Monoclonal antibodies (mAbs) targeting antigens expressed by plasma cells demonstrated major clinical activity in multiple myeloma patients and therefore became a new major class of drug for these ...patients. Elotuzumab is a humanized mAb targeting the cell surface signaling lymphocytic activation molecule family member 7, a glycoprotein highly expressed on plasma cells, that is the second mAb approved for the treatment of myeloma patients. The mechanism of action of elotuzumab includes natural killer cell (NK) mediated antibody-dependent cellular cytotoxicity and direct activation of NK-cells. Elotuzumab has been approved in combination with lenalidomide and dexamethasone (Elo-Rd) and pomalidomide and dexamethasone (Elo-Pd) for the treatment of relapsed myeloma patients. The present review will focus on elotuzumab, providing a summary of the mechanism of action, efficacy and safety and taking into consideration patients' selection.
A panel of members of the 2009 International Myeloma Workshop developed guidelines for standard investigative workup of patients with suspected multiple myeloma. Both serum and urine should be ...assessed for monoclonal protein. Measurement of monoclonal protein both by densitometer tracing and/by nephelometric quantitation is recommended, and immunofixation is required for confirmation. The serum-free light chain assay is recommended in all newly diagnosed patients with plasma cell dyscrasias. Bone marrow aspiration and/or biopsy along with demonstration of clonality of plasma cells are necessary. Serum β2-microglobulin, albumin, and lactate dehydrogenase are necessary for prognostic purposes. Standard metaphase cytogenetics and fluorescent in situ hybridization for 17p, t(4;14), and t(14;16) are recommended. The skeletal survey remains the standard method for imaging screening, but magnetic resonance imaging frequently provides valuable diagnostic and prognostic information. Most of these tests are repeated during follow-up or at relapse.
Summary
In this review, two types of soft‐tissue involvement in multiple myeloma are defined: (i) extramedullary (EMD) with haematogenous spread involving only soft tissues and (ii) paraskeletal (PS) ...with tumour masses arising from skeletal lesions. The incidence of EMD and PS plasmacytomas at diagnosis ranges from 1·7% to 4·5% and 7% to 34·4% respectively. EMD disease is often associated with high‐risk cytogenetics, resistance to therapy and worse prognosis than in PS involvement. In patients with PS involvement a proteasome inhibitor‐based regimen may be the best option followed by autologous stem cell transplantation (ASCT) in transplant eligible patients. In patients with EMD disease who are not eligible for ASCT, a proteasome inhibitor‐based regimen such as lenalidomide‐bortezomib‐dexamethasone (RVD) may be the best option, while for those eligible for high‐dose therapy a myeloma/lymphoma‐like regimen such as bortezomib, thalidomide and dexamethasone (VTD)‐RVD/cisplatin, doxorubicin, cyclophosphamide and etoposide (PACE) followed by SCT should be considered. In both EMD and PS disease at relapse many strategies have been tried, but this remains a high‐unmet need population.
Thirty patients, with high-risk acute myeloid leukemia (AML, n = 20) or myelodysplastic syndrome (MDS, n = 10), were enrolled in a phase II trial entailing prophylactic post-transplant azacitidine ...(AZA) plus escalated doses of donor lymphocyte infusion (DLI). The median number of AZA cycles was 5 (1-12) with 10 patients (33%) completing the 12 projected cycles. DLI were performed in 17 patients: 5 received one DLI, 2 received 2 DLI and 8 received 3 infusions. AZA was well tolerated, but discontinued in 20 patients primarily due to graft-versus-host disease (GvHD) and relapse. The cumulative incidence (CI) of grade 1-3 acute GvHD was 31.5% and the chronic GvHD CI was 53% at 2 years. At a median follow-up of 49 months (27-63), 18 patients are alive. The overall and disease-free survivals are 65.5% (CI 95% = 48.2-82.8) at 2 years. Cause of death was mainly relapse for 9 patients. The median time to relapse was 7 months (2.5-58) and the cumulative incidence of relapse at 2 years was 27.6% (CI 95% = 12.8-44.6). These results confirm that AZA is well tolerated as a prophylactic treatment to reduce the risk of post-transplantation relapse and compared favorably to those of patients who receive no post-transplant maintenance.
The development of proteasome inhibitors contributed to the dramatic life expectancy improvement observed in myeloma patients over the past decades. Ixazomib is a boron-containing selective and ...reversible proteasome inhibitor that demonstrated antimyeloma activity with excellent safety profile. Ixazomib is the first orally available proteasome inhibitor approved in combination with lenalidomide and dexamethasone for the treatment of myeloma patients who received at least one prior therapy. The present review addresses the current knowledge regarding the clinical use of ixazomib in relapsed myeloma patients.
Understanding the aging mechanism of silicon‐based negative electrodes for lithium‐ion batteries upon cycling is essential to solve the problem of low coulombic efficiency and capacity fading and ...further to implement this new high‐capacity material in commercial cells. Nevertheless, such studies have so far focused on half cells in which silicon is cycled versus an infinite reservoir of lithium. In the present work, the aging mechanism of silicon‐based electrodes is studied upon cycling in a full Li‐ion cell configuration with LiCoO2 as the positive electrode. Postmortem analyses of both electrodes clearly indicate that neither one of them contains lithium and that no discernible degradation results from the cycling. The aging mechanism can be explained by the reduction of solvent molecules. Electrons extracted from the positive electrode are responsible for an internal imbalance in the cell, which results in progressive slippage of the electrodes and reduces the compositional range of cyclable lithium ions for both electrodes.
