Ehsan Malek

Multiple Myeloma, version 3.2018: Featured updates to the NCCN guidelines

The NCCN Guidelines for Multiple Myeloma provide recommendations for diagnosis, evaluation, treatment, including supportive-care, and follow-up for patients with myeloma. These NCCN Guidelines Insights highlight the important updates/changes specific to the myeloma therapy options in the 2018 version of the NCCN Guidelines.

Abstract 2647: TGF-β type I receptor inhibitor (TEW-7197) diminishes myeloma progression by multiple immunomodulatory mechanisms in combination with ixazomib

Background: Multiple myeloma (MM) is an incurable cancer of plasma cells. MM thrives in the bone marrow tumor microenvironment (TME) where several factors sustain MM growth and viability. TGF-β is a multi-functional cytokine elaborated by MM cells and by cells in the bone marrow (BM) TME. TGF-β stimulates MM progression through promotion of catabolic bone remodeling, IL-6 secretion and Th17 T cell development, which act in concert to induce osteolytic bone disease, immune suppression and myeloma progression. Therefore, we evaluated the anti-MM therapeutic potential of a small molecule inhibitor of the TGF-β type I receptor kinase (TβRI), TEW-7197, in combination with the proteasome inhibitor, ixazomib. Currently, TEW-7197 is being evaluated in phase I clinical trials in patients with solid tumors, and exposure to this agent is associated with an acceptable tolerability profile. Methods: The preclinical immunocompetent 5T33MM model (C57BL/KaLwRij) was used to characterize the role of TGF-β signaling in the BM TME. Mice bearing 5T33MM cells expressing luciferase were treated with TEW-7197, ixazomib and the combination of TEW-7197 plus ixazomib daily for 3 weeks, and evaluated for MM growth by bioluminescence imaging (BLI). Cellular and molecular assays were performed in human RPMI8226 and U266 as well as murine 5T33MM cells via apoptosis, real-time PCR and Western blotting. Immunological assays were performed via immunohistochemistry and FACS analyses. Peripheral blood monoclonal protein concentration, M-spike, was measured by ELISA. Results: TEW-7197 attenuated the growth and viability of human and murine MM cells by inducing apoptosis and it inhibited TGF-β-induced activation of Smad2/3 in MM cells in vitro. In our 5T33MM preclinical model, oral administeration of TEW-7197 as single agent inhibited MM progression as measured by peripheral blood monoclonal protein concentration and BLI before and after treatment. TEW-7197 also induced a decrease in mortality and an increase in body weight of mice bearing MM. TEW-7197 alone or combination with ixazomib also attenuated TGF-β activation of Smad2/3, reduced the expansion of CD11b+Gr-1+ myeloid derived suppressor cells (MDSCs) in BM TME, and diminished the population of Foxp3+ regulatory T cells (Treg) in the spleen. Combination therapy of TEW-7197 plus ixazomib prolonged survival and exhibited a synergistic anti-tumor effect when compared to either TEW-7197 or ixazomib alone by significant a reduction in both the M-spike and BLI. Conclusion: Our data demonstrate that the small molecule inhibitor of the TβRI, TEW-7197, effectively modulate the MM TME and is associated with a potent anti-myeloma effect in an immunocompetent murine model of MM. These data provide a rationale for clinical evaluation of the combination therapy of ixazomib and TEW-7197 as a potential therapeutic strategy to improve outcomes in patients with MM. Citation Format: Byung-Gyu Kim, Olga Sergeeva, George Luo, Sung Hee Choi, Zhenghong Lee, Seong-Jin Kim, John Letterio, Ehsan Malek. TGF-β type I receptor inhibitor (TEW-7197) diminishes myeloma progression by multiple immunomodulatory mechanisms in combination with ixazomib [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 2647. doi:10.1158/1538-7445.AM2017-2647

Significance of the absolute lymphocyte/monocyte ratio as a prognostic immune biomarker in newly diagnosed multiple myeloma

Significance of the absolute lymphocyte/monocyte ratio as a prognostic immune biomarker in newly diagnosed multiple myeloma

Amifostine reduces gastro-intestinal toxicity after autologous transplantation for multiple myeloma

Abstract High-dose melphalan (HDM) followed by autologous hematopoietic cell transplantation (auto-HCT) remains the standard-of-care therapy for multiple myeloma (MM) even with the availability of proteasome inhibitors and immunomodulatory drugs. Gastrointestinal (GI) toxicity is the main cause of morbidity after HDM. Amifostine, a cytoprotective agent, may reduce HDM-associated GI toxicity. We conducted a case control study comparing HDM + auto-HCT with or without amifostine for MM patients. One hundred and seven patients treated at University Hospitals Cleveland Medical Center who received pre-transplant amifostine were compared to 114 patients treated at MD Anderson Cancer Center without use of this agent. Amifostine 740 mg/m2 was administered as a bolus infusion at 24 h and 15 min before HDM. Patients’ characteristics were similar in both the groups. Amifostine therapy was well tolerated without any significant adverse effects. Grade II or greater oral mucositis (27.1% vs 47.4%; p = .002), nausea (31.8% vs. 86.0%; p = .0001), vomiting (18.7% vs. 52.6%; p = .0001) and diarrhea (56.1% vs. 72.7%; p = .006) occurred less frequently in the amifostine-treated group. There was no discernable effect of amifostine on engraftment, progression-free or overall survival. Our results indicate that amifostine decreases GI toxicity while preserving anti-myeloma efficacy of HDM and auto-HCT.

