Current and Novel Alkylators in Multiple Myeloma.
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ABSTRACT:
SUBMITTER: Schjesvold F
PROVIDER: S-EPMC8158783 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Smoldering multiple myeloma (SMM) is an asymptomatic condition that occupies a space between monoclonal gammopathy of undetermined significance (MGUS) and multiple myeloma (MM) along the spectrum of clonal plasma cell proliferative disorders. It is not a biologic intermediate stage between MGUS and MM, but rather represents a heterogeneous clinically defined condition in which some patients (approximately two-thirds) have MGUS (pre-malignancy), and some (approximately one-third) have MM (biologic malignancy). Unfortunately, no single pathologic or molecular feature can reliably distinguish these two groups of patients. For purposes of practice and clinical trials, specific risk factors are used to identify patients with SMM in whom malignant transformation has already likely occurred (high risk SMM). Patients with newly diagnosed high risk SMM should be offered therapy with lenalidomide or lenalidomide plus dexamethasone (Rd) for 2 years, or enrollment in clinical trials. Patients with low risk SMM should be observed without therapy every 3-4 months.
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Project description:Multiple Myeloma (MM) remains a difficult to treat disease mainly due to its biological heterogeneity, of which we are more and more knowledgeable thanks to the development of increasingly sensitive molecular methods that allow us to build better prognostication models. The biological diversity translates into a wide range of clinical outcomes from long-lasting remission in some patients to very early relapse in others. In NDMM transplant eligible (TE) patients, the incorporation of mAb as daratumumab in the induction regimens, followed by autologous stem cell transplantation (ASCT) and consolidation/maintenance therapy, has led to a significant improvement of PFS and OS.; however, this outcome remains poor in ultra-high risk MM or in those who did not achieve a minimal residual disease (MRD) negativity. Several trials are exploring cytogenetic risk-adapted and MRD-driven therapies in these patients. Similarly, quadruplets-containing daratumumab, particularly when administered as continuous therapies, have improved outcome of patients not eligible for autologous transplant (NTE). Patients who become refractory to conventional therapies have noticeably poor outcomes, making their treatment a difficult challenge in need of novel strategies. In this review, we will focus on the main points regarding risk stratification, treatment and monitoring of MM, highlighting the most recent evidence that could modify the management of this still incurable disease.
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Project description:The survival rate of multiple myeloma (MM) patients has drastically increased recently as a result of the wide treatment options now available. Younger patients truly benefit from these innovations as they can support more intensive treatment, such as autologous stem cell transplant or multiple drug association (triplet, quadruplet). The emergence of immunotherapy allowed new combinations principally based on monoclonal anti-CD38 antibodies for these patients. Still, the optimal induction treatment has not been found yet. While consolidation is still debated, maintenance treatment is now well acknowledged to prolong survival. Lenalidomide monotherapy is the only drug approved in that setting, but many innovations are expected. Older patients, now logically named not transplant-eligible, also took advantage of these breakthrough innovations as most of the recent drugs have a more acceptable safety profile than previous cytotoxic agents. For this heterogenous subgroup, geriatric assessment has become an essential tool to identify frail patients and provide tailored strategies. At relapse, options are now numerous, especially for patients who were not treated with lenalidomide, or not refractory at least. Concerning lenalidomide refractory patients, approved combinations are lacking, but many trials are ongoing to fill that space. Moreover, innovative therapeutics are increasingly being developed with modern immunotherapy, such as chimeric antigen receptor T-cells (CAR-T cells), bispecific antibodies, or antibody-drug conjugates. For now, these treatments are usually reserved to heavily pre-treated patients with a poor outcome. MM drug classes have tremendously extended from historical alkylating agents to current dominant associations with proteasome inhibitors, immunomodulatory agents, and monoclonal anti-CD38/anti SLAMF7 antibodies. Plus, in only a couple of years, several new classes will enter the MM armamentarium, such as cereblon E3 ligase modulators (CELMoDs), selective inhibitors of nuclear export, and peptide-drug conjugates. Among the questions that will need to be answered in the years to come is the position of these new treatments in the therapeutic strategy, as well as the role of minimal residual disease-driven strategies which will be a key issue to elucidate. Through this review, we chose to enumerate and comment on the most recent advances in MM therapeutics which have undergone major transformations over the past decade.
