[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: We examined four clinically assessed cytogenetic subtypes (t(11;14), t(4;14), monosomy 13/del13q and monosomy 17/del17p in 292 black patients with newly diagnosed multiple myeloma (MM) from four medical centers, who had fluorescent in situ hybridization testing results available in their medical records. We then compared the prevalence of these abnormalities with a previously characterized Mayo Clinic cohort of 471 patients with MM. We found a significant difference in the prevalence of the t(11;14) immunoglobulin heavy chain (IgH) translocation between blacks and whites, 6.5% versus 17.6%, respectively, P<0.0001. Blacks also had lower rates of the t(4;14) IgH translocation, (5.5% versus 10%); monosomy 13/del13q (29.1 versus 49.3%); and monosomy 17/del17p (7.9% versus 13%). Consequently, 63.4% of blacks versus 34.6% of whites did not have any of the four abnormalities that we studied, P<0.001. As almost all MM is associated with either an IgH translocation or trisomies, we hypothesize that MM in blacks is associated with either excess prevalence of either the trisomic (hyperdiploid) form of MM or an IgH translocation besides t(11;14) or t(4;14). We conclude that there are significant differences in the cytogenetic subtypes of MM that occur in blacks and whites.
Blood Cancer Journal 01/2015; 4(2):e271. DOI:10.1038/bcj.2014.91 · 3.47 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Carfilzomib is an irreversible inhibitor of the constitutive proteasome and immunoproteasome. This phase I study evaluated the maximum-tolerated dose (MTD), pharmacokinetics, and pharmacodynamics of carfilzomib administered as a 30-minute intravenous (IV) infusion. Safety and efficacy of carfilzomib as a single agent or in combination with low-dose dexamethasone were assessed.
Patients and methods:
Patients with relapsed and/or refractory multiple myeloma (MM) were administered single-agent carfilzomib on days 1, 2, 8, 9, 15, and 16 of a 28-day cycle. Cycle one day 1 and 2 doses were 20 mg/m(2), followed thereafter by dose escalation to 36, 45, 56, or 70 mg/m(2). Additionally, carfilzomib was combined with low-dose dexamethasone (40 mg/wk).
Thirty-three patients were treated with single-agent carfilzomib. Dose-limiting toxicities in two patients at 70 mg/m(2) were renal tubular necrosis and proteinuria (both grade 3). The MTD was 56 mg/m(2). Nausea (51.5%), fatigue (51.5%), pyrexia (42.4%), and dyspnea and thrombocytopenia (each 39.4%) were the most common treatment-related toxicities. Overall response rate (ORR) was 50% (56-mg/m(2) cohort). Increasing carfilzomib dosing from 20 to 56 mg/m(2) resulted in higher area under the plasma concentration-time curve from time zero to last sampling and maximum plasma concentration exposure with short half-life (range, 0.837 to 1.21 hours) and dose-dependent inhibition of proteasome chymotrypsin-like activity. In 22 patients treated with 45 or 56 mg/m(2) of carfilzomib plus low-dose dexamethasone, the ORR was 55% with a safety profile comparable to that of single-agent carfilzomib.
Carfilzomib administered as a 30-minute IV infusion at 56 mg/m(2) (as single agent or with low-dose dexamethasone) was generally well tolerated and highly active in patients with relapsed and/or refractory MM. These data have provided the basis for the phase III randomized, multicenter trial ENDEAVOR.
[Show abstract][Hide abstract] ABSTRACT: Background. Peripheral neuropathy is the dose limiting toxicity of bortezomib in patients with multiple myeloma (MM). Objectives. To examine the safety, feasibility and efficacy of acupuncture in reducing bortezomib-induced peripheral neuropathy (BIPN) symptoms. Methods. Patients with MM experiencing persistent BIPN ≥grade 2 despite adequate medical intervention and discontinuation of bortezomib received 10 acupuncture treatments for 10 weeks (2×/week for 2 weeks, 1×/week for 4 weeks, and then biweekly for 4 weeks). Responses were assessed by the Clinical Total Neuropathy Score (TNSc), Functional Assessment of Cancer Therapy/Gynecologic Oncology Group-Neurotoxicity (FACT/GOG-Ntx) questionnaire, and the Neuropathy Pain Scale (NPS). Repeated-measures analysis of variance was used to test for monotonic decline in scores on each of the measures. Serial serum levels of proinflammatory and neurotrophic cytokines were obtained at baseline and weeks 1, 2, 4, 8, and 14. Results. Twenty-seven patients with MM were enrolled in the trial. There were no adverse events associated with the acupuncture treatments. TNSc data were deemed invalid and therefore were not reported. At weeks 10 and 14, FACT/GOG-Ntx and NPS showed significant reduction suggesting decreased pain, and improved function (P values were <.0001 for both FACT/GOG-Ntx and NPS at weeks 10 and 14). However, nerve conduction studies did not significantly change between baseline assessment and end of study. There was no correlation in serum cytokines for responders versus none responders. Conclusions. Acupuncture is safe, feasible and produces subjective improvements in patients' symptoms. A follow-up randomized controlled trial is warranted.
