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Bruton tyrosine kinase (BTK) inhibition is an effective treatment approach for patients with Waldenström macroglobulinemia (WM). The phase 3 ASPEN study compared the efficacy and safety of ibrutinib, a first-generation BTK inhibitor, with zanubrutinib, a novel, highly selective BTK inhibitor, in patients with WM. Patients with MYD88L265P disease were randomly assigned 1:1 to treatment with either ibrutinib or zanubrutinib. The primary endpoint was the proportion of patients achieving a complete or very good partial response (CR or VGPR) by independent review. Key secondary endpoints included major response rate (MRR), progression-free survival (PFS), duration of response (DOR), disease burden, and safety. A total of 201 patients were randomized, and 199 received ≥1 dose of study treatment. No patient achieved a CR. Twenty-nine (28%) zanubrutinib and 19 (19%) ibrutinib patients achieved a VGPR, a non-statistically significant difference (P = .09). MRRs were 77% and 78% , respectively. Median DOR and PFS were not reached; 84% and 85% of ibrutinib and zanubrutinib patients were progression-free at 18 months. Incidence of atrial fibrillation, contusion, diarrhea, peripheral edema, hemorrhage, muscle spasms, and pneumonia, as well as adverse events leading to treatment discontinuation, were all lower among zanubrutinib recipients. Incidence of neutropenia was higher with zanubrutinib, although grade ≥3 infection rates were similar in both arms (1.2 and 1.1 events/100 person-months). These results demonstrate that zanubrutinib and ibrutinib are highly effective in the treatment of WM, but zanubrutinib treatment was associated with a trend toward better response quality and less toxicity, particularly cardiovascular toxicity.

BACKGROUNDSystemic immunoglobulin light-chain (AL) amyloidosis is characterized by deposition of amyloid fibrils of light chains produced by clonal CD38+ plasma cells. Daratumumab, a human CD38-targeting antibody, may improve outcomes for this disease. METHODSWe randomly assigned patients with newly diagnosed AL amyloidosis to receive six cycles of bortezomib, cyclophosphamide, and dexamethasone either alone (control group) or with subcutaneous daratumumab followed by single-agent daratumumab every 4 weeks for up to 24 cycles (daratumumab group). The primary end point was a hematologic complete response. RESULTSA total of 388 patients underwent randomization. The median follow-up was 11.4 months. The percentage of patients who had a hematologic complete response was significantly higher in the daratumumab group than in the control group (53.3% vs. 18.1%) (relative risk ratio, 2.9; 95% confidence interval [CI], 2.1 to 4.1; P<0.001). Survival free from major organ deterioration or hematologic progression favored the daratumumab group (hazard ratio for major organ deterioration, hematologic progression, or death, 0.58; 95% CI, 0.36 to 0.93; P = 0.02). At 6 months, more cardiac and renal responses occurred in the daratumumab group than in the control group (41.5% vs. 22.2% and 53.0% vs. 23.9%, respectively). The four most common grade 3 or 4 adverse events were lymphopenia (13.0% in the daratumumab group and 10.1% in the control group), pneumonia (7.8% and 4.3%, respectively), cardiac failure (6.2% and 4.8%), and diarrhea (5.7% and 3.7%). Systemic administration-related reactions to daratumumab occurred in 7.3% of the patients. A total of 56 patients died (27 in the daratumumab group and 29 in the control group), most due to amyloidosis-related cardiomyopathy. CONCLUSIONSAmong patients with newly diagnosed AL amyloidosis, the addition of daratumumab to bortezomib, cyclophosphamide, and dexamethasone was associated with higher frequencies of hematologic complete response and survival free from major organ deterioration or hematologic progression. (Funded by Janssen Research and Development; ANDROMEDA ClinicalTrials.gov number, NCT03201965.

