Summary Treatment of multiple myeloma has substantially changed over the past decade with the introduction of several classes of new effective drugs that have greatly improved the rates and depth of ...response. Response criteria in multiple myeloma were developed to use serum and urine assessment of monoclonal proteins and bone marrow assessment (which is relatively insensitive). Given the high rates of complete response seen in patients with multiple myeloma with new treatment approaches, new response categories need to be defined that can identify responses that are deeper than those conventionally defined as complete response. Recent attempts have focused on the identification of residual tumour cells in the bone marrow using flow cytometry or gene sequencing. Furthermore, sensitive imaging techniques can be used to detect the presence of residual disease outside of the bone marrow. Combining these new methods, the International Myeloma Working Group has defined new response categories of minimal residual disease negativity, with or without imaging-based absence of extramedullary disease, to allow uniform reporting within and outside clinical trials. In this Review, we clarify several aspects of disease response assessment, along with endpoints for clinical trials, and highlight future directions for disease response assessments.
CD38 is highly and uniformly expressed on multiple myeloma (MM) cells, and at relatively low levels on normal lymphoid and myeloid cells, and in some tissues of nonhematopoietic origin. CD38 is a ...transmembrane glycoprotein with ectoenzymatic activity, and also functions as a receptor and adhesion molecule. Altogether, this has triggered the development of several CD38 antibodies including daratumumab (fully human), isatuximab (chimeric), and MOR202 (fully human). CD38 antibodies have pleiotropic mechanisms of action including Fc-dependent immune-effector mechanisms, direct apoptotic activity, and immunomodulatory effects by the elimination of CD38+ immune-suppressor cells. CD38-targeting antibodies are generally well tolerated and induce partial response or better in ∼30% of heavily pretreated MM patients as monotherapy. Based on their distinct mechanisms of action, favorable toxicity profile, and single-agent activity, CD38 antibodies are attractive partners in combination regimens. Indeed, deep responses and prolonged progression-free survival can be achieved in relapsed/refractory MM patients when CD38 antibodies are combined with immunomodulatory agents or proteasome inhibitors. Infusion-related reactions, which typically occur during the first infusion, are the most frequent adverse events. Attention should also be paid to the interference of CD38 antibodies with certain laboratory assays, which may complicate response evaluation and blood compatibility testing. Several studies are currently examining the role of CD38-based therapies in newly diagnosed and high-risk smoldering MM. Furthermore, CD38 antibodies are currently also under investigation in other hematologic malignancies, including acute lymphoblastic leukemia, natural killer/T-cell lymphoma, and acute myeloid leukemia, as well as in solid tumors.
Proteasome inhibitors are one of the most important classes of agents to have emerged for the treatment of multiple myeloma in the past two decades, and now form one of the backbones of treatment. ...Three agents in this class have been approved by the United States Food and Drug Administration—the first-in-class compound bortezomib, the second-generation agent carfilzomib, and the first oral proteasome inhibitor, ixazomib. The success of this class of agents is due to the exquisite sensitivity of myeloma cells to the inhibition of the 26S proteasome, which plays a critical role in the pathogenesis and proliferation of the disease. Proteasome inhibition results in multiple downstream effects, including the inhibition of NF-κB signaling, the accumulation of misfolded and unfolded proteins, resulting in endoplasmic reticulum stress and leading to the unfolded protein response, the downregulation of growth factor receptors, suppression of adhesion molecule expression, and inhibition of angiogenesis; resistance to proteasome inhibition may arise through cellular responses mediating these downstream effects. These multiple biologic consequences of proteasome inhibition result in synergistic or additive activity with other chemotherapeutic and targeted agents for myeloma, and proteasome inhibitor-based combination regimens have become established as a cornerstone of therapy throughout the myeloma treatment algorithm, incorporating agents from the other key classes of antimyeloma agents, including the immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. This review gives an overview of the critical role of the proteasome in myeloma and the characteristics of the different proteasome inhibitors and provides a comprehensive summary of key clinical efficacy and safety data with the currently approved proteasome inhibitors.
