Background: Older adults with acute myeloid leukemia (AML) represent a vulnerable population in whom disease-based and clinical risk factors, patient goals, prognosis, and practitioner- and patient-perceived treatment risks and benefits influence treatment recommendations. Objective: These evidence-based guidelines of the American Society of Hematology (ASH) are intended to support patients, clinicians, and other health care professionals in their decisions about management of AML in older adults. Methods: ASH formed a multidisciplinary guideline panel that included specialists in myeloid leukemia, geriatric oncology, patient-reported outcomes and decision-making, frailty, epidemiology, and methodology, as well as patients. The McMaster Grading of Recommendations Assessment, Development and Evaluation (GRADE) Centre supported the guideline-development process, including performing systematic evidence reviews (up to 24 May 2019). The panel prioritized clinical questions and outcomes according to their importance to patients, as judged by the panel. The panel used the GRADE approach, including GRADE’s Evidence-to-Decision frameworks, to assess evidence and make recommendations, which were subject to public comment. Results: The panel agreed on 6 critical questions in managing older adults with AML, mirroring real-time practitioner-patient conversations: the decision to pursue antileukemic treatment vs best supportive management, the intensity of therapy, the role and duration of postremission therapy, combination vs monotherapy for induction and beyond, duration of less-intensive therapy, and the role of transfusion support for patients no longer receiving antileukemic therapy. Conclusions: Treatment is recommended over best supportive management. More-intensive therapy is recommended over less-intensive therapy when deemed tolerable. However, these recommendations are guided by the principle that throughout a patient’s disease course, optimal care involves ongoing discussions between clinicians and patients, continuously addressing goals of care and the relative risk-benefit balance of treatment.
Introduction Reolysin®, a proprietary isolate of reovirus Type 3 Dearing, enters and preferentially induces apoptosis of malignant cells. RAS pathway activation has been associated with more efficient reoviral infectivity and enhanced oncolysis. Reovirus is currently in advanced solid tumor phase 1 – 2 trials; no clinical trials have been conducted in patients with hematologic malignancies. Methodologies A phase 1 trial treated 12 relapsed myeloma patients at two dose levels. Reolysin was infused daily for 5 days every 28 days. Bone marrow specimens were examined by In situ based hybridization (ISH) for CD138, p38, caspase-3, reoviral RNA and capsid protein at screening and cycle 1 day 8. Junctional adhesion molecule 1 (JAM-1) and cancer up regulated gene 2 (CUG2) were evaluated in patient samples and MM cell lines. Neutralizing Anti-Reovirus Antibody (NARA) assay was performed weekly during cycle 1. Results There were no dose limiting toxicities (DLTs), patients reached the 3 x 1010 TCID50 daily on days 1-5 dose level, and grade 3 laboratory toxicities included neutropenia, thrombocytopenia, and hypophosphatemia. In situ hybridization demonstrated reoviral genome confined in MM cells. Reoviral capsid protein and caspase-3 were rarely identified within reoviral RNA positive cells. The longest durations of stable disease were 4, 5 and 8 months. Conclusions Treatment with single-agent Reolysin was well tolerated and associated with avid reoviral RNA myeloma cell entry but only minimal intracellular reoviral protein production within MM cells. Our data support that in MM cells, Reolysin-induced oncolysis requires combination therapy, similar to other cancers.
A B S T R A C T PurposeMultiple myeloma (MM) is disproportionately diagnosed in older adults; with the aging of the population, the number of older adults diagnosed with MM will increase by nearly 80% in the next two decades. Duration of survival has improved dramatically over the last 20 years, but the improvements in older adults have not been as great as those in younger adults with MM. MethodsIn this article, we address treatment approaches in older adults who are eligible for and those ineligible for high-dose therapy with autologous stem-cell transplantation as well as supportive care considerations and the potential role for geriatric assessment in facilitating decision making for older adults with MM. ResultsThe evidence from recent studies demonstrates that combinations of novel and conventional antimyeloma agents result in improved response rates and, in some cases, improved progressionfree and overall survival. However, some older adults are particularly vulnerable to toxicities of therapy and discontinuation of therapy and, consequently, they have poorer survival. In addition, older adults may prioritize other outcomes of therapy, such as quality of life, over more conventional end points such as disease response and duration of survival. Geriatric assessment can facilitate risk-stratification of older adults at greater risk for adverse events from therapy and aid in personalizing therapy for vulnerable or frail older adults. ConclusionSurvival in older adults with MM is improving with novel therapeutics, but efficacy must be balanced with risk of toxicity of therapy and maintenance of quality of life. Novel instruments such as geriatric assessment tools may facilitate these aims.
