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Randomized studies have shown that bortezomib (BTZ) can be given weekly via intravenous (IV) route or twice weekly via subcutaneous (SC) route with lower neuropathy risk and no loss of anti-myeloma efficacy compared to original standard IV twice weekly schedule. Weekly SC should therefore yield the best therapeutic index and is widely used but has not been compared to established administration schedules in the context of a clinical trial. Comprehensive electronic medical record review was done for disease control and neuropathy symptoms of 344 consecutive patients who received their first BTZ-containing regimen for myeloma or AL amyloidosis before or after we changed to SC weekly in December 2010. Univariate and multivariable analyses were carried out that adjusted for age, underlying disease, concurrently used anticancer agents, underlying conditions predisposing to neuropathy, and number of prior regimens compared SC weekly to other schedules. Fifty-three patients received BTZ SC weekly, 17 SC twice weekly, 127 IV weekly and 147 IV twice weekly. Risk for neuropathy of any grade was higher with other schedules compared to SC weekly (44.3% vs. 26.9%, p = 0.001) while response rate was similar (72.1% vs. 76.6%, respectively, p = 0.15). Multivariable analyses upheld higher neuropathy risk (Odds ratio 2.45, 95% CI 1.26-4.76, p = 0.008) while the likelihood of not achieving a response (= partial response or better) was comparable (Odds ratio 1.25, 95% CI 0.58-2.71, p = 0.56) for other schedules compared to SC weekly, respectively. Lower neuropathy risk translated into longer treatment duration when BTZ was started SC weekly (p = 0.001). Weekly SC BTZ has activity comparable to other schedules and causes low rates of neuropathy.

Cardiac amyloidosis results in an infiltrative restrictive cardiomyopathy, with a number of characteristic features: biventricular hypertrophy, abnormal myocardial global longitudinal strain with relative apical sparing, biatrial dilation, and small pericardial effusion along with conduction abnormalities. Amyloid deposits leading to hemodynamically significant valvular heart disease are very rare. We describe a rare case of concomitant moderately severe tricuspid and mitral valve stenosis because of ongoing amyloid deposition in a patient with progressive multiple myeloma and fat pad biopsy‐proven light chain amyloidosis. Worsening infiltrative cardiomyopathy and valvulopathy despite evidence‐based chemotherapy and heart failure pharmacotherapy led to end‐stage disease and death. Valvular involvement in cardiac amyloidosis requires early recognition of the underlying disease condition to guide directed medical therapy and prevent its progression. In this instance, valvuloplasty or valve replacement is not a viable option.

The diagnosis of AL amyloidosis is often challenging due to its systemic nature and heterogeneous clinical presentation. Current serological biomarkers for diagnosis and monitoring are not optimal. We have considered the possibility that mononuclear cell‐type specific molecular expression can be used to develop blood‐based biomarkers to diagnose and monitor patients with AL amyloidosis. Peripheral blood monocytes and CD4+ T cells from patients with documented AL amyloidosis or myeloma without amyloidosis were assessed by enhanced flow cytometric analysis for expression levels of 20 analytes chosen for the possibility that their expression levels may lead to diagnostic assays and biomarkers. We found definitive expression level differences for brain‐derived neurotrophin factor (BDNF), calmodulin, and phospho‐TBK1 in CD4+ T cells and for phospho‐GSK3β in monocytes. Logistic regression and ROC analysis showed that BDNF in CD4+ T cells and heme oxygenase 1 in monocytes significantly distinguished between patients with myeloma versus patients with AL amyloidosis (AUC = 0.75). Additionally, we discovered remarkable differences in intermolecular associations between the samples from the two patient groups, suggesting the involvement of specific pathogenetic pathways. Our results demonstrate that mononuclear cell‐type specific molecular expression may be useful for developing a diagnostic assay and biomarkers for patients with AL amyloidosis.

