trigger an autologous immune response to MM cells and formed the framework for a clinical trial currently underway.

Multiple myeloma (MM) is associated with defects of humoral and cellular immunity, however, little is known about the frequency and function of antigen-specific CD8+ T cells. Such information might be critical for the development of immunotherapy for MM patients. As a model, we assessed the frequency and proliferation of CD8+ T cells specific for HLA-A*0201-restricted immunodominant epitopes from influenza A (Inf A) and Epstein-Barr virus (EBV). Experiments in identical twins demonstrated reduced numbers of antigen-specific T cells after ex-vivo antigenic challenge in the MM twin when compared with the healthy twin. Similarly, the proliferation and frequency of EBV- and Inf A-specific T cells was also significantly reduced in a cohort of 24 previously untreated or conventionally treated MM patients when compared with 19 healthy individuals. In contrast, MM patients studied after receiving an autologous stem cell transplantation showed strikingly higher frequencies of EBV-specific T cells with potential to proliferate ex vivo, suggesting that EBV-specific T cells are readily expandable under these circumstances. These data identify an impaired response of CD8+ T cells in MM patients, which might in part explain the relatively limited success of anti-MM immunisations. Prospective studies will determine whether such immune assessment strategies may identify patients more likely to benefit from cancer immunotherapy.