Early detection of treatment failure and early rescue intervention in multiple myeloma: time for new approaches.
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ABSTRACT:
SUBMITTER: Lahuerta JJ
PROVIDER: S-EPMC7948301 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:* Correspondence: kasiajanda@op [...].
| S-EPMC7355449 | biostudies-literature
Project description:Cellular immunotherapy can be an effective adjuvant treatment for multiple myeloma (MM), as demonstrated by induction of durable remissions after allogeneic stem cell transplantation. However, anti-myeloma immunity is often hampered by suppressive mechanisms in the tumor micro-environment resulting in relapse or disease progression. To overcome this immunosuppression, new cellular immunotherapies have been developed, based on the important effector cells in anti-myeloma immunity, namely T cells and natural killer cells. These effectors can be modulated to improve their functionality, activated by dendritic cell vaccines, or combined with immune stimulating antibodies or immunomodulatory drugs to enhance their efficacy. In this review, we discuss promising pre-clinical and clinical data in the field of cellular immunotherapy in MM. In addition, we address the potential of combining these strategies with other therapies to maximize clinical effects without increasing toxicity. The reviewed therapies might pave the way to effective personalized treatments for MM patients.
| S-EPMC4896532 | biostudies-literature
Project description:The multiple myeloma (MM) therapeutic landscape has evolved significantly with the approval of numerous novel agents, including next generation proteasome inhibitors (PIs), immunomodulatory agents (IMIDs), and monoclonal antibodies (MoABs) targeting CD38 and SLAMF7. While these discoveries have led to an unprecedented improval in patient outcomes, the disease still remains incurable. Immunotherapeutic approaches have shown substantial promise in recent studies of chimeric antigen receptor T-cell (CAR T-cell) therapy, bispecific antibodies, and antibody drug conjugates targeting B-cell maturation antigen (BCMA). This review will highlight these novel and targeted therapies in MM, with particular focus on PIs, IMIDs, MoAb and BCMA-directed immunotherapy.
| S-EPMC7569026 | biostudies-literature
Project description:The melphalan-prednisone regimen has been considered as standard therapy for patients with multiple myeloma (MM) for many years. Recently, high-dose chemotherapy with stem-cell support has extended progression-free survival and increased overall survival, and it is now considered conventional therapy in younger patients. However, most patients relapse and the salvage treatment is not very effective. New active drugs, including immunomodulatory agents, thalidomide (Thal) and lenalidomide, and the proteasome inhibitor bortezomib, have shown promising anti-myeloma activity. These novel treatments are aimed at overcoming resistance of tumour cells to conventional chemotherapy, acting both directly on myeloma cells and indirectly by blocking the interactions of myeloma cells with their local microenvironment and suppressing growth and survival signals induced by autocrine and paracrine loops in the bone marrow. Thal has been widely studied, mostly in combination regimens in patients with relapsed MM and, more recently, in front-line therapy, showing efficacy in terms of response rate and event-free survival. Bortezomib has been found to possess remarkable activity, especially in combination with other chemotherapeutic agents, in relapsed/refractory and newly diagnosed MM, as well as in patients presenting adverse prognostic factors. Lenalidomide, in combination with dexamethasone, is showing high overall response rates in relapsed and refractory MM and promising results also in first-line therapy. In this paper, the results of the most significant trials with Thal, bortezomib and lenalidomide are reported. Several ongoing clinical studies will hopefully allow the identification of the most active combinations capable of improving survival in patients with MM.
| S-EPMC2779346 | biostudies-other
Project description:The significant advances made in the treatment of multiple myeloma (MM) have allowed for a paradigm shift away from the early use of high-dose melphalan with autologous stem cell transplant (HDM-ASCT). In 2015 alone, the US Food and Drug Administration (FDA) approved 4 novel drugs for MM. Novel drugs and regimens have shown unprecedented efficacy, which has increased the tempo of new drug development. Furthermore, the FDA recently approved a diagnostic test to detect minimal residual disease (MRD) that will allow community clinicians to conduct real-time testing of MRD. Most importantly, frontline regimens based on immunomodulatory drugs (IMiDs) and proteasome inhibitors (PIs) have shown a large clinical benefit. The next era has begun, as several 4-drug combinations that include monoclonal antibodies are being evaluated in clinical trials in the attempt to replace HDM-ASCT in the treatment of MM. We and others have therefore questioned the need for early HDM-ASCT, especially in light of the possible complications. HDM-ASCT is associated not only with acute toxicities-cytopenia, infection, and even death-but also an increased risk of developing secondary cancers. This article discusses the historic context of HDM-ASCT, the modern role of HDM-ASCT given the availability of highly sensitive MRD testing, and the likely future of quadruplet treatment. In summary, patients who attain deep responses using IMiD- and PI-based regimens may not require early HDM-ASCT. A delayed approach to this treatment is acceptable, and might be preferred by patients.
