Siltuximab as a primary treatment for cytokine release syndrome in a patient receiving a bispecific antibody in a clinical trial setting.

INTRODUCTION: Cytokine release syndrome (CRS) and immune effector cell-associated neurotoxicity syndrome (ICANS) are common toxicities associated with immunotherapies, including T cell redirecting bispecific antibodies. Although cooperative group guidelines recommend the use of tocilizumab or other IL-6/IL-6R inhibitors for the management of CRS and ICANS, reports on the use of siltuximab, an IL-6 inhibitor, for the treatment of CRS are limited. CASE REPORT: We present the case of a 77-year-old male who received T cell redirecting bispecific antibody therapy with talquetamab for relapsed/refractory multiple myeloma (RRMM) and developed CRS with concurrent ICANS after receiving a second dose of talquetamab. MANAGEMENT AND OUTCOME: The patient received an infusion of siltuximab. The patient recovered from CRS within 1 h of siltuximab administration and ICANS within 7 h of siltuximab administration. Patient tolerated the subsequent dose of talquetamab with no evidence of CRS and continued on study. DISCUSSION: This case describes the successful use of siltuximab for the management of CRS in a patient treated with a T cell redirecting bispecific antibody for RRMM.

International myeloma working group consensus recommendations on imaging in monoclonal plasma cell disorders.

Recent advances in the treatment of multiple myeloma have increased the need for accurate diagnosis of the disease. The detection of bone and bone marrow lesions is crucial in the investigation of multiple myeloma and often dictates the decision to start treatment. Furthermore, detection of minimal residual disease is important for prognosis determination and treatment planning, and it has underscored an unmet need for sensitive imaging methods that accurately assess patient response to multiple myeloma treatment. Low-dose whole-body CT has increased sensitivity compared with conventional skeletal survey in the detection of bone disease, which can reveal information leading to changes in therapy and disease management that could prevent or delay the onset of clinically significant morbidity and mortality as a result of skeletal-related events. Given the multiple options available for the detection of bone and bone marrow lesions, ranging from conventional skeletal survey to whole-body CT, PET/CT, and MRI, the International Myeloma Working Group decided to establish guidelines on optimal use of imaging methods at different disease stages. These recommendations on imaging within and outside of clinical trials will help standardise imaging for monoclonal plasma cell disorders worldwide to allow the comparison of results and the unification of treatment approaches for multiple myeloma.

The roles of bone remodeling in normal hematopoiesis and age-related hematological malignancies.

Prior research establishing that bone interacts in coordination with the bone marrow microenvironment (BMME) to regulate hematopoietic homeostasis was largely based on analyses of individual bone-associated cell populations. Recent advances in intravital imaging has suggested that the expansion of hematopoietic stem cells (HSCs) and acute myeloid leukemia cells is restricted to bone marrow microdomains during a distinct stage of bone remodeling. These findings indicate that dynamic bone remodeling likely imposes additional heterogeneity within the BMME to yield differential clonal responses. A holistic understanding of the role of bone remodeling in regulating the stem cell niche and how these interactions are altered in age-related hematological malignancies will be critical to the development of novel interventions. To advance this understanding, herein, we provide a synopsis of the cellular and molecular constituents that participate in bone turnover and their known connections to the hematopoietic compartment. Specifically, we elaborate on the coupling between bone remodeling and the BMME in homeostasis and age-related hematological malignancies and after treatment with bone-targeting approaches. We then discuss unresolved questions and ambiguities that remain in the field.

Selinexor-Based Triplet Regimens in Patients With Multiple Myeloma Previously Treated With Anti-CD38 Monoclonal Antibodies.

BACKGROUND: The increasing use of anti-CD38 monoclonal antibodies (αCD38 mAbs) for newly diagnosed or early relapsed multiple myeloma (MM), especially in non-transplant eligible patients, may lead to more patients developing αCD38 mAb-refractory disease earlier in the treatment course with fewer treatment options. PATIENTS AND METHODS: We analyzed the efficacy and safety of selinexor-based triplets (selinexor+dexamethasone [Sd] plus pomalidomide [SPd, n = 23], bortezomib [SVd, n = 16] or carfilzomib (SKd, n = 23]) in a subset of STOMP (NCT02343042) and BOSTON (NCT03110562) study patients treated previously with αCD38 mAbs. RESULTS: Sixty-two patients (median 4 prior therapies, range 1 to 11, 90.3% refractory to αCD38 mAb) were included. Overall response rates (ORR) in the SPd, SVd and SKd cohorts were 52.2%, 56.3%, and 65.2%, respectively. Overall response rate was 47.4% among patients who had MM refractory to the third drug reintroduced in the Sd-based triplet. Median progression-free survival in the SPd, SVd, and SKd cohorts was 8.7, 6.7, and 15.0 months, respectively, and median overall survival was 9.6, 16.9, and 33.0 months, respectively. Median time to discontinuation in the SPd, SVd, and SKd cohorts was 4.4, 5.9, and 10.6 months, respectively. The most common hematological adverse events were thrombocytopenia, anemia, and neutropenia. Nausea, fatigue, and diarrhea were primarily grade 1/2. Adverse events were generally manageable with standard supportive care and dose modifications. CONCLUSION: Selinexor-based regimens may offer effective and well-tolerated therapy to patients with relapsed and/or refractory MM who had disease previously exposed or refractory to αCD38 mAb therapy and could help address the unmet clinical need in these high-risk patients.