Low dose anti-thymocyte globulin reduces chronic graft-versus-host disease incidence rates after matched unrelated donor transplantation

Abstract Anti-thymocyte globulin (ATG) is often added to hematopoietic stem cell transplant conditioning regimens to prevent graft rejection and reduce graft-versus-host disease (GVHD). Doses used in retrospective and prospective clinical trials have ranged from 2.5 to 20 mg/kg with rates of grade II–IV acute GVHD and chronic GVHD up to 40 and 60%, respectively. We retrospectively compared outcomes in recipients of matched unrelated donor (MUD) grafts given low dose rabbit ATG IV 3 mg/kg (n = 52) versus recipients of matched related donor (MRD) grafts (n = 48) without ATG. One year cumulative incidence of chronic GVHD was 25.2% in the MUD group versus 33.3% in the MRD group (p = .5). One-year cumulative incidence of extensive chronic GVHD was 9.6% in the MUD group versus 26.6% in the MRD group (p = .042). Our analysis supports the use of low dose ATG in MUD transplantation as an effective therapy to prevent chronic GVHD.

Staging Systems for Newly Diagnosed Myeloma Patients Undergoing Autologous Hematopoietic Cell Transplantation: The Revised International Staging System Shows the Most Differentiation between Groups

The Revised International Staging System (R-ISS) and the International Myeloma Working Group 2014 (IMWG 2014) are newer staging systems used to prognosticate multiple myeloma (MM) outcomes. We hypothesized that these would provide better prognostic differentiation for newly diagnosed multiple myeloma (MM) compared with ISS. We analyzed the Center for International Blood and Marrow Transplant Research database from 2008 to 2014 to compare the 3 systems (N = 628) among newly diagnosed MM patients undergoing upfront autologous hematopoietic cell transplantation (AHCT). The median follow-up of survivors was 48 (range, 3 to 99) months. The R-ISS provided the greatest differentiation between survival curves for each stage (for overall survival [OS], the differentiation was 1.74 using the R-ISS, 1.58 using ISS, and 1.60 using the IMWG 2014) . Univariate analyses at 3 years for OS showed R-ISS I at 88% (95% confidence interval [CI], 83% to 93%), II at 75% (95% CI, 70% to 80%), and III at 56% (95% CI, 3% to 69%; P < .001). An integrated Brier score function demonstrated the R-ISS had the best prediction for PFS, though all systems had similar prediction for OS. Among available systems, the R-ISS is the most optimal among available prognostic tools for newly diagnosed MM undergoing AHCT. We recommend that serum lactate dehydrogenase and cytogenetic data be performed on every MM patient at diagnosis to allow accurate prognostication.

Interference of Therapeutic Monoclonal Antibodies With Routine Serum Protein Electrophoresis and Immunofixation in Patients With MyelomaFrequency and Duration of Detection of Daratumumab and Elotuzumab

Objectives We investigated the frequency and pattern of detection of therapeutic monoclonal antibodies (t-mAbs) daratumumab and elotuzumab by routine serum protein electrophoresis (SPE) and immunofixation (IF) in treated patients with myeloma. Methods Detection of t-mAb was assessed in 22 patients by retrospective review of SPE/IF ordered prior to, during, and after 26 individual courses of therapy. Results t-mAb was distinguishable from M-protein in 16 of 26 courses, with daratumumab detected in nine of nine and elotuzumab in six of seven patients. t-mAb was detected on first follow-up SPE/IF in 12 patients, with earliest detection 7 days after therapy initiation and latest detection 70 days after therapy. t-mAb persisted throughout induction therapy in most patients, with loss of detection during maintenance daratumumab. Conclusions When distinguishable from M-protein, t-mAbs are detectable in 93% of treated patients as soon as 7 days after the initial dose and are consistently observed throughout induction therapy, warranting increased monitoring and careful interpretation of SPE/IF.

Allograft for myeloma: Examining pieces of the Jigsaw Puzzle

Multiple myeloma (MM) cure remains elusive despite the availability of newer anti-myeloma agents. Patients with high-risk disease often suffer from early relapse and short survival. Allogeneic hematopoietic cell transplantation (allo-HCT) is an “immune-based” therapy that has the potential to offer long-term remission in a subgroup of patients, at the expense of high rates of transplant-related morbidity and mortality. Donor lymphocyte infusion (DLI) upon disease relapse after allo-HCT is able to generate an anti-myeloma response suggestive of a graft-versus-myeloma effect. Allo-HCT provides a robust platform for additional immune-based therapy upon relapse including DLI and, maintenance with immunomodulatory drugs and immunosuppressive therapy. There have been conflicting findings from randomized prospective trials questioning the role of allo-HCT. However, to this date, allo-HCT remains the only potential curable treatment for MM and its therapeutic role needs to be better defined especially for patients with high-risk disease. This review examines different aspects of this treatment and summarizes ongoing attempts at improving its therapeutic index.