| S-EPMC7451402 | biostudies-literature
Project description:Myeloma therapy has undergone significant advances in recent years resulting in a marked improvement in survival. Knowledge of the active pathways involved in myeloma pathogenesis has led to the discovery of novel agents and greatly expanded the potential armamentarium available for treatment. This better understanding of the disease and resistance mechanisms has resulted in new agent classes that are being evaluated in preclinical and early clinical studies. In addition, dosing for existing agents is being optimized, and they are being given in new combinations. In this article, we review experimental agents that are showing promise in multiple myeloma treatment. New biological agents in clinical trials hold the promise of efficacy through novel mechanisms of action, with a significant reduction of dose-limiting toxicities compared with classic cytotoxic chemotherapeutics. Second-generation proteasome inhibitors and immunomodulatory agents are furthest along in clinical development, and histone deacetylase inhibitors, heat shock protein 90 inhibitors, Akt inhibitors and monoclonal antibodies are some of the other agents entering later-phase clinical trials. We also review developments in targeting the myeloma stem cell as an exciting new treatment direction.
| S-EPMC3573409 | biostudies-literature
Project description:Interrogation of cell-free DNA (cfDNA) represents an emerging approach to non-invasively estimate disease burden in multiple myeloma (MM). Here, we examined low-pass whole genome sequencing (LPWGS) of cfDNA for its predictive value in relapsed/ refractory MM (RRMM). We observed that cfDNA positivity, defined as ≥10% tumor fraction by LPWGS, was associated with significantly shorter progression-free survival (PFS) in an exploratory test cohort of 16 patients who were actively treated on diverse regimens. We prospectively determined the predictive value of cfDNA in 86 samples from 45 RRMM patients treated with elotuzumab, pomalidomide, bortezomib, and dexamethasone in a phase II clinical trial (NCT02718833). PFS in patients with tumor-positive and -negative cfDNA after two cycles of treatment was 1.6 and 17.6 months, respectively (HR 7.6, P < 0.0001). Multivariate hazard modelling confirmed cfDNA as independent risk factor (HR 96.6, P = 6.92e-05). While correlating with serum-free light chains and bone marrow, cfDNA additionally discriminated patients with poor PFS among those with the same response by IMWG criteria. In summary, detectability of MM-derived cfDNA, as a measure of substantial tumor burden with therapy, independently predicts poor PFS and may provide refinement for standard-of-care response parameters to identify patients with poor response to treatment earlier than is currently feasible.
| S-EPMC8983453 | biostudies-literature
Project description:Multiple myeloma, a bone marrow cancer, is preceded by precursor stages called monoclonal gammopathy of unknown significance and smoldering multiple myeloma. Over the past few years, highly effective and safe therapies have been made available to treat multiple myeloma. This represents a major breakthrough and has major therapeutic implications. Treatment for multiple myeloma has evolved to include treatment of precursor stages (early treatment) as these therapies are shown to be safe and effective also in smoldering myeloma. Randomized studies have shown that early treatment can delay the onset of multiple myeloma and even improve overall survival compared to observation in smoldering myeloma. The best therapeutic course and selection of patients with smoldering myeloma to treat is still a matter of debate. In this manuscript, we review the definition, management, clinical implications of smoldering myeloma and early detection of myeloma in the current context and with up-to-date data.
| S-EPMC7069728 | biostudies-literature
Project description:Smoldering multiple myeloma has been recognized for over 40 years and represents a pre-symptomatic phase of the 2nd most common hematologic malignancy. 1/3 of patients will remain asymptomatic at 10 years. There is an identifiable subset of patients that will develop CRAB within 2 years of recognition and these patients are considered for therapeutic intervention before the development of potentially irreversible complications. Obstacles to widespread implementation of therapeutic guidelines are limited by the variable definitions associated with this high-risk group as well as the poor concordance between classification schemes. Analysis of clinical trial outcomes as well as uniform eligibility helps determine whether a given patient should be considered for therapeutic intervention outside of a clinical trial.
| S-EPMC9719610 | biostudies-literature
Project description:The development of novel cellular therapies and bispecific T-cell-engaging antibodies is occurring at breakneck speed in multiple myeloma (MM). While groundbreaking, these agents have their unique logistical and toxicity issues and currently do not represent a curative approach. In this context, there continues to be an urgent need to develop novel, off-the-shelf immunotherapy approaches to add to the armamentarium. This article explores novel agents being investigated in combination with standard immunomodulatory drugs as well as next-generation cereblon E3 ligase modulators. These novel agents include drugs being repurposed from their use in other diseases as well as novel monoclonal antibodies. In addition, agents under development such as immunocytokines, immunotoxins, and natural killer-cell activators/engagers are reviewed. These novel therapeutic strategies hold the promise of countermanding the immunosuppressive tumor microenvironment, leading to enhanced anti-MM activity.
| S-EPMC9820703 | biostudies-literature