Hematology/oncology Clinics of North America

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During the last 20 years, proteasome inhibitors have been a cornerstone for the therapeutic management of multiple myeloma (MM). This review highlights how MM research has evolved over time in terms of our understanding of the mechanistic basis for the pronounced clinical activity of proteasome inhibitors in MM, compared with the limited clinical applications of this drug class outside the setting of plasma cell dyscrasias.

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Consolidation therapy consists of short-term therapy after stem cell transplant in multiple myeloma. Key consolidation trials have shown mixed results on whether consolidation should be included after transplant, leading to varied clinical practice. Maintenance therapy consists of long-term, typically fixed-duration or indefinite, therapy. Standard-risk patients typically receive single-agent therapy, whereas high-risk may benefit from doublet therapy and beyond. Adverse events and quality of life concerns should be considered, as optimal duration of maintenance therapy continues to be studied...

Immunocompetent mouse models of multiple myeloma (MM) are particularly needed in the era of T cell redirected therapy to understand drivers of sensitivity and resistance, optimize responses, and prevent toxicities. Three mouse models have been extensively characterized: the Balb/c plasmacytomas, the 5TMM, and the Vk*MYC. In the last year, additional models have been generated, which, for the first time, capture primary MM initiating events, like MMSET/NSD2 or cyclin D1 dysregulation. However, the long latency needed for tumor development and the lack of transplantable lines limit their utilization...

Despite improved treatments, most patients with multiple myeloma (MM) will experience relapse. Several novel agents have demonstrated activity and tolerability in early phase clinical trials. Venetoclax is a B-cell lymphoma 2 (Bcl-2) inhibitor with activity in patients with t(11;14) and/or Bcl-2 expression. Iberdomide and mezigdomide are cereblon E3 ligase modulators with higher potency, immunomodulatory, and antiproliferative activity compared with lenalidomide and pomalidomide. They have shown promising activity in heavily pretreated patients...

Multiple myeloma is characterized by a highly heterogeneous disease distribution within the bone marrow-containing skeletal system. In this review, we introduce the molecular mechanisms underlying clonal heterogeneity and the spatio-temporal evolution of myeloma. We discuss the clinical impact of clonal heterogeneity, which is thought to be one of the biggest obstacles to overcome therapy resistance and to achieve cure.

Improving the outcome of high-risk myeloma (HRMM) is a key therapeutic aim for the next decade. To achieve this aim, it is necessary to understand in detail the genetic drivers underlying this clinical behavior and to target its biology therapeutically. Advances have already been made, with a focus on consensus guidance and the application of novel immunotherapeutic approaches. Cases of HRMM are likely to have impaired prognosis even with novel strategies. However, if disease eradication and minimal disease states are achieved, then cure may be possible...

Measurable (minimal) residual disease (MRD) has already proven to be one of the most important prognostic factors in multiple myeloma (MM). Each improvement in the depth of MRD testing has led to superior discrimination of outcomes, and sustained MRD negativity seems to be paramount to durable responses. Peripheral blood assays to assess for MRD are still under investigation but hold promise as complementary tools to bone marrow MRD assays such as next-generation sequencing and flow cytometry. Herein, the authors explore the evidence and potential benefits and drawbacks of MRD-adapted clinical decision-making in MM...

Smoldering multiple myeloma (SMM) is an intermediate clinical stage in the spectrum of monoclonal plasma cell disorders. It represents a heterogeneous clinically defined condition in which some patients (approximately 50%) have monoclonal gammopathy of undetermined significance (premalignancy), and some (approximately 50%) have multiple myeloma (biologic malignancy). Using specific prognostic factors, patients with SMM, in whom malignant transformation has already likely occurred, can be identified. These patients are considered to have high-risk SMM...