Integrative Cancer Therapies 05/2014; 13(5). DOI:10.1177/1534735414534729 · 2.36 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Multiple myeloma (MM) in patients aged greater than 80 years poses an increasingly common challenge for oncology providers. A multidisciplinary workshop was held in which MM-focused hematologists/oncologists, geriatricians, and associated health-care team members discussed the state of research for MM therapy, as well as themes from geriatric medicine that pertain directly to this patient population. A summary statement of our discussions is presented here, in which we highlight several topics. MM disproportionately affects senior adults, and demographic trends indicate that this trend will accelerate. Complex issues impact cancer in seniors, and although factors such as social environment, comorbidities, and frailty have been well characterized in nononcological geriatric medicine, these themes have been inadequately explored in cancers such as MM, despite their clear relevance to this field. Therapeutically, novel agents have improved survival for MM patients of all ages, but less so for seniors than younger patients for a variety of reasons. Lastly, both MM- and treatment-related symptoms and toxicities require special attention in senior adults. Existing research provides limited insight into how best to manage these often complex patients, who are often not reflected in typical clinical trial populations. We hence offer suggestions for clinical trials that address knowledge gaps in how to manage very old and/or frail patients with MM, given the complicated issues that often surround this patient population.
Journal of the National Cancer Institute 04/2014; 106(5). DOI:10.1093/jnci/dju067 · 12.58 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Purpose:
Myeloma-directed cellular immune responses after autologous stem cell transplantation (ASCT) may reduce relapse rates. We studied whether coinjecting the TLR-3 agonist and vaccine adjuvant Poly-ICLC with a MAGE-A3 peptide vaccine was safe and would elicit a high frequency of vaccine-directed immune responses when combined with vaccine-primed and costimulated autologous T cells.
In a phase II clinical trial (NCT01245673), we evaluated the safety and activity of ex vivo expanded autologous T cells primed in vivo using a MAGE-A3 multipeptide vaccine (compound GL-0817) combined with Poly-ICLC (Hiltonol), granulocyte macrophage colony-stimulating factor (GM-CSF) ± montanide. Twenty-seven patients with active and/or high-risk myeloma received autografts followed by anti-CD3/anti-CD28-costimulated autologous T cells, accompanied by MAGE-A3 peptide immunizations before T-cell collection and five times after ASCT. Immune responses to the vaccine were evaluated by cytokine production (all patients), dextramer binding to CD8(+) T cells, and ELISA performed serially after transplant.
T-cell infusions were well tolerated, whereas vaccine injection site reactions occurred in >90% of patients. Two of nine patients who received montanide developed sterile abscesses; however, this did not occur in the 18 patients who did not receive montanide. Dextramer staining demonstrated MAGE-A3-specific CD8 T cells in 7 of 8 evaluable HLA-A2(+) patients (88%), whereas vaccine-specific cytokine-producing T cells were generated in 19 of 25 patients (76%). Antibody responses developed in 7 of 9 patients (78%) who received montanide and only weakly in 2 of 18 patients (11%) who did not. The 2-year overall survival was 74% [95% confidence interval (CI), 54%-100%] and 2-year event-free survival was 56% (95% CI, 37%-85%).
A high frequency of vaccine-specific T-cell responses were generated after transplant by combining costimulated autologous T cells with a Poly-ICLC/GM-CSF-primed MAGE-A3 vaccine.
Clinical Cancer Research 02/2014; 20(5). DOI:10.1158/1078-0432.CCR-13-2817 · 8.72 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: We retrospectively evaluated the tolerability and efficacy of fractionated total body irradiation (TBI) (1,200 cGy) and melphalan (MEL) (100-110 mg/m(2)) myeloablative conditioning in 48 patients with nonremission AML (n = 14), ALL (n = 10), NHL (n = 18), and other refractory hematologic malignancies (n = 6) who received allogeneic stem cell transplantation (SCT) between 2002 and 2011. Median age was 48 years (22 to 68); 14 out of 26 leukemia patients (54 %) had circulating blasts at transplant, 20 (50 %) evaluable patients had poor-risk cytogenetics, 12 (25 %) had prior SCT, and 10 (21 %) received stem cells from a mismatch donor. All patients received tacrolimus with or without methotrexate for GVHD prophylaxis. At the time of analysis, 13 patients (27 %) were alive and disease free. Engraftment was complete in all patients. The median time to ANC recovery (>500) was 12 days (range, 6-28). The most common grade III and IV toxicities were mucositis and infections. Eighteen patients (43 %) developed grade II-IV acute GVHD, and eight (26 %) had extensive chronic GVHD. Of 44 evaluable patients for response, 28 (64 %) achieved a complete remission (CR), and seven (15 %) had a partial remission after the transplant. With a median follow-up of 30 months (4 to 124 months) for surviving patients, the cumulative incidence of relapse was 45 % at 1 year, and the probability of overall survival (OS) at 5 years was 22.5 %. Multivariate analysis showed that platelet count (<80,000/mL) and lactic dehydrogenase (>500 IU/L) at SCT were associated with relapse. Age less than 53 years and CR after SCT were associated with better OS. Our data suggest that TBI-MEL can result in CR in two thirds, durable remission in one third, and 5-year survival in about one quarter of patients with nonremission hematologic malignancies. Further studies with TBI-MEL in standard risk transplant patients are warranted.
