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Proteasome inhibitors are one of the most important classes of agents to have emerged for the treatment of multiple myeloma in the past two decades, and now form one of the backbones of treatment. Three agents in this class have been approved by the United States Food and Drug Administration—the first-in-class compound bortezomib, the second-generation agent carfilzomib, and the first oral proteasome inhibitor, ixazomib. The success of this class of agents is due to the exquisite sensitivity of myeloma cells to the inhibition of the 26S proteasome, which plays a critical role in the pathogenesis and proliferation of the disease. Proteasome inhibition results in multiple downstream effects, including the inhibition of NF-κB signaling, the accumulation of misfolded and unfolded proteins, resulting in endoplasmic reticulum stress and leading to the unfolded protein response, the downregulation of growth factor receptors, suppression of adhesion molecule expression, and inhibition of angiogenesis; resistance to proteasome inhibition may arise through cellular responses mediating these downstream effects. These multiple biologic consequences of proteasome inhibition result in synergistic or additive activity with other chemotherapeutic and targeted agents for myeloma, and proteasome inhibitor-based combination regimens have become established as a cornerstone of therapy throughout the myeloma treatment algorithm, incorporating agents from the other key classes of antimyeloma agents, including the immunomodulatory drugs, monoclonal antibodies, and histone deacetylase inhibitors. This review gives an overview of the critical role of the proteasome in myeloma and the characteristics of the different proteasome inhibitors and provides a comprehensive summary of key clinical efficacy and safety data with the currently approved proteasome inhibitors.

Multiple myeloma (MM) is a plasma-cell neoplasm that is treated with high-dose chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. The presence of somatic mutations in the peripheral blood is termed clonal hematopoiesis of indeterminate potential (CHIP) and is associated with adverse outcomes. Targeted sequencing of the stem cell product from 629 MM patients treated by ASCT at the Dana-Farber Cancer Institute (2003–2011) detects CHIP in 136/629 patients (21.6%). The most commonly mutated genes are DNMT3A, TET2, TP53, ASXL1 and PPM1D. Twenty-one from fifty-six patients (3.3%) receiving first-line IMiD maintenance develop a therapy-related myeloid neoplasm (TMN). However, regardless of CHIP status, the use of IMiD maintenance associates with improved PFS and OS. In those not receiving IMiD maintenance, CHIP is associated with decreased overall survival (OS) (HR:1.34, p  = 0.02) and progression free survival (PFS) (HR:1.45, p  < 0.001) due to an increase in MM progression. Multiple myeloma (MM) is treated with induction chemotherapy, autologous stem cell transplant (ASCT) and long-term immunomodulatory drug (IMiD) maintenance. Here, the authors show that the presence of clonal haematopoiesis of indeterminate potential (CHIP) at time of ASCT is associated with adverse outcomes in MM patients.

Daratumumab was associated with impressive antitumor responses, including complete and very good partial responses, in heavily pretreated patients with myeloma. Infusion reactions were the main adverse effect. Current therapies, including proteasome inhibitors and immunomodulatory agents, have improved outcomes substantially in patients with multiple myeloma. 1 Unfortunately, the majority of these patients have a relapse and have limited treatment options after exposure to these classes of agents. 2 , 3 Patients with disease that is refractory to both proteasome inhibitors and immunomodulatory drugs have poor prognoses; the estimated median overall survival is 9 months, and the estimated event-free survival is 5 months at best. 2 , 3 CD38 is a 45-kD, type II transmembrane glycoprotein that associates with cell-surface receptors in lipid rafts, regulates cytoplasmic Ca 2+ flux, and mediates signal transduction in lymphoid . . .

Substantial improvements in survival have been seen in multiple myeloma (MM) over recent years, associated with the introduction and widespread use of multiple novel agents and regimens, as well as the emerging treatment paradigm of continuous or long-term therapy. However, these therapies and approaches may have limitations in the community setting, associated with toxicity burden, patient burden, and other factors including cost. Consequently, despite improvements in efficacy in the rigorously controlled clinical trials setting, the same results are not always achieved in real-world practice. Furthermore, the large number of different treatment options and regimens under investigation in various MM settings precludes the feasibility of obtaining head-to-head clinical trial data, and there is a temptation to use cross-trial comparisons to evaluate data across regimens. However, multiple aspects, including patient-related, disease-related, and treatment-related factors, can influence clinical trial outcomes and lead to differences between studies that may confound direct comparisons between data. In this review, we explore the various factors requiring attention when evaluating clinical trial data across available agents/regimens, as well as other considerations that may impact the translation of these findings into everyday MM management. We also investigate discrepancies between clinical trial efficacy and real-world effectiveness through a literature review of non-clinical trial data in relapsed/refractory MM on novel agent−based regimens and evaluate these data in the context of phase 3 trial results for recently approved and commonly used regimens. We thereby demonstrate the complexity of interpreting data across clinical studies in MM, as well as between clinical studies and routine-care analyses, with the aim to help clinicians consider all the necessary issues when tailoring individual patients’ treatment approaches.

