Evaluating early intervention in smoldering myeloma clinical trials: a systematic review.

BACKGROUND: Smoldering multiple myeloma (SMM), an asymptomatic precursor of multiple myeloma (MM), carries a variable risk of progression to MM. There is little consensus on the efficacy or optimal timing of treatment in SMM. We systematically reviewed the landscape of all clinical trials in SMM. We compared the efficacy of treatment regimens studied in SMM to results from these regimens when used in newly diagnosed multiple myeloma (NDMM), to determine whether the data suggest deeper responses in SMM versus NDMM. METHODS: All prospective interventional clinical trials for SMM, including published studies, meeting abstracts, and unpublished trials listed on ClinicalTrials.gov up to April 1, 2023, were identified. Trial-related variables were captured, including treatment strategy and efficacy results. Relevant clinical endpoints were defined as overall survival (OS) and quality of life. RESULTS: Among 45 SMM trials identified, 38 (84.4%) assessed active myeloma drugs, while 7 (15.6%) studied bone-modifying agents alone. Of 18 randomized trials in SMM, only one (5.6%) had a primary endpoint of OS; the most common primary endpoint was progression-free survival (n = 7, 38.9%). Among 32 SMM trials with available results, 9 (28.1%) met their prespecified primary endpoint, of which 5 were single-arm studies. Six treatment regimens were tested in both SMM and NDMM; 5 regimens yielded a lower rate of very good partial response rate or better (≥VGPR) in SMM compared to the corresponding NDMM trial (32% vs 63%, 43% vs 53%, 40% vs 63%, 86% vs 89%, 92% vs 95%, and 94% vs 87%, respectively). CONCLUSION: In this systematic review of all prospective interventional clinical trials in SMM, we found significant variability in trial design, including randomization status, primary endpoints, and types of intervention used. Despite the statistical limitations, comparison of treatment regimens revealed no compelling evidence that the treatment is more effective when introduced early in SMM compared to NDMM.

Persistent challenges with treating multiple myeloma early.

Over the past decade, 2 strategies have advanced the treatment of patients with multiple myeloma and its precursor diseases. First, the definition has changed to include patients without end organ damage, who previously would not have been treated. Second, there is widespread enthusiasm for treating high-risk, smoldering multiple myeloma. In this commentary, we explore the evidence supporting these therapeutic expansions. Although early treatment adds cost and therapeutic burden, it remains unknown whether survival and health-related quality of life are improved by early treatment. Herein, we consider the implications of diagnostic expansion in multiple myeloma.

Erdheim-Chester disease: consensus recommendations for evaluation, diagnosis, and treatment in the molecular era.

Erdheim-Chester disease (ECD) is a rare histiocytosis that was recently recognized as a neoplastic disorder owing to the discovery of recurrent activating MAPK (RAS-RAF-MEK-ERK) pathway mutations. Typical findings of ECD include central diabetes insipidus, restrictive pericarditis, perinephric fibrosis, and sclerotic bone lesions. The histopathologic diagnosis of ECD is often challenging due to nonspecific inflammatory and fibrotic findings on histopathologic review of tissue specimens. Additionally, the association of ECD with unusual tissue tropism and an insidious onset often results in diagnostic errors and delays. Most patients with ECD require treatment, except for a minority of patients with minimally symptomatic single-organ disease. The first ECD consensus guidelines were published in 2014 on behalf of the physicians and researchers within the Erdheim-Chester Disease Global Alliance. With the recent molecular discoveries and the approval of the first targeted therapy (vemurafenib) for BRAF-V600-mutant ECD, there is a need for updated clinical practice guidelines to optimize the diagnosis and treatment of this disease. This document presents consensus recommendations that resulted from the International Medical Symposia on ECD in 2017 and 2019. Herein, we include the guidelines for the clinical, laboratory, histologic, and radiographic evaluation of ECD patients along with treatment recommendations based on our clinical experience and review of literature in the molecular era.

T-Cell Lymphomas, Version 2.2022, NCCN Clinical Practice Guidelines in Oncology.