Annals of Hematology 10/2013; 93(4). DOI:10.1007/s00277-013-1908-9 · 2.63 Impact Factor
[Show abstract][Hide abstract] ABSTRACT: Carfilzomib, a selective proteasome inhibitor, was approved in 2012 for the treatment of relapsed and refractory multiple myeloma. Safety data for single-agent carfilzomib have been analyzed for 526 patients with advanced multiple myeloma who took part in 1 of 4 phase 2 studies (PX-171-003-A0, PX- 171-003-A1, PX-171-004, and PX-171-005). Overall analyses of adverse events and treatment modifications are presented, as well as specific analyses of adverse events by organ system. Overall, the most common adverse events of any grade included fatigue (55.5%), anemia (46.8%), and nausea (44.9%). In the grouped analyses, any grade adverse events were reported in 22.1% for any cardiac (7.2% cardiac failure), 69.0% for any respiratory (42.2% dyspnea), and 33.1% for any grouped renal impairment adverse event (24.1% increased serum creatinine). The most common non-hematologic adverse events were generally Grade 1 or 2 in severity, while Grade 3/4 adverse events were primarily hematologic and mostly reversible. There was no evidence of cumulative bone marrow suppression, either neutropenia or thrombocytopenia, and febrile neutropenia occurred infrequently (1.1%). Notably, the incidence of peripheral neuropathy was low overall (13.9%) including in patients with baseline peripheral neuropathy (12.7%). Additionally, the incidence of discontinuations or dose reductions attributable to adverse events was low. These data demonstrate that single-agent carfilzomib has an acceptable safety profile in heavily pretreated patients with relapsed/refractory multiple myeloma. The tolerable safety profile allows for administration of full dose carfilzomib, both for extended periods and in a wide spectrum of patients with advanced multiple myeloma, including those with pre-existing comorbidities.
[Show abstract][Hide abstract] ABSTRACT: This phase 2 study assessed the safety, pharmacokinetics, pharmacodynamics, and efficacy of carfilzomib, a selective proteasome inhibitor, in patients with multiple myeloma and varying degrees of renal impairment, including patients on chronic hemodialysis. Patients were grouped by creatinine clearance: >80, 50-80, 30-49, <30 ml/min, and chronic hemodialysis. Carfilzomib was administered on Days 1, 2, 8, 9, 15, and 16 in 28-day cycles: 15 mg/m(2) (Cycle 1), 20 mg/m(2) (Cycle 2), and 27 mg/m(2) (Cycles 3+). There were no differences in carfilzomib clearance or exposure among patients with normal renal function and any group with renal impairment. Grade 3/4 adverse events included anemia (28.0%), thrombocytopenia (20.0%), lymphopenia (18.0%), and fatigue (14.0%). Adverse events were similar among groups. At 15 mg/m(2), proteasome inhibition up to 85% was observed and did not differ among groups. Although nearly 50% of patients were refractory to both bortezomib and lenalidomide, end of study partial response or better (overall response rate) was 25.5% with 7.9 months median duration of response. In conclusion, the pharmacokinetics and safety of carfilzomib were not influenced by the degree of baseline renal impairment, including in patients on dialysis, and carfilzomib was well tolerated and demonstrated promising efficacy.Leukemia accepted article preview online, 31 January 2013; doi:10.1038/leu.2013.29.
Leukemia: official journal of the Leukemia Society of America, Leukemia Research Fund, U.K 01/2013; 27(8). DOI:10.1038/leu.2013.29 · 10.43 Impact Factor
HAA 2013 SBOC October 23-26, Brasilia, Brasil Società Italiana di Ematologia (SIE) 2013 – October 20-23; Verona, Italy Deutsche Gesellschaft für Hämatologie und Onkologie (DGHO) 2013 October 19-23, Vienna, Austria; 01/2013