Multiple myeloma (MM) is a hematological malignancy of clonal plasma cells in the bone marrow (BM). The microenvironment plays a key role in MM cell survival and drug resistance through release of soluble factors, expression of adhesion molecules and release of extracellular vesicles (EV). The aim of this manuscript is to use proteomic profiling of EVs as a tool to identify circulating tumor associated markers in MM patients. First, we characterized the EV protein content obtained from different MM cell lines. Then, we established differences in protein abundance among EVs isolated from MM patient serum and BM and the serum of healthy donors. These data show the Major Histocompatibility Complex Class I is highly enriched in EVs of MM cell lines and MM patient's serum. Next, we show that CD44 is highly expressed in the EVs isolated from the corticosteroid resistant MM cell line, MM.1R. Furthermore, CD44 was found to be differentially expressed in EVs isolated from newly diagnosed MM patients. Finally through ELISA analysis, we establish the potential of serum CD44 as a predictive biomarker of overall survival. These results support the analysis of EVs as an easily accessible source for MM biomarkers.
High dose melphalan followed by autologous stem cell transplantation remains standard of care for eligible patients with multiple myeloma, but disease response and toxicity, including severe mucositis, varies among patients. Our randomized trial investigated duration of cryotherapy (2 and 6 hours) for reduction of mucositis prevalence and severity and explored factors associated with variability in pharmacokinetics and outcomes from melphalan therapy. The results demonstrate 2-hour is at least as effective as 6-hour cryotherapy in decreasing severe mucositis. From a population pharmacokinetic model, we identified fat free mass, hematocrit, and creatinine clearance were significant covariates, as had been reported previously. Furthermore, we observed the rs4240803 SLC7A5 polymorphism was significantly associated with pharmacokinetic variability, and pharmacokinetics was associated with both mucositis and neutropenia. However, melphalan exposure was not associated with progression-free or overall survival in our dataset. These findings contribute to ongoing efforts to personalize melphalan dosing in transplant patients.
Our data illustrate that a GA can identify individuals with MM who are at greater risk for morbidity following ASCT.
Background Multiple myeloma (MM) is characterized by expression of the cell surface protein B-cell maturation antigen (BCMA), a validated target for therapeutic intervention. REGN5458 is a BCMA x CD3 bispecific antibody (Ab) that binds to both BCMA and CD3, thereby targeting MM cells with T-cell effector function via BCMA. Previously, we presented data showing REGN5458 has an acceptable safety profile with evidence of clinical efficacy in heavily pre-treated patients with RRMM. Here we describe the updated safety and response durability in a Phase 1 trial of REGN5458 monotherapy in patients with RRMM (NCT03761108). Methods The primary objectives of the Phase 1 portion of the study are to determine the safety, tolerability, and occurrence of dose-limiting toxicities (DLTs) of REGN5458. Key secondary objectives include assessment of objective response rate (ORR), duration of response (DOR), minimum residual disease (MRD) status, pharmacokinetics (PK), and pharmacodynamics. Enrollment into the Phase 1 portion follows a standard 4+3 dose escalation design. Enrolled patients must have progressive MM after ≥3 prior lines of systemic therapy, including a proteasome inhibitor, an immunomodulatory agent, and an anti-CD38 Ab. Treatment consists of weekly doses of REGN5458, followed by a maintenance phase administered every 2 weeks. Response assessments are according to modified International Myeloma Working Group criteria. MRD is assessed by flow cytometry. Results As of the June 15, 2020 data cut-off, 45 patients were treated with REGN5458. The median age at enrollment was 64.0 years (range, 41−81), of which 14 (31.1%) patients were >70 years. As per Revised International Staging System, 60.0% and 22.2% of patients were stage 2 and 3, respectively. Patients had a median of 5.0 (range, 2−17) prior lines of systemic therapy; 32 patients (71.1%) received a prior autologous stem cell transplant. All patients were refractory to an anti-CD38 Ab; 6.7% were triple-refractory, 33.3% were quad-refractory, and 53.3% were penta-refractory. REGN5458 was escalated in cohorts from 3−96 mg over six dose levels. The median duration of follow-up was 2.37 months (range, 0.7−12.3). The most common treatment-related adverse events (TRAEs) include cytokine release syndrome (CRS; 37.8%), fatigue (17.8%), nausea (17.8%), and myalgias (13.3%). CRS occurred primarily during the initial doses and was Grade (Gr) 1 in 88.2% of patients. No