Purpose Lenalidomide maintenance therapy after autologous stem-cell transplantation (ASCT) demonstrated prolonged progression-free survival (PFS) versus placebo or observation in several randomized ...controlled trials (RCTs) of patients with newly diagnosed multiple myeloma (NDMM). All studies had PFS as the primary end point, and none were powered for overall survival (OS) as a primary end point. Thus, a meta-analysis was conducted to better understand the impact of lenalidomide maintenance in this setting. Patients and Methods The meta-analysis was conducted using primary-source patient-level data and documentation from three RCTs (Cancer and Leukemia Group B 100104, Gruppo Italiano Malattie Ematologiche dell'Adulto RV-MM-PI-209, and Intergroupe Francophone du Myélome 2005-02) that met the following prespecified inclusion criteria: an RCT in patients with NDMM receiving ASCT followed by lenalidomide maintenance versus placebo or observation with patient-level data available and achieved database lock for primary efficacy analysis. Results Overall, 1,208 patients were included in the meta-analysis (605 patients in the lenalidomide maintenance group and 603 in the placebo or observation group). The median PFS was 52.8 months for the lenalidomide group and 23.5 months for the placebo or observation group (hazard ratio, 0.48; 95% CI, 0.41 to 0.55). At a median follow-up time of 79.5 months for all surviving patients, the median OS had not been reached for the lenalidomide maintenance group, whereas it was 86.0 months for the placebo or observation group (hazard ratio, 0.75; 95% CI, 0.63 to 0.90; P = .001). The cumulative incidence rate of a second primary malignancy before disease progression was higher with lenalidomide maintenance versus placebo or observation, whereas the cumulative incidence rates of progression, death, or death as a result of myeloma were all higher with placebo or observation versus lenalidomide maintenance. Conclusion This meta-analysis demonstrates a significant OS benefit and confirms the PFS benefit with lenalidomide maintenance after ASCT in patients with NDMM when compared with placebo or observation.
Summary 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.
Novel agents, including the proteasome inhibitor bortezomib, have significantly improved the response and survival of patients with multiple myeloma over the last decade. Despite these advances, many ...patients relapse or do not benefit from the currently available therapies; thus, multiple myeloma remains an incurable disease. Deacetylase inhibitors (DACi), including panobinostat and vorinostat, have recently emerged as novel agents being evaluated in the treatment of multiple myeloma. Deacetylases are a group of enzymes with effects on various intracellular proteins, including histones, transcription factors, and molecular chaperones. Although DACi inhibit cell growth and induce apoptosis in multiple myeloma cells as a single agent, synergistic activity has been observed when they were used in combination with bortezomib. The mechanistic basis of synergy is multifactorial and includes disruption of protein degradation and inhibition of the interaction of multiple myeloma cells with the tumor microenvironment. This review summarizes recent advancements in the understanding of the mechanism of action of proteasome inhibitors and DACi in multiple myeloma and examines the biological basis of their synergistic effects. Data from the studies summarized here have been used as the rationale for the implementation of phase II and III clinical trials of DACi, alone and combined with bortezomib, in relapsed and refractory multiple myeloma.
Panobinostat for the Treatment of Multiple Myeloma Laubach, Jacob P; Moreau, Philippe; San-Miguel, Jesús F ...
Clinical cancer research,
2015-Nov-01, 2015-11-01, 20151101, Letnik:
21, Številka:
21
Journal Article
Recenzirano
Panobinostat is a potent oral deacetylase inhibitor that alters gene expression through epigenetic mechanisms and inhibits protein degradation. It was recently approved by the FDA and EMA for use in ...combination with bortezomib and dexamethasone in patients with multiple myeloma who have received ≥2 prior regimens, including bortezomib and an immunomodulatory drug. Panobinostat was approved based on results from the phase III PANORAMA 1 trial in patients with relapsed or relapsed and refractory multiple myeloma, which showed that panobinostat plus bortezomib and dexamethasone significantly extended progression-free survival (median, 12.0 months) compared with placebo plus bortezomib and dexamethasone (median, 8.1 months; P < 0.0001). Additional ongoing trials are evaluating panobinostat in combination with other partners in the relapsed/refractory and newly diagnosed treatment settings. This review focuses on panobinostat and its mechanism of action, pharmacokinetics, and clinical data in the treatment of relapsed or relapsed and refractory multiple myeloma.
