Risks of SARS-CoV-2 Breakthrough Infection and Hospitalization in Fully Vaccinated Patients With Multiple Myeloma

Data from early in the COVID-19 pandemic when vaccines were not available showed that patients with multiple myeloma (MM) were at increased risk for COVID-19 infection and severe outcomes.^1,2 Recent studies showed a low rate of seroconversion after messenger RNA (mRNA) anti-SARS-CoV-2 vaccination in patients with MM and other hematological malignant neoplasms.^3,4 However, the risk and outcomes of SARS-CoV-2 breakthrough infection in vaccinated patients with MM remains unknown.

This cohort study used the cloud based TriNetX Analytics network platform to access deidentified patient electronic health records (EHRs) from 63 health care organizations in the United States.⁵ The study population comprised 507 288 patients who fulfilled the following inclusion criteria: had recent medical encounter(s) with health care organizations since December 1, 2020; had documented evidence of full vaccination in the EHRs (Pfizer-BioNTech, Moderna, or Johnson & Johnson vaccine) between December 1, 2020, and October 8, 2021; and had no prior COVID-19 infection. EHR data are deidentified, and this study was exempt from institutional review board approval and informed consent per the US Federal Policy for the Protection of Human Subjects. We tested whether fully vaccinated patients with MM had higher risk for breakthrough infections than individuals without cancer after propensity score matching for demographics, adverse socioeconomic determinants of health, transplant procedures, comorbidities, vaccine types, and medications. Kaplan-Meier analysis was used to estimate probability of breakthrough infections starting 14 days after full vaccination. Comparisons between cohorts were made using Cox proportional hazards model and hazard ratio (HR). We tested whether hospitalization rates differed between patients with MM with breakthrough infections and propensity score–matched patients with MM without breakthrough infections. Statistical tests were either conducted within the TriNetX Analytics Platform or using R statistical software (version 3.6.3) with significance set at P < .05 (2-sided). Details of TriNetX, study population, and statistical analysis were described in the eMethods in the Supplement. This study followed the Strengthening the Reporting of Observational Studies in Epidemiology (STROBE) reporting guidelines.⁶

The characteristics of the fully vaccinated population with MM and the population of patients without cancer are shown in the Table. Among 1182 vaccinated patients with MM, 33.8% had monoclonal gammopathy of undetermined significance (MGUS), 11.7% were in relapse, 88.7% had never achieved remission, 60.0% had chemotherapy, 50.3% had targeted therapy, 12.1% had radiation therapy, and 26.5% had stem cell transplant; mean (SD) blood lymphocyte count was 2.08  × 10⁹/L (12.2 × 10⁹/L). Among 187 patients with MM with SARS-CoV-2 breakthrough infections, 34.8% had MGUS, 15.5% were in relapse, 86.6% had never achieved remission, 64.2% had chemotherapy, 54.3% had targeted therapy, 11.2% had radiation therapy, and 27.8% had stem cell transplant; mean (SD) blood lymphocytes count was 1.63 × 10⁹/L (2.01 × 10⁹/L). The overall risk of SARS-CoV-2 breakthrough infections was 15.4% in the MM population and 3.9% in the noncancer population. After propensity score matching for demographics, adverse socioeconomic determinants of health, transplant procedures, comorbidities, vaccine types, and medications, patients with MM remained at significantly increased risk for breakthrough infections compared with matched patients without cancer (HR, 1.34; 95% CI, 1.06-1.69). The estimated probability of hospitalization at the end of the time window (October 8, 2021) was 34.4% for patients with MM with breakthroughs, compared with 4.5% for matched patients without breakthroughs (HR, 15.9; 95% CI, 6.2-40.3) (Figure).

This study found that patients with MM were at increased risk of breakthrough infections and that breakthrough infections were associated with increased risk for hospitalization. These findings raise consideration for the development and implementation of enhanced mitigation strategies and the need for studies to evaluate the timing and impact of vaccine boosters in this unique, immunosuppressed population. Despite the limitations inherent to observational analysis based on patient EHRs, our study leveraged a federated nationwide and real-time patient EHR database that allowed us to electronically monitor the risks and outcomes of vaccine breakthrough infections in a real-world vulnerable population (ie, patients with MM).

Accepted for Publication: October 11, 2021.

Published: November 23, 2021. doi:10.1001/jamanetworkopen.2021.37575

Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Wang L et al. JAMA Network Open.

Corresponding Authors: Nathan A. Berger, MD, Center for Science, Health, and Society, 2103 Cornell Rd, Cleveland, OH 44106 (nab@case.edu); Rong Xu, PhD, Center for Artificial Intelligence in Drug Discovery, 2103 Cornell Rd, Cleveland, OH 44106 (rxx@case.edu).

Author Contributions: Dr Xu had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Wang, Xu.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Wang, Xu.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Wang.

Obtained funding: Berger, Xu.

Administrative, technical, or material support: Xu.

Supervision: Berger, Xu.

Conflict of Interest Disclosures: Dr Berger reported grants from the National Institutes of Health (NIH) during the conduct of the study. No other disclosures were reported.

Funding/Support: We acknowledge support from NIH National Cancer Institute R25CA221718, American Cancer Society Research Scholar Grant RSG-16-049-01 – MPC, NIH National Institute of Aging R01 AG057557, R01 AG061388, R56 AG062272, National Institute on Alcohol Abuse and Alcoholism (grant No. R01AA029831), The Clinical and Translational Science Collaborative (CTSC) of Cleveland 1UL1TR002548-01, Case Comprehensive Cancer Center P30 CA043703, Case Comprehensive Cancer Center Cancer Health Disparities SPORE Planning Grant P20 CA2332216.

Role of the Funder/Sponsor: The sponsors had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Contributions: We would like to thank David C Kaelber, MD, PhD, MPH, from The MetroHealth System and Case Western Reserve University for facilitating our access to TriNetX.