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.
Certain clinical features predict progression from smoldering to overt multiple myeloma. Patients with high-risk features who were treated with lenalidomide and dexamethasone were less likely to have ...disease progression and had a higher rate of survival than untreated patients.
Smoldering multiple myeloma is a plasma-cell proliferative disorder characterized by a monoclonal component of at least 3 g per deciliter, a level of plasma-cell infiltration into bone marrow of at least 10%, or both features.
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Currently, patients with smoldering myeloma are not treated until symptomatic disease develops.
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In the past, few drugs were effective against myeloma, and the available treatments, mainly alkylating agents, led to concerns about long-term toxicity. Attempts at early intervention with alkylating agents,
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bisphosphonates,
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–
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antagonists of the receptor of interleukin-1β,
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or thalidomide
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–
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failed to show a significant benefit.
Although the risk of progression to . . .
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.
Fire has a diverse range of impacts on Earth's physical and social systems. Accurate and up to date information on areas affected by fire is critical to better understand drivers of fire activity, as ...well as its relevance for biogeochemical cycles, climate, air quality, and to aid fire management. Mapping burned areas was traditionally done from field sketches. With the launch of the first Earth observation satellites, remote sensing quickly became a more practical alternative to detect burned areas, as they provide timely regional and global coverage of fire occurrence. This review paper explores the physical basis to detect burned area from satellite observations, describes the historical trends of using satellite sensors to monitor burned areas, summarizes the most recent approaches to map burned areas and evaluates the existing burned area products (both at global and regional scales). Finally, it identifies potential future opportunities to further improve burned area detection from Earth observation satellites.
•A review of burned area trends in past 40 years of RS is performed.•Different sensors used for BA mapping presented, including Radar and Lidar.•Main burned area products are commented
Roadmap to cure multiple myeloma Rodriguez-Otero, Paula; Paiva, Bruno; San-Miguel, Jesús F.
Cancer treatment reviews,
November 2021, 2021-11-00, 20211101, Letnik:
100
Journal Article
Recenzirano
Odprti dostop
•Despite significant advances in the treatment of multiple myeloma which had led to unprecedented rates of response and survival, patients still relapse, and cure remains elusive.•Circulating tumor ...cells and minimal residual disease clones are paramount in MM pathogenesis. The former is responsible for dissemination and extramedullary disease and the later represent the reservoir of clonal evolution and disease recurrence. Understand the biology of these two cell types is paramount to advance in the cure of this disease.•Complete eradication of all tumor cells is a prerequisite for cure, also in myeloma. This requires high-sensitive techniques to evaluate response to treatment both within the bone marrow compartment and outside the bone marrow.•Early detection and early intervention in high-risk smoldering myeloma may not only contribute to delay disease progression into active disease but also to increase the cure rates.•If cure is our goal, we should give best treatment options upfront for standard risk patients. For patients with high-risk disease, early rescue intervention strategies using new treatment modalities should be implemented with the goal of eradicating all tumor clones, and achieving minimal residual disease negativity.
Despite significant advances in the treatment of multiple myeloma which had led to unprecedented rates of response and survival, patients still relapse, and cure remains elusive. We propose in this review a roadmap to achieve the dream of cure for multiple myeloma based on five complementary strategies. First, to increase knowledge about disease pathogenesis with a focus on the biology of circulating tumor cells, responsible for dissemination and extramedullary disease, and minimal residual disease clones who represent the reservoir of clonal evolution and disease recurrence. Second, to consider undetectable measurable residual disease (MRD), defined by high-sensitive techniques, as the new endpoint of therapy. Third, to treat disease causation instead of symptomatology through early detection and intervention. Thereby, by treating high-risk smoldering myeloma patients early, we may not only contribute to delay disease progression into active disease but also to increase the cure rates. Fourth, to use the most active scheme in standard-risk patients if the cure is in the horizon. Fifth, to investigate experimental therapies in newly diagnosed patients with high-risk MM, implementing early rescue intervention strategies with the goal of eradicating all tumor clones, and achieving minimal residual disease negativity.
Assessing measurable residual disease (MRD) has become standard with many tumors, but the clinical meaning of MRD in multiple myeloma (MM) remains uncertain, particularly when assessed by ...next-generation flow (NGF) cytometry. Thus, we aimed to determine the applicability and sensitivity of the flow MRD-negative criterion defined by the International Myeloma Working Group (IMWG).