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Project description:Multiple myeloma (MM) is a treatable plasma cell cancer with no cure. Clinical evidence shows that the status of minimal residual disease (MRD) after treatment is an independent prognostic factor of MM. MRD indicates the depth of post-therapeutic remission. In this review article, we outlined the major clinical trials that have determined the prognostic value of MRD in MM. We also reviewed different methods that were used for MM MRD assessment. Most important, we reviewed our current understanding of MM MRD biology. MRD studies strongly indicate that MRD is not a uniform declination of whole MM tumor population. Rather, MM MRD exhibits unique signatures of cytogenetic aberration and gene expression profiles, unlike those of MM cells before therapy. Diagnostic high-risk MM and low-risk MM exhibited a diversity of MRD features. Clonal evaluation may occur at the MRD stage in MM. The dynamics from the diagnostic MM to MRD correlate with the disease prognosis. Lastly, on the aspect of omics, we performed data-based analysis to address the biological features underlying the course of diagnostic-to-MRD MM. To summarize, the MRD stage of disease represents a critical step in MM pathogenesis and progression. Demonstration of MM MRD biology should help us to deal with the curative difficulties.
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Project description:Although multiple myeloma (MM) is still considered an incurable disease, the treatment philosophy is changing due to the introduction of novel agents. Standard treatment consists of an induction phase and autologous stem cell transplantation in patients under 65-70 years. Prolonged treatment (consolidation and/or maintenance) is being introduced in many countries. We present a review of clinical trials dedicated to consolidation treatment in multiple myeloma. Bortezomib, lenalidomide and carfilzomib in different combinations were tested in the trials mentioned below. Although they did not prolong overall survival, the data are very promising. Three very important large clinical trials are still in progress. The results might help to establish the actual value of consolidation treatment.
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Project description:The therapeutic landscape of multiple myeloma (MM) has dramatically changed in the last 15 years with the advent of immunomodulatory drugs and proteasome inhibitors. However, majority of MM patients relapse, and new therapies are needed. Various agents with diverse mechanisms of action and distinct targets, including cellular therapies, monoclonal antibodies, and small molecules, are currently under investigation. In this review, we report novel drugs recently approved or under advanced investigation that will likely be incorporated in the future as new standard for MM treatment, focusing on their mechanisms of action, cellular targets, and stage of development.
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Project description:Purpose of reviewThe treatment landscape of multiple myeloma is rapidly changing; however, despite improvement in patients' survival, it still remains a largely incurable disease. One hallmark of myeloma is substantial immune dysfunction leading to an increased infection rate and the inability of immune surveillance to detect neoplastic cells. Here, we critically analyze clinical approaches to harness the immune system to overcome this defect with a focus on antibody based and adoptive cellular therapies.Recent findingsClinical trials exploring these immunotherapies to treat myeloma are now well underway and show promising results. In relapsed myeloma, monoclonal antibodies directed against plasma cell antigens and immune checkpoints have already shown substantial efficacy. In parallel, trials of adoptive cellular therapy have exciting promise in myeloma, having induced dramatic responses in a handful of early study participants. Taken together, immunotherapeutic approaches hold enormous potential in the field of multiple myeloma and in the near future can be combined with or even replace the current standard of care.
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Project description:Supportive care in multiple myeloma (MM) can have a major impact on quality of life and the survival outcomes of MM patients. In this review, we will focus on disease and treatment related toxicities experienced by MM patients and what are the best approaches to date to help mitigate the effects. We will specifically focus on a practical approach to managing bone disease, thrombosis, infection risk, peripheral neuropathy, dermatologic complications, gastrointestinal and ocular toxicities, and fatigue in MM.
| S-EPMC8688260 | biostudies-literature
Project description:Inhibition of proteasome, a proteolytic complex responsible for the degradation of ubiquitinated proteins, has emerged as a powerful strategy for treatment of multiple myeloma (MM), a plasma cell malignancy. First-in-class agent, bortezomib, has demonstrated great positive therapeutic efficacy in MM, both in pre-clinical and in clinical studies. However, despite its high efficiency, a large proportion of patients do not achieve sufficient clinical response. Therefore, the development of a second-generation of proteasome inhibitors (PIs) with improved pharmacological properties was needed. Recently, several of these new agents have been introduced into clinics including carfilzomib, marizomib and ixazomib. Further, new orally administered second-generation PI oprozomib is being investigated. This review provides an overview of main mechanisms of action of PIs in MM, focusing on the ongoing development and progress of novel anti-proteasome therapeutics.
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Project description:Smoldering multiple myeloma (SMM) is an asymptomatic plasma cell proliferative disorder associated with risk of progression to symptomatic multiple myeloma (MM) or amyloidosis. In comparison to monoclonal gammopathy of undetermined significance (MGUS), SMM has a much higher risk of progression to MM. Thanks to advances in our understanding of the risk factors, the subset of patients with ultra-high risk of progression to MM (80%-90% at 2 years) has been identified. The revision of the diagnostic criteria resulted in changes in the management of this cohort of patients. In contrast to the management guidelines for MGUS patients, SMM patients need to be studied more intensively in order to identify biomarkers necessary for accurate risk stratification. In this review, we focus on the risk of progression from SMM to MM, as well as the influence of early treatment on overall survival, time to progression and quality of life.
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