Peripheral T-cell lymphomas (PTCLs) are a heterogeneous group of lymphoproliferative disorders arising from mature T cells, accounting for about 10% of non-Hodgkin lymphomas. PTCL-not otherwise specified is the most common subtype, followed by angioimmunoblastic T-cell lymphoma, anaplastic large cell lymphoma, anaplastic lymphoma kinase-positive, anaplastic large cell lymphoma, anaplastic lymphoma kinase-negative, and enteropathy-associated T-cell lymphoma. This discussion section focuses on the diagnosis and treatment of PTCLs as outlined in the NCCN Guidelines for T-Cell Lymphomas.

Histiocytic Neoplasms, Version 2.2021, NCCN Clinical Practice Guidelines in Oncology.

Histiocytic neoplasms are rare hematologic disorders accounting for less than 1% of cancers of the soft tissue and lymph nodes. Clinical presentation and prognosis of these disorders can be highly variable, leading to challenges for diagnosis and optimal management of these patients. Treatment often consists of systemic therapy, and recent studies support use of targeted therapies for patients with these disorders. Observation ("watch and wait") may be sufficient for select patients with mild disease. These NCCN Guidelines for Histiocytic Neoplasms include recommendations for diagnosis and treatment of adults with the most common histiocytic disorders: Langerhans cell histiocytosis, Erdheim-Chester disease, and Rosai-Dorfman disease.

Novel somatic alterations in unicentric and idiopathic multicentric Castleman disease.

OBJECTIVES: Castleman disease (CD) is a heterogeneous group of disorders involving systemic inflammation and lymphoproliferation. Recently, clonal mutations have been identified in unicentric CD (UCD) and idiopathic multicentric CD (iMCD), suggesting a potential underlying neoplastic process. METHODS: Patients with UCD or iMCD with next generation sequencing (NGS) data on tissue DNA and/or circulating tumor DNA (ctDNA) were included. RESULTS: Five patients were included, 4 with iMCD and 1 with UCD. Four patients (80%) were women; median age was 40 years. Three of five patients (60%) had ≥1 clonal mutation detected on biopsy among the genes included in the panel. One patient with iMCD had a 14q32-1p35 rearrangement and a der(1)dup(1)(q42q21)del(1)(q42) (1q21 being IL-6R locus) on karyotype. This patient also had a NF1 K2459fs alteration on ctDNA (0.3%). Another patient with iMCD had a KDM5C Q836* mutation, and one patient with UCD had a TNS3-ALK fusion but no ALK expression by immunohistochemistry. CONCLUSIONS: We report 4 novel somatic alterations found in patients with UCD or iMCD. The 1q21 locus contains IL-6R, and duplication of this locus may increase IL-6 expression. These findings suggest that a clonal process may be responsible for the inflammatory phenotype in some patients with UCD and iMCD.

Cutaneous intralymphatic anaplastic lymphoma kinase-negative anaplastic large-cell lymphoma arising in a patient with multiple rounds of breast implants.

Primary cutaneous anaplastic large-cell lymphoma and breast implant-associated ALCL (BIA-ALCL) are rare subtypes of anaplastic lymphoma kinase (ALK)-negative ALCLs originating from skin and breast implants, respectively. Herein, we report a unique case of cutaneous ALK-negative ALCL occurring in the skin of left medial breast from a patient with multiple rounds of bilateral breast implants and a history of breast carcinoma. The lymphoma cells are entirely confined to the lymphatic channels in the dermis, and the patient has no other areas of skin abnormality, no lymphadenopathy, peri-implant fluid accumulation, or masses from the bilateral capsules of implants. The differential diagnosis and its relationship with breast implants are further explored.

Rosai-Dorfman-Destombes (RDD) disease presenting as palindromic rheumatism.

BACKGROUND: Rosai-Dorfman-Destombes (RDD) disease, is a rare proliferative and inflammatory disorder of non-Langerhans cell histiocytes. CASE PRESENTATION: We report a 35-year-old woman, who originally presented with recurrent episodes of lower extremity joint/bone pain and chronic nasal stuffiness and congestion. Her worsening nasal congestion was due to an obstructing nasal cavity lesion which was subsequently biopsied. Pathology was consistent with RDD. 18F-FDG PET images demonstrated intense uptake in the paranasal sinuses and a large pelvic lymph node. Focal osseous lesions with intense 18F-FDG uptake were also observed in the lower extremity, corresponding to areas of peri-articular pain. Rheumatologic work-up was consistent with palindromic rheumatism. She was diagnosed with immune-related disseminated RDD, presenting as palindromic rheumatism. CONCLUSIONS: This is the first case of RDD presenting as palindromic rheumatism. RDD should be considered as a possible but rare diagnosis in young patients with sinus-related symptoms and lymphadenopathy. The disease can on rare occasions be disseminated and can also present as immune-related RDD, such as in this patient.

