Patients with multiple myeloma have a compromised immune system, due to both the disease and antimyeloma therapies, and may therefore be particularly susceptible to COVID-19. Here, we report outcomes and risk factors for serious disease in patients with multiple myeloma treated at five large academic centers in New York City in the spring of 2020, during which it was a global epicenter of the SARS-CoV-2 pandemic. Of 100 patients with multiple myeloma (male 58%; median age 68) diagnosed with COVID-19, 75 were admitted; of these, 13 patients (17%) were placed on invasive mechanical ventilation, and 22 patients (29%) expired. Of the 25 nonadmitted patients, 4 were asymptomatic. There was a higher risk of adverse outcome (intensive care unit admission, mechanical ventilation, or death) in Hispanics/Latinos (n = 21), OR = 4.7 (95% confidence interval, 1.3–16.7), and African American Blacks (n = 33), OR = 3.5 (1.1–11.5), as compared with White patients (n = 36). Patients who met the adverse combined endpoint had overall higher levels of inflammatory markers and cytokine activation. None of the other studied risk factors were significantly associated (P > 0.05) with adverse outcome: hypertension (n = 56), OR = 2.2 (0.9–5.4); diabetes (n = 18), OR = 0.9 (0.3–2.9); age >65 years (n = 63), OR = 1.8 (0.7–4.6); high-dose melphalan with autologous stem cell transplant <12 months (n = 7), OR = 0.9 (0.2–5.4); and immunoglobulin G <650 mg/dL (n = 42), OR = 0.9 (0.3–2.2). In this largest cohort to date of patients with multiple myeloma and COVID-19, we found the case fatality rate to be 29% among hospitalized patients and that race/ethnicity was the most significant risk factor for adverse outcome.Significance: Patients with multiple myeloma are immunocompromised, raising the question whether they are at higher risk of severe COVID-19 disease. In this large case series on COVID-19 in patients with multiple myeloma, we report 29% mortality rates among hospitalized patients and identify race/ethnicity as the most significant risk factor for severe outcome.See related video: https://vimeo.com/486246183/559a80cfaeSee related commentary by Munshi and Anderson, p. 218.This article is highlighted in the In This Issue feature, p. 215

Autologous stem cell transplant (ASCT) is a standard-of-care treatment for patients with multiple myeloma (MM). However, only 20%-30% of patients with MM for whom the procedure is indicated undergo ASCT. Barriers to ASCT may be informational, financial, logistic, or cultural and may affect patients and/or treating oncologists. The availability and accessibility of accurate ASCT-related information are essential to overcome these barriers. Such resources can be created by blood and marrow transplantation societies and patient advocacy groups, ideally in collaboration with MM specialists at transplant centers. An umbrella office at the society level is also recommended to connect oncologists, advocacy groups, and transplant specialists; provide informational resources to patients; and conduct research into the region- and population-specific barriers to ASCT.

We carried out a single-cell multiomic analysis on a series of MYD88-mutated Waldenström macroglobulinemia (WM) patients and identified 2 distinct subtypes of disease, memory B-cell (MBC)–like and plasma cell (PC)–like, based on their expression of key lineage defining genes. Biologically, the subtypes are characterized by their variable capacity to differentiate fully toward a PC and exhibit unique transcriptomic, chromatin accessibility, and genomic profiles. The MBC-like subtype is unable to differentiate beyond the MBC stage, upregulates key MBC genes, and is characterized by upregulated B-cell receptor and phosphatidylinositol 3-kinase/protein kinase B/mammalian target of rapamycin (PI3K/AKT/mTOR) signaling. In contrast, the PC-like subtype can partially differentiate toward a PC, upregulates key PC genes, has enhanced NF-κB signaling, and has an upregulated unfolded protein response. Pseudotime trajectory analysis of combined single-cell RNA sequencing and single-cell assay for transposase-accessible chromatin with sequencing supports the variable differentiation capacity of each subtype and implicate key transcription factors SPI1, SPIB, BCL11A, and XBP1 in these features. The existence and generalizability of the 2 disease subtypes were validated further using hierarchical clustering of bulk RNA-sequencing data from a secondary set of patients. The biological significance of the subtypes was further established using whole-genome sequencing, in which it was shown that CXCR4, NIK, and ARID1A mutations occur predominantly in the MBC-like subtype, and 6q deletions in the PC-like subtype. We conclude that the variable differentiation blockade seen in WM manifests itself clinically as 2 disease subtypes with distinct epigenetic, mutational, transcriptional, and clinical features, with potential implications for WM treatment strategies.