patients had Gr >3 CRS. Infusion-related reactions occurred in 6.7% of patients. Infection-related adverse events (AEs) occurred in 46.7% of patients (Gr ≥3 20%). Gr >3 treatment-related neurological events occurred in one patient (Gr 3 syncope 130 days after first infusion). Four patients discontinued due to AE with one patient having a TRAE (also DLT) of Gr 4 acute kidney injury. One patient had a DLT due to transient Gr 3 liver transaminases associated with CRS. Upon recovery, the patient continued study drug and has achieved ongoing partial remission. Gr >3 TRAEs occurred in 28.9% of patients, with the most common being anemia (8.9%) and lymphopenia (6.7%). Serious TRAEs occurred in 22.2% of patients, with the most common due to CRS (11.1%). Gr 5 AEs (all unrelated to study drug) occurred in three patients: two sepsis and one COVID-19. ORR was 35.6% across all dose levels (60% in highest dose level), with 81.3% of responders achieving at least a very good partial response; 31.3% had a complete response (CR) or stringent CR. A total of 43.8% of responders had a DOR >4 months and 18.8% had a DOR >8 months. The ORR in patients with extramedullary plasmacytomas was 16.7%. Additional efficacy, PK, and biomarker data will be available at the time of presentation. Conclusions In this updated analysis of the first-in-human study, REGN5458 continues to show an acceptable safety profile and durable efficacy in heavily pre-treated patients with RRMM. Enrollment in the Phase 1 dose escalation portion is ongoing, and the Phase 2 portion of the study is recruiting. Disclosures Madduri: Janssen: Consultancy, Honoraria; Foundation Medicine: Consultancy, Honoraria; Legend: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; Kinevant: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Speaking Engagement, Speakers Bureau; AbbVie: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Celgene: Consultancy, Honoraria. Brayer:Janssen: Consultancy; Bristol-Myers Squibb, WindMIL Therapeutics: Research Funding; Bristol-Myers Squibb, Janssen, Amgen: Speakers Bureau. Zonder:Prothena: Consultancy; BMS: Consultancy, Research Funding; Caelum: Consultancy; Oncopeptide: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Amgen: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Janssen: Consultancy, Other: Personal fees; Alnylam: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Intellia: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Personal fees; Celgene: Research Funding. Bensinger:Sanofi: Consultancy, Honoraria, Research Funding, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Regeneron Pharmaceuticals, Inc.: Membership on an entity's Board of Directors or advisory committees; GSK: Consultancy, Honoraria, Research Funding, Speakers Bureau; BMS: Consultancy, Honoraria, Research Funding, Speakers Bureau. Li:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company. Xu:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Adriaens:Regeneron Pharmaceuticals, Inc: Current Employment, Current equity holder in publicly-traded company, Patents & Royalties: Dosing regime that mitigates cytokine release syndrome for therapeutic antibodies (status: pending). Chokshi:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Zhang:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Boyapati:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Sharma:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Seebach:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Sirulnik:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Weinreich:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Yancopoulos:Regeneron Pharmaceuticals, Inc.: Current Employment, Current equity holder in publicly-traded company. Dhodapkar:Amgen: Membership on an entity's Board of Directors or advisory committees, Other; Kite: Membership on an entity's Board of Directors or advisory committees, Other; Janssen: Membership on an entity's Board of Directors or advisory committees, Other; Celgene/BMS: Membership on an entity's Board of Directors or advisory committees, Other; Roche/Genentech: Membership on an entity's Board of Directors or advisory committees, Other; Lava Therapeutics: Membership on an entity's Board of Directors or advisory committees, Other. Lentzsch:Mesoblast: Divested equity in a private or publicly-traded company in the past 24 months; Caelum Biosciences: Current equity holder in private company, Membership on an entity's Board of Directors or advisory committees; Celularity: Consultancy, Other; Janssen: Consultancy; Karyopharm: Research Funding; Magenta: Current equity holder in private company. Jagannath:BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy. OffLabel Disclosure: The data described in the abstract will report on use of REGN5458 in a first-in-human trial in patients with multiple myeloma.
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