Summary Background Histone deacetylase (HDAC) inhibitors are an important new class of therapeutics for treating multiple myeloma. Ricolinostat (ACY-1215) is the first oral selective HDAC6 inhibitor ...with reduced class I HDAC activity to be studied clinically. Motivated by findings from preclinical studies showing potent synergistic activity with ricolinostat and lenalidomide, our goal was to assess the safety and preliminary activity of the combination of ricolinostat with lenalidomide and dexamethasone in relapsed or refractory multiple myeloma. Methods In this multicentre phase 1b trial, we recruited patients aged 18 years or older with previously treated relapsed or refractory multiple myeloma from five cancer centres in the USA. Inclusion criteria included a Karnofsky Performance Status score of at least 70, measureable disease, adequate bone marrow reserve, adequate hepatic function, and a creatinine clearance of at least 50 mL per min. Exclusion criteria included previous exposure to HDAC inhibitors; previous allogeneic stem-cell transplantation; previous autologous stem-cell transplantation within 12 weeks of baseline; active systemic infection; malignancy within the last 5 years; known or suspected HIV, hepatitis B, or hepatitis C infection; a QTc Fridericia of more than 480 ms; and substantial cardiovascular, gastrointestinal, psychiatric, or other medical disorders. We gave escalating doses (from 40–240 mg once daily to 160 mg twice daily) of oral ricolinostat according to a standard 3 + 3 design according to three different regimens on days 1–21 with a conventional 28 day schedule of oral lenalidomide (from 15 mg in one cohort to 25 mg in all other cohorts once daily) and oral dexamethasone (40 mg weekly). Primary outcomes were dose-limiting toxicities, the maximum tolerated dose of ricolinostat in this combination, and the dose and schedule of ricolinostat recommended for further phase 2 investigation. Secondary outcomes were the pharmacokinetics and pharmacodynamics of ricolinostat in this combination and the preliminary anti-tumour activity of this treatment. The trial is closed to accrual and is registered at ClinicalTrials.gov , number NCT01583283. Findings Between July 12, 2012, and Aug 20, 2015, we enrolled 38 patients. We observed two dose-limiting toxicities with ricolinostat 160 mg twice daily: one (2%) grade 3 syncope and one (2%) grade 3 myalgia event in different cohorts. A maximum tolerated dose was not reached. We chose ricolinostat 160 mg once daily on days 1–21 of a 28 day cycle as the recommended dose for future phase 2 studies in combination with lenalidomide 25 mg and dexamethasone 40 mg. The most common adverse events were fatigue (grade 1–2 in 14 37% patients; grade 3 in seven 18%) and diarrhoea (grade 1–2 in 15 39% patients; grade 3 in two 5%). Our pharmacodynamic studies showed that at clinically relevant doses, ricolinostat selectively inhibits HDAC6 while retaining a low and tolerable level of class I HDAC inhibition. The pharmacokinetics of ricolinostat and lenalidomide were not affected by co-administration. In a preliminary assessment of antitumour activity, 21 (55% 95% CI 38–71) of 38 patients had an overall response. Interpretation The findings from this study provide preliminary evidence that ricolinostat is a safe and well tolerated selective HDAC6 inhibitor, which might partner well with lenalidomide and dexamethasone to enhance their efficacy in relapsed or refractory multiple myeloma. Funding Acetylon Pharmaceuticals.
Proteasome inhibition has emerged as an important therapeutic strategy in multiple myeloma (MM). Since the publication of the first phase 1 trials of bortezomib 10 years ago, this first-in-class ...proteasome inhibitor (PI) has contributed substantially to the observed improvement in survival in MM patients over the past decade. Although first approved as a single agent in the relapsed setting, bortezomib is now predominantly used in combination regimens. Furthermore, the standard twice-weekly schedule may be replaced by weekly infusion, especially when bortezomib is used as part of combination regimens in frontline therapy. Indeed, bortezomib is an established component of induction therapy for patients eligible or ineligible for autologous stem cell transplantation. Bortezomib has also been incorporated into conditioning regimens before autologous stem cell transplantation, as well as into post-ASCT consolidation therapy, and in the maintenance setting. In addition, a new route of bortezomib administration, subcutaneous infusion, has recently been approved. Recently, several new agents have been introduced into the clinic, including carfilzomib, marizomib, and MLN9708, and trials investigating these “second-generation” PIs in patients with relapsed/refractory MMs have demonstrated positive results. This review provides an overview of the role of PIs in the treatment of MM, focusing on developments over the past decade.
Nonstructural carbohydrate reserves support tree metabolism and growth when current photosynthates are insufficient, offering resilience in times of stress.
We monitored stemwood nonstructural ...carbohydrate (starch and sugars) concentrations of the dominant tree species at three sites in the northeastern United States. We estimated the mean age of the starch and sugars in a subset of trees using the radiocarbon (14C) bomb spike. With these data, we then tested different carbon (C) allocation schemes in a process-based model of forest C cycling.
We found that the nonstructural carbohydrates are both highly dynamic and about a decade old. Seasonal dynamics in starch (two to four times higher in the growing season, lower in the dormant season) mirrored those of sugars. Radiocarbon-based estimates indicated that the mean age of the starch and sugars in red maple (Acer rubrum) was 7–14 yr.
A two-pool (fast and slow cycling reserves) model structure gave reasonable estimates of the size and mean residence time of the total NSC pool, and greatly improved model predictions of interannual variability in woody biomass increment, compared with zero- or one-pool structures used in the majority of existing models. This highlights the importance of nonstructural carbohydrates in the context of forest ecosystem carbon cycling.
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