Characterization of relapse patterns in patients with acute lymphoblastic leukemia treated with blinatumomab.

INTRODUCTION: Blinatumomab is a CD19/CD3 bispecific T-cell engager (BiTE) antibody that simultaneously binds CD19 on the surface of B-cells and CD3 on the surface of T-cells, resulting in tumor cell lysis. It is approved for the treatment of patients with relapsed/refractory B-cell acute lymphoblastic leukemia (B-ALL) and in patients with minimal residual disease after intensive induction chemotherapy. Relapse patterns after treatment with blinatumomab have not been well characterized. METHODS: We reviewed patients treated with blinatumomab with relapsed, refractory or minimal residual disease-positive B-ALL from 1 December 2014 to 31 December 2018 at a single academic medical center. Patient demographics, blast percentage prior to blinatumomab initiation, prior lines of therapy, blinatumomab treatment duration, sites of relapse, progression free survival, and overall survival were collected. RESULTS: A total of 20 patients were identified. Four (20%) patients developed extramedullary relapse following blinatumomab. The median time from treatment initiation to extramedullary relapse was 179 days (range 47-241). Sites of extramedullary relapse included the pancreas, adrenal gland, kidneys, liver, parotid gland, and brain. CONCLUSION: Extramedullary relapse occurs frequently following treatment of B-ALL with blinatumomab. Further studies aimed at preventing extramedullary relapse following blinatumomab treatment are warranted.

Real-World Toxicity Experience with BRAF/MEK Inhibitors in Patients with Erdheim-Chester Disease.

BACKGROUND: Erdheim-Chester disease (ECD) is a rare non-Langerhans cell histiocytosis. The BRAF inhibitor vemurafenib is approved by the U.S. Food and Drug Administration (FDA) for patients with ECD harboring a BRAF V600E mutation. Successful treatment has also been reported with MEK-targeted therapies, likely because of the fact that BRAF mutant-negative patients harbor MEK pathway alterations. In our Rare Tumor Clinic, we noted that these patients have frequent drug-related toxicity, consistent with previous reports indicating the need to markedly lower doses of interferon-alpha when that agent is used in these patients. PATIENTS AND METHODS: We performed a review of ten patients with ECD seen at the Rare Tumor Clinic at University of California San Diego receiving 16 regimens of targeted BRAF, MEK, or combined therapies. RESULTS: The median age of the ten patients with ECD was 53 years (range, 29-77); seven were men. The median dose percentage (percent of FDA-approved dose) tolerated was 25% (range, 25%-50%). The most common clinically significant adverse effects resulting in dose adjustments of targeted therapies were rash, arthralgias, and uveitis. Renal toxicity and congestive heart failure were seen in one patient each. In spite of these issues, eight of ten patients (80%) achieved a partial remission on therapy. DISCUSSION: Patients with ECD appear to require substantially reduced doses of BRAF and MEK inhibitors but are responsive to these lower doses.

NCCN Guidelines Insights: T-Cell Lymphomas, Version 1.2021.

Hepatosplenic T-cell lymphoma (HSTCL) is a rare subtype of T-cell lymphoma associated with an aggressive clinical course and a worse prognosis. HSTCL develops in the setting of chronic immune suppression or immune dysregulation in up to 20% of cases and is most often characterized by spleen, liver, and bone marrow involvement. Diagnosis and management of HSTCL pose significant challenges given the rarity of the disease along with the absence of lymphadenopathy and poor outcome with conventional chemotherapy regimens. These Guidelines Insights focus on the diagnosis and treatment of HSTCL as outlined in the NCCN Guidelines for T-Cell Lymphomas.

NCCN Guidelines Insights: Primary Cutaneous Lymphomas, Version 2.2020.

