[Show abstract][Hide abstract] ABSTRACT: In contrast to the upfront setting in which the role of high dose therapy with autologous hematopoietic cell transplantation (HCT) as consolidation of a 1(st) 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.
Biology of blood and marrow transplantation: journal of the American Society for Blood and Marrow Transplantation 10/2015; 21(12). DOI:10.1016/j.bbmt.2015.09.016 · 3.40 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Treatment options for patients with heavily pretreated relapsed and/or refractory multiple myeloma remain limited. We evaluated a novel therapeutic regimen consisting of carfilzomib, pomalidomide, and dexamethasone in an open-label, multicenter, phase 1, dose-escalation study. Patients that relapsed after prior therapy or were refractory to the most recently received therapy were eligible. All patients were refractory to prior lenalidomide. Patients received carfilzomib intravenously on days 1, 2, 8, 9, 15, and 16 (starting dose of 20/27 mg/m(2)), pomalidomide once daily on days 1-21 (4 mg as the initial dose level) and dexamethasone (40 mg oral or IV) on days 1, 8, 15, and 22 of 28-day cycles. The primary objective was to evaluate the safety and determine the maximum tolerated dose (MTD) of the regimen. A total of 32 patients were enrolled. The MTD of the regimen was dose level 1 (carfilzomib 20/27 mg/m(2), pomalidomide 4 mg, dexamethasone 40 mg). Hematological adverse events occurred in ≥60% of all patients, including eleven patients with grade ≥3 anemia. Dyspnea was limited to grade 1/2 in ten patients. Peripheral neuropathy was uncommon and limited to grade 1/2. Eight patients had dose reductions during therapy, and seven patients discontinued treatment due to adverse events. Two deaths were noted on study due to pneumonia and pulmonary embolism (n=1 each). The combination of carfilzomib, pomalidomide, and dexamethasone is well-tolerated and highly active in patients with RRMM. This study was funded by Onyx Pharmaceuticals, Inc., an Amgen subsidiary, and Celgene Corporation. The trial was registered with www.Clinicaltrials.gov: identifier NCT01464034.
[Show abstract][Hide abstract] ABSTRACT: A patient with refractory multiple myeloma received an infusion of CTL019 cells, a cellular therapy consisting of autologous T cells transduced with an anti-CD19 chimeric antigen receptor, after myeloablative chemotherapy (melphalan, 140 mg per square meter of body-surface area) and autologous stem-cell transplantation. Four years earlier, autologous transplantation with a higher melphalan dose (200 mg per square meter) had induced only a partial, transient response. Autologous transplantation followed by treatment with CTL019 cells led to a complete response with no evidence of progression and no measurable serum or urine monoclonal protein at the most recent evaluation, 12 months after treatment. This response was achieved despite the absence of CD19 expression in 99.95% of the patient's neoplastic plasma cells. (Funded by Novartis and others; ClinicalTrials.gov number, NCT02135406.).
New England Journal of Medicine 09/2015; 373(11):1040-7. DOI:10.1056/NEJMoa1504542 · 55.87 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: In patients with multiple myeloma (MM) undergoing autologous hematopoietic cell transplantation (auto-HCT), peripheral blood progenitor cells may be collected following mobilization with growth factor alone (GF) or cytotoxic chemotherapy plus GF (CC+GF). It is uncertain whether the method of mobilization affects post-transplant outcomes. We compared these mobilization strategies in a retrospective analysis of 968 patients with MM from the Center for International Blood and Marrow Transplant Research database who received an auto-HCT in the US and Canada between 2007 and 2012. The kinetics of neutrophil engraftment (⩾0.5 × 10(9)/L) was similar between groups (13 vs 13 days, P=0.69) while platelet engraftment (⩾20 × 10(9)/L) was slightly faster with CC+GF (19 vs 18 days, P=0.006). Adjusted 3-year PFS was 43% (95% confidence interval (CI) 38-48) in GF and 40% (95% CI 35-45) in CC+GF, P=0.33. Adjusted 3-year OS was 82% (95% CI 78-86) vs 80% (95% CI 75-84), P=0.43 and adjusted 5-year OS was 62% (95% CI 54-68) vs 60% (95% CI 52-67), P=0.76, for GF and CC+GF, respectively. We conclude that MM patients undergoing auto-HCT have similar outcomes irrespective of the method of mobilization and found no evidence that the addition of chemotherapy to mobilization contributes to disease control.Bone Marrow Transplantation advance online publication, 24 August 2015; doi:10.1038/bmt.2015.190.