Bone marrow transplant for multiple myeloma: impact of distance from the transplant center.

PURPOSE: This study investigated the impact of prognostic variables, including the distance a patient lives from a transplant center, on the outcome of autologous hematopoietic stem cell transplantation (ASCT) for multiple myeloma. METHODS: This retrospective analysis included 77 myeloma patients who received an ASCT at Dartmouth Hitchcock Medical Center between 1996 and 2009, 70 of whom were treated between 2002 and 2009. Using linear regression and univariate analysis, we examined the impact of distance from the transplant center on survival. Kaplan-Meier curves identified overall and event-free survival. An association between distance from the transplant center and survival was examined using Cox regression analysis, while adjusting for patient-, disease-, and treatment-related variables. RESULTS: Increasing distance from the transplant center correlated with improved overall survival (P=.004), but had no impact on disease-free survival (P=.26). CONCLUSIONS: These results suggest that the distance from a transplant center should not be a barrier to ASCT for eligible patients with multiple myeloma.

Application of risk factors for venous thromboembolism in patients with multiple myeloma starting chemotherapy, a real-world evaluation.

INTRODUCTION: Within the first year of diagnosis, up to 1 in 3 multiple myeloma (MM) patients will experience a venous thromboembolism (VTE). The International Myeloma Working Group (IMWG) has thromboprophylaxis guidelines that stratify patients into low or high risk for thrombosis and subsequently recommend thromboprophylaxis, but it is unknown if these recommendations are being followed or if they are effective. The purpose of this study was to assess efficacy of the IMWG guidelines and investigate other potential VTE risk factors. METHODS: Study participants were treated at the University of Kansas Medical Center between 2007 and 2013, and charts were reviewed to extract data. Cases (MM and VTE) were matched to controls (MM and no VTE) at approximately 1:3 ratio based on gender, age (±5 years), and time of MM diagnosis (±5 years). RESULTS: A total of 80 cases and 211 controls were matched. Most patients (82%) were considered high risk for experiencing a VTE at the time of their MM diagnosis and 18% were considered low risk. Neither risk category (P = 0.16) nor thromboprophylaxis at baseline (P = 0.37) predicted VTE, though cases were more likely than controls to have an increased risk of thrombosis at the time of clot compared to their baseline risk (P = 0.09). CONCLUSION: Our results suggest that IMWG guidelines are not being consistently followed and therefore could not be validated. Additional risk factors were not identified, but risk for VTE may change over time suggesting patients may require ongoing assessment of VTE risk and thromboprophylaxis throughout the disease course.

IgG kappa monoclonal gammopathy of undetermined significance presenting as acquired type III Von Willebrand syndrome.

Acquired von Willebrand syndrome (AVWS) is a rare bleeding disorder associated with hematoproliferative disorders, autoimmune conditions, neoplasia and cardiovascular disorders that often present a diagnostic challenge. Monoclonal gammopathy of undetermined significance (MGUS) is one of the most common causes of AVWS that typically presents later in life with mucocutaneous or postsurgical bleeding and multimers consistent with type I or II von Willebrand disease (VWD). Here, we present the case of a patient with a 32-year history of type III VWD that was ultimately found to be AVWS related to an IgG MGUS. In this case report, we highlight the diagnostic challenges of AVWS to ensure proper identification and potentially lifesaving treatment of this rare disorder.

Von Willebrand disease in pregnancy.

Because von Willebrand factor (VWF) levels increase during pregnancy, many women with VWD, though not requiring support with hemostatic agents, are at increased risk for delayed postpartum hemorrhage as coagulation factor levels fall to their prepregnancy levels in the puerperium. Women with moderate or severe disease or complicated pregnancies are best served by delivering at a center with an obstetrician, hematologist, and anesthesiologist experienced in managing coagulation disorders. In addition, on-site laboratory facilities with specialized coagulation testing capability, pharmacy, and blood bank support are critical for success. Ensuring optimal outcomes for pregnant women with VWD requires a multidisciplinary approach.

Lipoprotein lipase links dietary fat to solid tumor cell proliferation.

Many types of cancer cells require a supply of fatty acids (FA) for growth and survival, and interrupting de novo FA synthesis in model systems causes potent anticancer effects. We hypothesized that, in addition to synthesis, cancer cells may obtain preformed, diet-derived FA by uptake from the bloodstream. This would require hydrolytic release of FA from triglyceride in circulating lipoprotein particles by the secreted enzyme lipoprotein lipase (LPL), and the expression of CD36, the channel for cellular FA uptake. We find that selected breast cancer and sarcoma cells express and secrete active LPL, and all express CD36. We further show that LPL, in the presence of triglyceride-rich lipoproteins, accelerates the growth of these cells. Providing LPL to prostate cancer cells, which express low levels of the enzyme, did not augment growth, but did prevent the cytotoxic effect of FA synthesis inhibition. Moreover, LPL knockdown inhibited HeLa cell growth. In contrast to the cell lines, immunohistochemical analysis confirmed the presence of LPL and CD36 in the majority of breast, liposarcoma, and prostate tumor tissues examined (n = 181). These findings suggest that, in addition to de novo lipogenesis, cancer cells can use LPL and CD36 to acquire FA from the circulation by lipolysis, and this can fuel their growth. Interfering with dietary fat intake, lipolysis, and/or FA uptake will be necessary to target the requirement of cancer cells for FA.