The combination of bortezomib, lenalidomide, and dexamethasone is a highly effective therapy for newly diagnosed multiple myeloma. Ixazomib is an investigational, oral, proteasome inhibitor with promising anti-myeloma effects and low rates of peripheral neuropathy. In a phase 1/2 trial we aimed to assess the safety, tolerability, and activity of ixazomib in combination with lenalidomide and dexamethasone in newly diagnosed multiple myeloma. We enrolled patients newly diagnosed with multiple myeloma aged 18 years or older with measurable disease, Eastern Cooperative Oncology Group performance status 0–2, and no grade 2 or higher peripheral neuropathy, and treated them with oral ixazomib (days 1, 8, 15) plus lenalidomide 25 mg (days 1–21) and dexamethasone 40 mg (days 1, 8, 15, 22) for up to 12 28-day cycles, followed by maintenance therapy with ixazomib alone. In phase 1, we gave patients escalating doses of ixazomib (1·68–3·95 mg/m2) to establish the recommended dose for phase 2. The primary endpoints were maximum tolerated dose for phase 1, and the rate of very good partial response or better for phase 2. Safety analyses were done in all patients who received at least one dose of study drug; efficacy analyses were done in all patients who received at least one dose of study drug at the phase 2 dose, had measurable disease at baseline, and had at least one post-baseline response assessment. This study is registered at ClinicalTrials.gov, number NCT01217957. Between Nov 22, 2010, and Feb 28, 2012, we enrolled 65 patients (15 to phase 1 and 50 to phase 2). Four dose-limiting toxic events were noted in phase 1: one at a dose of ixazomib of 2·97 mg/m2 and three at 3·95 mg/m2. The maximum tolerated dose of ixazomib was established as 2·97 mg/m2 and the recommended phase 2 dose was 2·23 mg/m2, which was converted to a 4·0 mg fixed dose based on population pharmacokinetic results. Grade 3 or higher adverse events related to any drug were reported in 41 (63%) patients, including skin and subcutaneous tissue disorders (11 patients, 17%), neutropenia (eight patients, 12%), and thrombocytopenia (five patients, 8%); drug-related peripheral neuropathy of grade 3 or higher occurred in four (6%) patients. Five patients discontinued because of adverse events. In 64 response-evaluable patients, 37 (58%, 95% CI 45–70) had a very good partial response or better. The all-oral combination of weekly ixazomib plus lenalidomide and dexamethasone was generally well tolerated and appeared active in newly diagnosed multiple myeloma. These results support the phase 3 trial development of this combination for multiple myeloma. Millennium Pharmaceuticals, a wholly owned subsidiary of Takeda Pharmaceutical International Company.

In a large, multinational, randomized trial, continuous lenalidomide maintenance therapy after triplet therapy (lenalidomide, bortezomib, and dexamethasone) and autologous stem-cell transplantation resulted in longer progression-free survival than triplet therapy alone.

To evaluate the prevalence of monoclonal gammopathy (MG) in patients with wild-type transthyretin amyloidosis (ATTRwt) (formerly known as senile amyloidosis). We retrospectively analyzed the serum protein electrophoresis and serum immunofixation results, free light chain (FLC) levels, and renal function of 113 consecutive patients with ATTRwt seen at the Brigham and Women's Hospital's Cardiac Amyloidosis Program between February 21, 2006, and November 9, 2016. Monoclonal gammopathy was defined as a monoclonal protein present in the serum. Light chain MG was defined as an abnormal serum FLC κ/λ ratio with an elevated FLC level in the absence of a monoclonal protein. In patients with renal dysfunction, the renal FLC reference range was used. The mean age of the population was 75 years, 3 of the 113 patients (3%) were female, and 110 (97%) were white. Monoclonal gammopathy was present in 26 patients (23%), 24 of whom had monoclonal protein present and 2 others who met criteria for light chain MG. Most clones (12 of 20 [60%]) were λ restricted. Another 7 patients had an abnormal FLC κ/λ ratio in the setting of renal dysfunction. In this study, MG was present in 23% of patients with ATTRwt. The finding of MG or an abnormal FLC κ/λ ratio in an elderly man may cause diagnostic confusion during subtyping of amyloidosis. A high degree of clinical suspicion for ATTRwt and precise tissue typing using mass spectrometry may overcome such diagnostic challenges.

