Faculty Bibliography

BACKGROUND: New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma. METHODS: In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age >/=18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126. FINDINGS: The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation. INTERPRETATION: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients. FUNDING: Janssen Research & Development.

In contrast to the upfront setting in which the role of high dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a 1st remission in patients with multiple myeloma (MM) is well established, the role of high dose therapy with autologous or allogeneic HCT has not been extensively studied in MM patients relapsing after primary therapy. The International Myeloma Working Group together with the Blood and Marrow Transplant Clinical Trials Network (BMT-CTN), the American Society of Blood and Marrow Transplantation (ASBMT), and the European Society of Blood and Marrow Transplantation (EBMT) convened a meeting of MM experts to: 1. Summarize current knowledge regarding the role of autologous or allogeneic HCT in MM patients progressing after primary therapy; 2. Propose guidelines for the use of salvage HCT in MM; 3. Identify knowledge gaps; 4 Propose a research agenda and 5. Develop a collaborative initiative to move the research agenda forward. After reviewing the available data, the expert committee came to the following consensus statement for salvage autologous HCT: 1. In transplant eligible patients relapsing after primary therapy that did NOT include an autologous HCT, high dose therapy with HCT as part of salvage therapy should be considered standard; 2. High dose therapy and autologous HCT should be considered appropriate therapy for any patients relapsing after primary therapy that includes an autologous HCT with initial remission duration of more than 18 months; 3. High dose therapy and autologous HCT can be used as a bridging strategy to allogeneic HCT; 4. The role of post salvage HCT maintenance needs to be explored in the context of well designed prospective trials that should include new agents such as monoclonal antibodies, immune-modulating agents and oral proteasome inhibitors; 5. Autologous HCT consolidation should be explored as a strategy to develop novel conditioning regimens or post HCT strategies in patients with short (less than 18 months remissions) after primary therapy; 6. Prospective randomized trials need to be performed to define the role of salvage autologous HCT in patients with MM relapsing after primary therapy comparing to "best non HCT" therapy. The expert committee also underscored the importance of collecting enough hematopoietic stem cells to perform two transplants early in the course of the disease. In regards to allogeneic HCT the expert committee agreed on the following consensus statements: 1. Allogeneic HCT should be considered appropriate therapy for any eligible patient with early relapse (less than 24 months) after primary therapy that included an autologous HCT and/or high risk features (i.e cytogenetics, extramedullary disease, plasma cell leukemia or high LDH); 2. Allogeneic HCT should be performed in the context of a clinical trial if possible; 3. The role of post allogeneic HCT maintenance therapy needs to be explored in the context of well designed prospective trials; 4. Prospective randomized trials need to be performed to define the role salvage allogeneic HCT in patients with MM relapsing after primary therapy.

BackgroundThe personalization of cancer treatments implies the reconsideration of a one-size-fits-all paradigm. This move has spawned increased use of next generation sequencing to understand mutations and copy number aberrations in cancer cells. Initial personalization successes have been primarily driven by drugs targeting one patient-specific oncogene (e.g., Gleevec, Xalkori, Herceptin). Unfortunately, most cancers include a multitude of aberrations, and the overall impact on cancer signaling and metabolic networks cannot be easily nullified by a single drug.MethodsWe used a novel predictive simulation approach to create an avatar of patient cancer cells using point mutations and copy number aberration data. Simulation avatars of myeloma patients were functionally screened using various molecularly targeted drugs both individually and in combination to identify drugs that are efficacious and synergistic. Repurposing of drugs that are FDA-approved or under clinical study with validated clinical safety and pharmacokinetic data can provide a rapid translational path to the clinic. High-risk multiple myeloma patients were modeled, and the simulation predictions were assessed ex vivo using patient cells.ResultsHere, we present an approach to address the key challenge of interpreting patient profiling genomic signatures into actionable clinical insights to make the personalization of cancer therapy a practical reality. Through the rational design of personalized treatments, our approach also targets multiple patient-relevant pathways to address the emergence of single therapy resistance. Our predictive platform identified drug regimens for four high-risk multiple myeloma patients. The predicted regimes were found to be effective in ex vivo analyses using patient cells.ConclusionsThese multiple validations confirm this approach and methodology for the use of big data to create personalized therapeutics using predictive simulation approaches.

Background: Extracellular matrix (ECM) characteristics, including stiffness, geometry, chemistry, and spatial interaction with the neighboring cells and soluble factors are key components for cancer cell survival in a pathogenic tissue microenvironment (TME). However, poor performance of 2D in vitro systems and animal models for metastatic cancer types demands physiologically relevant well controlled 3D platforms to quantitatively assess (a) metastatic cancer stem cell survival (b) oncogenic mechanisms and (c) drug resistant phenotypes and (d) new drug efficacy. Advances in the "state of the art" 3D platforms with difference in matrix stiffness and viscoelastic properties are showing promising results in identifying changes in drug resistant phenotypes, cell behavior and gene expression profiles. Preliminary findings by us and others using 3D matrices for human multiple myeloma (MM) reveal promising results on cancer /stromal cell interactions. In this study we have shown that Hyaluronic acid (HA) based 3D hydrogel support human metastatic MM cancer cells survival and thus reveal new oncogenic mechanisms of drug resistant cancer stem cells. Experimental approaches: Bone marrow derived CD138 positive cells and BMSCs were isolated from MM patient samples (with IRB approval) using magnetically labeled CD138 MicroBeads (autoMACS Pro Starting Kit). Bone marrow stromal cells (BMSCs) were cultured as described by us earlier. Cell viability measurements and quantitative RT-PCR for c-myc and other related gene targets were performed using total RNA. Me-HA-3D hydrogels were created containing either fibronectin/collagen/laminin or ME-HA mixture of Matrigel/fibronectin/laminin in different ratios. Cells were grown as surface seeded or encapsulated in Me-HA gels, and analyzed between 4 and 21 days in the conditioned medium. Cell proliferation analysis was performed by both MTS and live dead cell assays using CFSE stain. Results: The overall cell viability by surface coating and in encapsulated gel was found to be higher than 80% for up to 21 days in all the conditions including changes in the UV cross linking time and gel stiffness. Colony forming units (CFU) of the mononuclear cells were higher (27%) at 21 days compared to the 4 days 3% (p>0.001). Spheroids were found on the surface of the hydrogels with PC-3 cells as well as inside the encapsulated hydrogels specifically for MM, and were higher in numbers (>30%) compared to that in surface coating (5%) p>0.001. qRT-PCR analysis determined c-myc, cyclin D1, E-cadherin, and ZEB-1 showed>4 fold increase (p>0.001) in encapsulated cells compared to that in cells transfected with siRNA for c-myc, suggesting c-myc mediated cell survival in 3D. Summary: Me-HA hydrogels are found to be suitable platform for the first time to identify new metastatic cancer phenotypes types and to investigate drug resistance mechanisms