Long‐distance cycling: Electrons extracted from the positive electrode are responsible for an internal imbalance in the Li‐ion cell that results in progressive slippage of the electrodes and reduces the compositional range of cyclable lithium ions. This explains the capacity fade by a loss of cyclable lithium. LCO=lithium cobalt oxide.
Multiple myeloma (MM) is accompanied by heterogeneous somatic alterations. The overall goal of this study was to describe the genomic landscape of myeloma using deep whole-genome sequencing (WGS) and ...develop a model that identifies patients with long survival.
We analyzed deep WGS data from 183 newly diagnosed patients with MM treated with lenalidomide, bortezomib, and dexamethasone (RVD) alone or RVD + autologous stem cell transplant (ASCT) in the IFM/DFCI 2009 study (ClinicalTrials.gov identifier: NCT01191060). We integrated genomic markers with clinical data.
We report significant variability in mutational load and processes within MM subgroups. The timeline of observed activation of mutational processes provides the basis for 2 distinct models of acquisition of mutational changes detected at the time of diagnosis of myeloma. Virtually all MM subgroups have activated DNA repair-associated signature as a prominent late mutational process, whereas APOBEC signature targeting C>G is activated in the intermediate phase of disease progression in high-risk MM. Importantly, we identify a genomically defined MM subgroup (17% of newly diagnosed patients) with low DNA damage (low genomic scar score with chromosome 9 gain) and a superior outcome (100% overall survival at 69 months), which was validated in a large independent cohort. This subgroup allowed us to distinguish patients with low- and high-risk hyperdiploid MM and identify patients with prolongation of progression-free survival. Genomic characteristics of this subgroup included lower mutational load with significant contribution from age-related mutations as well as frequent
mutation. Surprisingly, their overall survival was independent of International Staging System and minimal residual disease status.
This is a comprehensive study identifying genomic markers of a good-risk group with prolonged survival. Identification of this patient subgroup will affect future therapeutic algorithms and research planning.
Since the mid 1990s, high-dose therapy followed by autologous stem-cell transplantation (ASCT) has been considered the standard of care for frontline therapy in younger patients with multiple myeloma ...(MM). During the past 10 years, thalidomide, bortezomib, and lenalidomide have been widely incorporated to the therapeutic armamentarium for the treatment of this disease. These agents show promise for improving the rate of complete remission both before and after ASCT without increasing toxicity. However, it is not clear whether such therapies are superior if they are used as an alternative to transplantation or whether they may reduce the need for and use of transplantation in patients in whom treatment is indicated. Therefore, the role of ASCT itself is a matter of debate: Should it be used upfront or as salvage treatment at the time of progression in patients initially treated with novel agents? This review presents current trends in ASCT for MM in the era of novel therapies.
Certain cytogenetic abnormalities are known to adversely impact outcomes in patients with multiple myeloma (MM). The phase 3 TOURMALINE-MM1 study demonstrated a significant improvement in ...progression-free survival (PFS) with ixazomib-lenalidomide-dexamethasone (IRd) compared with placebo-lenalidomide-dexamethasone (placebo-Rd). This preplanned analysis assessed the efficacy and safety of IRd vs placebo-Rd according to cytogenetic risk, as assessed using fluorescence in situ hybridization. High-risk cytogenetic abnormalities were defined as del(17p), t(4;14), and/or t(14;16); additionally, patients were assessed for 1q21 amplification. Of 722 randomized patients, 552 had cytogenetic results; 137 (25%) had high-risk cytogenetic abnormalities and 172 (32%) had 1q21 amplification alone. PFS was improved with IRd vs placebo-Rd in both high-risk and standard-risk cytogenetics subgroups: in high-risk patients, the hazard ratio (HR) was 0.543 (95% confidence interval CI, 0.321-0.918; P = .021), with median PFS of 21.4 vs 9.7 months; in standard-risk patients, HR was 0.640 (95% CI, 0.462-0.888; P = .007), with median PFS of 20.6 vs 15.6 months. This PFS benefit was consistent across subgroups with individual high-risk cytogenetic abnormalities, including patients with del(17p) (HR, 0.596; 95% CI, 0.286-1.243). PFS was also longer with IRd vs placebo-Rd in patients with 1q21 amplification (HR, 0.781; 95% CI, 0.492-1.240), and in the “expanded high-risk” group, defined as those with high-risk cytogenetic abnormalities and/or 1q21 amplification (HR, 0.664; 95% CI, 0.474-0.928). IRd demonstrated substantial benefit compared with placebo-Rd in relapsed and/or refractory MM (RRMM) patients with high-risk and standard-risk cytogenetics, and improves the poor PFS associated with high-risk cytogenetic abnormalities. This trial was registered at www.clinicaltrials.gov as #NCT01564537.
•IRd was associated with a consistent PFS benefit vs placebo-Rd in RRMM patients with high-risk and standard-risk cytogenetics.•The addition of ixazomib to Rd overcomes the poor PFS associated with high-risk cytogenetics in patients with RRMM.
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