Patients with multiple myeloma who have relapsed after or become refractory to lenalidomide in early treatment lines represent a clinically important population in need of effective therapies. The safety and efficacy of pomalidomide, low-dose dexamethasone, and daratumumab was evaluated in lenalidomide-pretreated patients with relapsed or refractory multiple myeloma (RRMM) after one to two prior treatment lines in the phase 2 MM-014 study. Patients received pomalidomide 4 mg daily from days 1–21 and dexamethasone 40 mg weekly (28-day cycles). Daratumumab 16 mg/kg was administered per label. Primary endpoint was overall response rate (ORR); secondary endpoints included progression-free survival (PFS) and safety. Per protocol, all patients (N = 112) had received lenalidomide in their most recent prior regimen (75.0% lenalidomide refractory). ORR was 77.7% (76.2% in lenalidomide-refractory patients); median follow-up was 17.2 months. Median PFS was not reached (1-year PFS rate 75.1%). The most common hematologic grade 3/4 treatment-emergent adverse event was neutropenia (62.5%). Grade 3/4 infections were reported in 31.3% of patients, including 13.4% with grade 3/4 pneumonia. These results demonstrate the safety and efficacy of pomalidomide-based therapy as early as second line in patients with RRMM, even immediately after lenalidomide failure, indicating that switching from the immunomodulatory agent class is not necessary.

Multiple myeloma (MM) is a hematologic malignancy caused by the clonal expansion of immunoglobulin-producing plasma cells in the bone marrow and/or extramedullary sites. Common manifestations of MM include anemia, renal dysfunction, infection, bone pain, hypercalcemia, and fatigue. Despite numerous recent advancements in the MM treatment paradigm, current therapies demonstrate limited long-term effectiveness and eventual disease relapse remains exceedingly common. Myeloma cells often develop drug resistance through clonal evolution and alterations of cellular signaling pathways. Therefore, continued research of new targets in MM is crucial to circumvent cumulative drug resistance, overcome treatment-limiting toxicities, and improve outcomes in this incurable disease. This article provides a comprehensive overview of the landscape of novel treatments and emerging therapies for MM grouped by molecular target. Molecular targets outlined include BCMA, GPRC5D, FcRH5, CD38, SLAMF7, BCL-2, kinesin spindle protein, protein disulfide isomerase 1, peptidylprolyl isomerase A, Sec61 translocon, and cyclin-dependent kinase 6. Immunomodulatory drugs, NK cell therapy, and proteolysis-targeting chimera are described as well.

Signalling networks have been assessed in blood cells by assessing individual phosphoantigens. We considered the possibility that bivariate correlations involving a series of signalling molecules could be used to delineate functional signalling networks in cells from clinical samples. Here, we describe a novel approach to signalling network analysis using enhanced flow cytometry to provide increased resolving power and restricted‐dimensional cytometry which simplifies the analysis so that the precision of the analysis is optimised. This approach has been validated in short‐term cultures by recapitulating known tenets of two distinct pathways. Additionally, new findings from our unique approach provide both expanded and nuanced views of signalling circuits. Applying our technology platform to blood mononuclear cells from patients with plasma cell disorders, we identified cell‐type specific features of signalling pathways by distinct patterns of bivariate correlations. The intermolecular relationships between signalling analytes provide a description of the signalling network in blood cells from clinical samples. Consequently, our approach has the potential to assess how the blood mononuclear cell‐type specific signalling network affects pathophysiology and pathogenesis.

Multiple myeloma (MM) is the second most common hematologic malignancy in adults worldwide. Over the past few years, major therapeutic advances have improved progression-free and overall survival, as well as quality of life. Despite this recent progress, MM remains incurable in the vast majority of cases. Patients eventually relapse and become refractory to multiple drug classes, making long-term management challenging. In this review, we will focus on the treatment paradigm of relapsed/refractory MM (RRMM) in the era of advanced therapies emphasizing the available novel modalities that have recently been incorporated into routine practice, such as chimeric antigen receptor T-cell therapy, bispecific antibodies, and other promising approaches. We will also discuss major factors that influence the selection of appropriate drug combinations or cellular therapies, such as relapse characteristics, and other disease and patient related parameters. Our goal is to provide insight into the currently available and experimental therapies for RRMM in an effort to guide the therapeutic decision-making process.