The incorporation of monoclonal antibodies into backbone regimens has substantially improved the clinical outcomes of patients with newly diagnosed and relapsed/refractory multiple myeloma (MM). Although the SLAMF7-targeting antibody elotuzumab has no single- agent activity, there is clinical synergy between elotuzumab and immunomodulatory drugs in patients with relapsed/refractory disease. Daratumumab and isatuximab are CD38-targeting antibodies which have single-agent activity and a favorable safety profile, which make these agents an attractive component of combination regimens...

No therapy in multiple myeloma has been as extensively investigated as stem cell transplantation following high-dose chemotherapy. A search of the national library of medicine in February 2023 revealed over 27,000 publications covering stem cell transplantation. No other treatment for multiple myeloma has been so vigorously investigated. However, given the rapid advances seen in the treatment of multiple myeloma, it is legitimate to ask whether the technique first introduced in 1983 by Thomas McIlwain still has relevance...

The advent of chimeric antigen receptor (CAR)-T cell therapy has revolutionized the treatment of several hematological malignancies. Although the initial benefit was mainly observed in aggressive leukemias and lymphomas, recent data have resulted in the approval of multiple CAR-T therapies in indolent lymphomas, with ongoing research showing great promise for further improvements and therapeutic optimizations. In this article, we review the published data and approved therapies for CAR-T cell therapy for indolent lymphomas focusing on mantle cell lymphoma and follicular lymphoma while describing the work in chronic lymphocytic leukemia and future strategies...

Up to 30% of patients with acute myeloid leukemia (AML) who undergo chimeric antigen receptor (CAR) T-cell therapy have evidence of response, although trials are highly heterogeneous. These responses are rarely deep or durable. CD123, CD33, and CLL-1 have emerged as the most common targets for CAR T cells in AML. CAR T cells against myeloid antigens cause myeloablation as well as cytokine release syndrome, although neurotoxicity is rarely seen. Future efforts should focus on AML-specific antigen discovery or engineering, and on further enhancing the activity of CAR T cells...

In locally advanced RCC, 6 phase 3 randomized controlled trials (RCTs) were designed in the perioperative setting with immune checkpoint inhibitor (ICI) monotherapy or combinations. Adjuvant trials with atezolizumab, pembrolizumab, and nivolumab with ipilimumab reported results, as did the only perioperative trial with nivolumab. Of these, only 1 year of adjuvant pembrolizumab improved disease-free survival (DFS) versus placebo, with the other trials showing no improvement in DFS. In the purely neoadjuvant setting, phase 1 b/2 ICI trials have demonstrated safety, efficacy, and dynamic changes of immune infiltrates, and provide a rationale for randomized trial concepts...

The development of brain metastases is a poor prognostic indicator in renal cell carcinoma. Regular imaging and clinical examinations are necessary to monitor the brain before or during systemic therapy. Central nervous system-targeted radiation therapy, including stereotactic radiosurgery, whole-brain radiation therapy, and surgical resection, is a standard treatment option. Clinical trials are currently investigating the role of targeted therapy and immune checkpoint inhibitor combinations in treating brain metastases and decreasing intracranial disease progression...

Inequity exists along the continuum of cancer and cancer care delivery in the United States. Marginalized populations have later stage cancer at diagnosis, decreased likelihood of receiving cancer-directed care, and worse outcomes from treatment. These inequities are driven by historical, structural, systemic, interpersonal, and internalized factors that influence cancer across the pathologic and clinical continuum. To ensure equity in cancer care, interventions are needed at the level of policy, care delivery, interpersonal communication, diversity within the clinical workforce, and clinical trial accessibility and design...

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Lifestyle factors play a major role in the risk of breast cancer. This review aimed to examine the size of the effect of select lifestyle factors on risk for breast cancer and assess the quality of existing evidence. The authors performed an umbrella review of systematic reviews. The authors found an increased risk for breast cancer associated with obesity, alcohol intake, and smoking and a decreased risk due to physical activity. The evidence for sleep disruption and duration indicates risk for breast cancer, but it is limited in size, statistical significance, and quality of evidence...