Reports of secondary malignancies after chimeric antigen receptor (CAR)-T and possible CAR-T derived malignant transformation necessitate caution. Here we describe a patient with diffuse large B-cell lymphoma who developed new lymphadenopathy 2.5 years after CAR-T in the context of COVID-19 infection with histopathologic features consistent with T-cell lymphoma (TCL). Deep molecular interrogation with genomic sequencing and single-cell spatial transcriptomics reveals a highly proliferative clonal T-cell population co-expressing CD4 and CD8 with biallelic TCR rearrangement and no evidence of the CAR construct. The expanded clonotype displayed T follicular helper (TFH) cell transcriptomic programs and occupies immune-excluded spatial niches within the lymph node, supportive of TFH-like neoplastic T cell behavior. Remarkably, the lymphadenopathy spontaneously resolved on interval imaging. Our data underscore the need for better understanding of post-CAR-T clonal T-cell lymphoproliferative disorders to avoid unnecessary treatment and higher specificity in diagnostic methods for TCL. Secondary malignancies and chimeric antigen receptor (CAR)-T-derived malignant T cell transformation have been reported after CAR-T therapy. Here, the authors describe a patient with diffuse large B-cell lymphoma (DLBCL) who developed new lymphadenopathy 2.5 years after CAR-T in the context of COVID-19 infection with histopathologic features consistent with T-cell lymphoma (TCL).

In a study conducted at three institutions, ibrutinib was associated with major responses in 73% of patients with Waldenström's macroglobulinemia who had received at least one previous treatment. Toxic effects of grade 2 or higher included neutropenia in 22% of the patients. Waldenström’s macroglobulinemia is a malignant B-cell lymphoma that is associated with an accumulation of clonal lymphoplasmacytic cells and monoclonal IgM secretion. 1 Despite advances in treatment, the disease eventually progresses in most patients, and new treatment options are needed. Whole-genome sequencing has revealed a single activating somatic mutation in MYD88 (resulting in a predicted protein change from leucine to proline at amino acid position 265) and multiple activating mutations in the C-terminal domain of CXCR4 in patients with Waldenström’s macroglobulinemia. 2 , 3 In tumor cells, MYD88L265P triggers activation of nuclear factor κB (NF-κB) through two divergent pathways involving Bruton’s tyrosine kinase (BTK) . . .

Early therapeutic intervention in high-risk smoldering multiple myeloma (HR-SMM) has shown benefits, however, no studies have assessed whether biochemical progression or response depth predicts long-term outcomes. The single-arm I-PRISM phase II trial (NCT02916771) evaluated ixazomib, lenalidomide, and dexamethasone in 55 patients with HR-SMM. The primary endpoint, median progression-free survival (PFS), was not reached (NR) (95% CI: 57.7–NR, median follow-up 50 months). The secondary endpoint, biochemical PFS, was 48.6 months (95% CI: 39.9–NR) and coincided with or preceded SLiM-CRAB in eight patients. For additional secondary objectives, the overall response rate was 93% with 31% achieving complete response (CR) and 45% very good partial response (VGPR) or better. CR correlated strongly with the absence of SLiM-CRAB and biochemical progression. MRD-negativity (10 -5 sensitivity) predicted a 5-year biochemical PFS of 100% versus 40% in MRD-positive patients (p = 0.051), demonstrating that deep responses significantly improve time to progression. Exploratory single-cell RNA sequencing linked tumor MHC class I expression to proteasome inhibitor response, and a lower proportion of GZMB+ T cells within clonally expanded CD8+ T cells associated with suboptimal outcomes. Depth of response (CR/VGPR, MRD-) links to better outcomes, while biochemical progression predicts end-organ damage. Higher MHC-I on tumors and greater GZMB+ T cells in clonally expanded CD8+ T cells are tied to improved outcomes.