ultiple myeloma is a hematologic malignancy characterized by abnormal clonal plasma cells in the bone marrow, with potential for uncontrolled growth causing destructive osseous bone lesions, acute kidney injury, anemia, and hypercalcemia. The median age at onset of multiple myeloma is 69 years, and approximately 63% of patients diagnosed with multiple myeloma are older than 65 years. 1 In 2021, an estimated 34 290 new diagnoses of multiple myeloma and 12 410 deaths occurred in the US. In 2019, more than 155 688 people were diagnosed with multiple myeloma worldwide. 2 Approximately 100 000 deaths from multiple myeloma occur each year worldwide. 1 This review summarizes current evidence regarding the epidemiology, clinical presentation, diagnosis, and management of multiple myeloma. MethodsA literature search of the PubMed database was performed between January 1, 2000, through October 6, 2021, for Englishlanguage studies of the epidemiology, diagnosis, clinical presentation, and treatment of multiple myeloma. Additional papers were identified from review of the references from identified relevant articles. A total of 111 reports were identified and reviewed. IMPORTANCE Multiple myeloma is a hematologic malignancy characterized by presence of abnormal clonal plasma cells in the bone marrow, with potential for uncontrolled growth causing destructive bone lesions, kidney injury, anemia, and hypercalcemia. Multiple myeloma is diagnosed in an estimated 34 920 people in the US and in approximately 588 161 people worldwide each year. OBSERVATIONS Among patients with multiple myeloma, approximately 73% have anemia, 79% have osteolytic bone disease, and 19% have acute kidney injury at the time of presentation. Evaluation of patients with possible multiple myeloma includes measurement of hemoglobin, serum creatinine, serum calcium, and serum free light chain levels; serum protein electrophoresis with immunofixation; 24-hour urine protein electrophoresis; and full-body skeletal imaging with computed tomography, positron emission tomography, or magnetic resonance imaging. The Revised International Staging System combines data from the serum biomarkers β 2 microglobulin, albumin, and lactate dehydrogenase in conjunction with malignant plasma cell genomic features found on fluorescence in situ hybridization-t(4;14), del(17p), and t(14;16)-to assess estimated progression-free survival and overall survival. At diagnosis, 28% of patients are classified as having Revised International Staging stage I multiple myeloma, and these patients have a median 5-year survival of 82%. Among all patients with multiple myeloma, standard first-line (induction) therapy consists of a combination of an injectable proteasome inhibitor (ie, bortezomib), an oral immunomodulatory agent (ie, lenalidomide), and dexamethasone and is associated with median progression-free survival of 41 months, compared with historical reports of 8.5 months without therapy. This induction therapy combined with autologous hematopoietic stem cell transplantation followed by...

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Background: B-cell maturation antigen (BCMA) is a tumour necrosis superfamily cell-surface receptor required for plasma cell survival. This study evaluated safety, tolerability and preliminary clinical activity of GSK2857916, a novel anti-BCMA antibody conjugated to microtubule-disrupting agent monomethyl auristatin-F, in patients with relapsed/refractory multiple myeloma (MM). Methods: This international, multicentre, open-label, first-in-human Phase 1 study comprised dose escalation (Part 1) and dose expansion (Part 2) phases. Adults with histologically or cytologically confirmed MM, Eastern Cooperative Oncology Group performance status 0/1, and progressive disease following stem cell transplant, alkylators, proteasome inhibitors and immunomodulators were recruited. In Part 1, patients received GSK2857916 (0 03–4 6 mg/kg) via 1-hour intravenous infusion. In Part 2, patients received the selected dose of GSK2857916 (3 4 mg/kg) every 3 weeks. Primary endpoints were maximum tolerated dose (MTD) and recommended Phase 2 dose (RP2D). All patients who received ≥1 dose were included in this prespecified administrative interim analysis (cut-off: 26 June 2017), which was performed for internal purposes. The study is ongoing (NCT02064387). Findings: Between July 2014 and February 2017, 73 patients were treated (Part 1 n=38; Part 2 n=35). No MTD was identified in Part 1. Based on safety/clinical activity, 3 4 mg/kg was selected as RP2D. Corneal events were common (42/73; 58%); most (37/42) were Grade 1/2 and did not result in treatment discontinuation in Part 2. The other most common Grade 3/4 events were thrombocytopenia (25/73; 34%) and anaemia (11/73; 15%). There were 12 treatmentrelated serious adverse events and no treatment-related deaths. Overall response rate at 3 4 mg/kg in Part 2 was 60% (21/35; 95% confidence interval: 42 1%–76 1%). Interpretation: At the identified RP2D, GSK2857916 is well tolerated and data suggest it has good clinical activity in heavily pretreated patients, thereby indicating that this may be a promising candidate for the treatment of relapsed/refractory MM. Funding: GlaxoSmithKline plc

Among patients with previously untreated follicular lymphoma, efficacy results were similar with rituximab plus lenalidomide and rituximab plus chemotherapy (with both regimens followed by rituximab maintenance therapy). The safety profile differed in the two groups. (Funded by Celgene; RELEVANCE ClinicalTrials.gov numbers, NCT01476787 and NCT01650701 , and EudraCT number, 2011-002792-42 .).

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