Mycosis fungoides (MF) is the most common subtype of cutaneous T-cell lymphoma (CTCL), and Sézary syndrome (SS) is a rare erythrodermic and leukemic subtype of CTCL characterized by significant blood involvement. Although early-stage disease can be effectively treated predominantly with skin-directed therapies, systemic therapy is often necessary for the treatment of advanced-stage disease. Systemic therapy options have evolved in recent years with the approval of novel agents such as romidepsin, brentuximab vedotin, and mogamulizumab. These NCCN Guidelines Insights discuss the diagnosis and management of MF and SS (with a focus on systemic therapy).

Safety and efficacy of direct oral anticoagulants for venous thromboembolism and stroke prophylaxis in patients with hematologic malignancies.

PURPOSE: Low-molecular-weight heparins are currently the recommended antithrombotic therapy for treatment and prevention of malignancy-related venous thromboembolism. Currently, the evidence evaluating direct oral anticoagulants versus low-molecular-weight heparins or a vitamin K antagonist in cancer patients with hematologic malignancies is limited. We evaluated the safety and efficacy of direct oral anticoagulants for venous thromboembolism treatment or stroke prevention for non-valvular atrial fibrillation in patients with hematologic malignancies. METHODS: This was a retrospective evaluation of adult patients with hematologic malignancies who received at least one dose of the Food and Drug Administration-approved direct oral anticoagulant for venous thromboembolism treatment or stroke prevention. We determined the frequency of major bleeding events, non-major bleeding events, stroke, systemic embolism, appropriateness of initial direct oral anticoagulant doses, holding practices prior to procedures, and the rate of all-cause mortality. An analysis was also performed to compare the incidence of bleeding between patients with a history of hematopoietic stem cell transplant to non-transplant patients. RESULTS: A total of 103 patients were identified, with the majority of patients receiving rivaroxaban for venous thromboembolism treatment. Major bleeding events occurred in four patients and no fatal bleeding events occurred. Non-major bleeding occurred in 29 patients, most commonly epistaxis and bruising. Two patients experienced a systemic embolism while on direct oral anticoagulant therapy. CONCLUSION: Direct oral anticoagulants may be a safe and effective alternative for anticoagulation therapy in patients with hematologic malignancies. However, larger prospective studies comparing direct oral anticoagulants to low-molecular-weight heparins or vitamin K antagonists are warranted to compare efficacy and safety outcomes in this patient population.

GNAS, GNAQ, and GNA11 alterations in patients with diverse cancers.

BACKGROUND: Advances in deep sequencing technology have uncovered a widespread, protumorigenic role of guanine nucleotide-binding (G protein) α (GNA) subunits, particularly GNA subunits Gs (GNAS), Gq (GNAQ), and G11 (GNA11) (GNA*), in a diverse collection of malignancies. The objectives of the current study were: 1) to determine GNA* aberration status in a cohort of 1348 patients with cancer and 2) to examine tumor mutational burden, overall survival rates, and treatment outcomes in patients with GNA*-positive tumors versus those with tumors that had wild-type GNA*. METHODS: For each patient, clinical and genomic data were collected from medical records. Next-generation sequencing was performed for each patient (range, 182-236 genes). RESULTS: Aberrations of GNA* genes were identified in a subset of patients who had 8 of the 12 cancer types examined, and a significant association was observed for appendiceal cancer and ocular melanoma (P < .0001 for both; multivariate analysis). Overall, 4.1% of the cancer population was affected. GNA* abnormalities were associated with higher numbers of co-alterations in univariate (but not multivariate) analysis and were most commonly accompanied by Aurora kinase A (AURKA), Cbl proto-oncogene (CBL), and LYN proto-oncogene (LYN) co-alterations (all P < .0001; multivariate analysis). GNA* alterations were correlated with a trend toward lower median overall survival (P = .085). The median tumor mutational burden was 4 mutations per megabase in both GNA*-altered and GNA* wild-type tumors. For this limited sample of GNA*-positive patients, longer survival was not correlated with any specific treatment regimens. CONCLUSIONS: In the current sample, the genes GNAS, GNAQ, and GNA11 were widely altered across cancer types, and these alterations often were accompanied by specific genomic abnormalities in AURKA, CBL, and LYN. Therefore, targeting GNA* alterations may require drugs that address the GNA* signal and important co-alterations. Cancer 2018;00:000-000. © 2018 American Cancer Society.

#MedEd: Medical Education and Knowledge Translation on Social Media.

This Viewpoint discusses the potential educational benefits of social media in the health sciences.