In the PETHEMA/GEM2012MENOS65 trial, 458 patients with newly diagnosed MM had longitudinal assessment of MRD after six induction cycles with bortezomib, lenalidomide, and dexamethasone (VRD), autologous transplantation, and two consolidation courses with VRD. MRD was assessed in 1,100 bone marrow samples from 397 patients; the 61 patients without MRD data discontinued treatment during induction and were considered MRD positive for intent-to-treat analysis. The median limit of detection achieved by NGF was 2.9 × 10
. Patients received maintenance (lenalidomide ± ixazomib) according to the companion PETHEMA/GEM2014MAIN trial.
Overall, 205 (45%) of 458 patients had undetectable MRD after consolidation, and only 14 of them (7%) have experienced progression thus far; seven of these 14 displayed extraosseous plasmacytomas at diagnosis and/or relapse. Using time-dependent analysis, patients with undetectable MRD had an 82% reduction in the risk of progression or death (hazard ratio, 0.18; 95% CI, 0.11 to 0.30;
< .001) and an 88% reduction in the risk of death (hazard ratio, 0.12; 95% CI, 0.05 to 0.29;
< .001). Timing of undetectable MRD (after induction
intensification) had no impact on patient survival. Attaining undetectable MRD overcame poor prognostic features at diagnosis, including high-risk cytogenetics. By contrast, patients with Revised International Staging System III status and positive MRD had dismal progression-free and overall survivals (median, 14 and 17 months, respectively). Maintenance increased the rate of undetectable MRD by 17%.
The IMWG flow MRD-negative response criterion is highly applicable and sensitive to evaluate treatment efficacy in MM.
In this phase 1–2 study involving patients with relapsed or refractory myeloma, a bispecific antibody (teclistamab) that mediates T-cell activation and subsequent lysis of myeloma cells expressing ...B-cell maturation antigen induced responses in 63% of the patients, including a complete response in nearly 40%.
Patients with newly diagnosed multiple myeloma who were ineligible for treatment with high-dose chemotherapy plus hematopoietic stem-cell transplantation were randomly assigned to receive either ...melphalan and prednisone alone or melphalan and prednisone plus bortezomib. The time to disease progression (the primary outcome) was longer in the bortezomib group. The combination of bortezomib, melphalan, and prednisone appears to be effective as initial treatment in patients with multiple myeloma who cannot withstand high-dose therapy.
The combination of bortezomib, melphalan, and prednisone appears to be effective as initial treatment in patients with multiple myeloma who cannot withstand high-dose therapy.
Therapy with melphalan plus prednisone, which has been the standard of care for patients with newly diagnosed multiple myeloma for more than 40 years,
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,
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is associated with a median survival of 29 to 37 months.
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During the past decade, high-dose therapy with hematopoietic stem-cell transplantation has become the preferred treatment for patients under the age of 65 years,
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but older patients and patients with clinically significant coexisting illnesses usually do not tolerate this treatment. Since the median age at diagnosis of myeloma is approximately 70 years,
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more than half the patients with newly diagnosed myeloma may not . . .
Summary Introduction of the proteasome inhibitor bortezomib and the immunomodulatory drugs thalidomide and lenalidomide has substantially improved outcomes for patients with multiple myeloma. As a ...result, these drugs have become cornerstones of current antimyeloma treatment regimens. However, after several years of clinical experience it has become apparent that peripheral neuropathy is the most common and potentially disabling non-haematological side-effect associated with thalidomide and bortezomib. Maximising treatment benefit while preserving quality of life therefore requires a careful balance between achieving optimum activity and minimising toxicity, including neuropathy, to further enhance efficacy. In this review, we discuss all aspects of drug-induced peripheral neuropathy in myeloma, with a particular focus on thalidomide and bortezomib.
Multiple myeloma is the second most frequent hematological disease. The introduction of melphalan as high-dose therapy followed by autologous hematopoietic cell transplantation (HDT/ASCT) for young ...patients and the availability of novel agents for young and elderly patients with multiple myeloma have dramatically changed the perspective of treatment. However, further research is necessary if we want definitively to cure the disease. Treatment goals for transplant-eligible and non-transplant-eligible patients should be to prolong survival by achieving the best possible response while ensuring quality of life. For young patients, HDT-ASCT is a standard of care for treatment, and its efficacy has been enhanced and challenged by the new drugs. For elderly patients, treatment options were once limited to alkylators, but new upfront treatment combinations based on novel agents (proteasome inhibitors and immunomodulatory drugs) combined or not with alkylators have significantly improved outcomes. Extended treatment of young and elderly patients improves the quality and duration of clinical responses; however, the optimal scheme, appropriate doses, and duration of long-term therapy have not yet been fully determined. This review summarizes progress in the treatment of patients with newly diagnosed multiple myeloma, addressing critical questions such as the optimal induction, early vs late ASCT, consolidation and/or maintenance for young patients, and how we can choose the best treatment option for non-transplant-eligible patients.
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