Bone marrow transplantation 08/2015; DOI:10.1038/bmt.2015.190 · 3.57 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Despite recent therapeutic advances, multiple myeloma (MM) remains largely incurable. Here we report results of a phase I/II trial to evaluate the safety and activity of autologous T cells engineered to express an affinity-enhanced T cell receptor (TCR) recognizing a naturally processed peptide shared by the cancer-testis antigens NY-ESO-1 and LAGE-1. Twenty patients with antigen-positive MM received an average 2.4 × 10(9) engineered T cells 2 d after autologous stem cell transplant. Infusions were well tolerated without clinically apparent cytokine-release syndrome, despite high IL-6 levels. Engineered T cells expanded, persisted, trafficked to marrow and exhibited a cytotoxic phenotype. Persistence of engineered T cells in blood was inversely associated with NY-ESO-1 levels in the marrow. Disease progression was associated with loss of T cell persistence or antigen escape, in accordance with the expected mechanism of action of the transferred T cells. Encouraging clinical responses were observed in 16 of 20 patients (80%) with advanced disease, with a median progression-free survival of 19.1 months. NY-ESO-1-LAGE-1 TCR-engineered T cells were safe, trafficked to marrow and showed extended persistence that correlated with clinical activity against antigen-positive myeloma.
Nature medicine 07/2015; 21(8). DOI:10.1038/nm.3910 · 27.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: This phase 1/2 study was the first to evaluate the safety and efficacy of the cyclin-dependent kinase (CDK) 4/6-specific inhibitor palbociclib (PD-0332991) in sequential combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. The recommended phase 2 dose was palbociclib 100 mg orally once daily on days 1-12 of a 21-day cycle with bortezomib 1.0 mg/m(2) (intravenous) and dexamethasone 20 mg (orally 30 min pre-bortezomib dosing) on days 8 and 11 (early G1 arrest) and days 15 and 18 (cell cycle resumed). Dose-limiting toxicities were primarily cytopenias; most other treatment-related adverse events were grade ≤3. At a bortezomib dose lower than that in other combination therapy studies, antitumor activity was observed (phase 1). In phase 2, objective responses were achieved in 5 (20%) patients; 11 (44%) achieved stable disease. Biomarker and pharmacodynamic assessments demonstrated that palbociclib inhibited CDK4/6 and the cell cycle initially in most patients. ClinicalTrials.gov number=NCT00555906.
[Show abstract][Hide abstract] ABSTRACT: Background Circulating plasma cells (PCs) have been identified as a prognostic factor in patients with myeloma precursor states (MGUS and SMM) and active multiple myeloma (MM). Enumeration of circulating PCs by available methods is not suitable for widespread use and does not provide molecular characterization. We developed and evaluated a novel method for enumeration and molecular characterization of circulating PCs (circulating multiple myeloma cells, “CMMC”), based on the CELLSEARCH® System (Janssen Diagnostics LLC, Raritan, NJ), an automated technology for the capture, enumeration and characterization of rare cells in the peripheral blood.
Methods We are performing a prospective study of patients with MGUS and SMM to evaluate CMMCs as biomarker for progression to active MM. Utilizing the CELLSEARCH® System CMMCs were captured by CD138 ferrofluid magnetic particles and identification was defined as CD38+ and CD19-, CD45-. Nonviable cells were excluded by DAPI. Isolated CMMCs were stored and FISH for t(4:14), t(14;16) and del17 was performed.
Results We have enrolled 16 patients, MGUS = 3, SMM = 11, and newly diagnosed MM = 2. The Mayo Risk stratification for MGUS patients was: low risk = 2, low-intermediate = 1. All SMM patients were low risk by Mayo Model incorporating serum free light chains. The median number of bone marrow plasma cells for MGUS patients was 7 (range 7-9) and for SMM patients was 15 (range 10-40). The median CMMCs for MGUS = 6 (range 2-55), median CMMCs for SMM = 31 (5-1918). The two patients with NDMM had 5870 and 5 CMMCs, respectively. A single patient with SMM progressed with a symptomatic solitary lumbar plasmacytoma and had CMMCs of 5 and 3 at baseline and progression, respectively. Abnormalities by FISH were detected in both bone marrow and CMMCs. Accrual is ongoing and additional data will be presented at the meeting.
Conclusions The CELLSEARCH® CMMC assay can detect, quantify and provide molecular characterization of circulating PCs in MGUS/SMM/MM; longer prospective follow-up is needed to test the prognostic value of CMMCs.
Disclosures Weiss: Janssen: Consultancy, Research Funding. Sasser: Janssen: Employment. Rao: Janssen: Employment, Equity Ownership. Foulk: Janssen: Employment. Gross: Johnson & Johnson: Employment, Equity Ownership. Cohen: Janssen: Membership on an entity's Board of Directors or advisory committees. Vogl: Celgene Corporation: Consultancy; Amgen: Consultancy; Millennium/Takeda: Research Funding; GSK: Research Funding; Acetylon: Research Funding. Stadtmauer: Janssen: Consultancy.