key: cord-0032145-3xt5hgob
authors: La, Jennifer; Wu, Julie Tsu-Yu; Branch-Elliman, Westyn; Huhmann, Linden; Han, Summer S; Brophy, Mary; Do, Nhan V; Lin, Albert Y; Fillmore, Nathanael R; Munshi, Nikhil C
title: Increased COVID-19 Breakthrough Infection Risk in Patients with Plasma Cell Disorders
date: 2022-05-25
journal: Blood
DOI: 10.1182/blood.2022016317
sha: 41c5f2660066bbb81c97449ae26bcb101e9af754
doc_id: 32145
cord_uid: 3xt5hgob

nan

Jennifer La, PhD* 1 , Julie Tsu-Yu Wu, MD, PhD* 2,3 , Westyn Branch-Elliman, MD, MMSc 1,4,5 , Linden Huhmann, PhD 1 , Summer S Han, PhD 2 , Mary Brophy, MD 1,6 , Nhan V Do, MD 1,6 , Albert Y Lin, MD, MPH 2,3 , Nathanael R Fillmore, PhD +1,5,7 , Nikhil C Munshi, MD +1, 5, 7 * equal contribution as co-first authors + equal contribution as co-senior authors Patients with multiple myeloma (MM) are at increased risk of infection and severe outcomes from COVID-19 infection 1,2 , partly due to inadequate protection by SARS-CoV-2 vaccination 2-7 . Their susceptibility stems from both immune-suppressive treatments used for MM and underlying immune-deficiency from the disease itself 4, 6, 8 . However, it is unknown how much risk is shared by patients with monoclonal gammopathy of undetermined significance (MGUS) 9,10 , a precursor state to MM that does not require immune-suppressive treatment but may be associated with immune-deficiency. Here, we measured the risk of breakthrough infections among vaccinated patients with MM or MGUS relative to the patients without MM or MGUS in the national Veterans Affairs (VA) health care system and describe the association of MM-specific treatments with breakthrough risk.

We used a matched cohort design to measure the risk of breakthrough infection among patients with MM or MGUS relative to those without, using a similar matching procedure as recently used in the VA cancer patient population 7 . Veterans with fully-vaccinated with mRNAbased vaccine were identified using the VA Corporate Data Warehouse (CDW), which collates electronic health record (EHR) information from VA facilities nationwide. Full vaccination was defined to start 14 days after receipt of the second dose of BNT162b2 or mRNA-1273 vaccine. Patients vaccinated with Janssen/Johnson & Johnson Ad26.COV2.S or prior SARS-CoV-2 infection were excluded. Patients with MM were identified using the VA CDW using a previously published algorithm 11 . They were required to have at least 3 MM International Classification of Disease coded-visits and have received at least one MM-specific treatment prior to 12/15/2020. Patients with MGUS were required to have at least 3 MGUS International Classification of Disease coded-visits and to never had any MM-specific treatment prior to 12/15/2020. We filtered for regular users of the VA system, which is defined as those who had at least 1 outpatient or inpatient visit every year 3 years prior to study start date, to exclude patients whose data may be incomplete. Data was primarily obtained from the VA CDW and SARS-CoV-2 vaccination and infection status was obtained from the VA COVID-19 Shared Data Resource.

Fully-vaccinated patients with MM and MGUS were matched 1:1 with vaccinated controls on factors potentially associated with SARS-CoV-2 exposure: specifically, age, race, VA facility, and rurality of home address. VA facility was defined as the location where the last COVID-19 vaccine dose was administered. Age, race, and rurality of home address are available as structured data in the CDW. We used minimum distance matching for age and exact matching for other variables. For each day of the study period, each new fully-vaccinated patient with MM or MGUS was matched with a control patient without MM or MGUS. The primary outcome was reverse transcriptase-polymerase chain reaction or antigen-confirmed SARS-CoV-2 infection. The secondary outcome of severe COVID-19 was defined as SARS-CoV-2 infection within -1 to 14 days of a documented oxygen saturation less than 94% or supplemental oxygen use, as defined in our previous work 12 . Each pair was followed until SARS-CoV-2 infection, death or end of study. The Fine-Gray subdistribution hazard was used to measure risk of infection with the competing risk of death. Next, we wanted to determine how cancer treatment affects breakthrough infection risk among fully vaccinated patients with MM. Prior studies have shown decreased vaccine response in patients on anti-CD38 directed therapies and chemotherapy 4, 7 . However, the effect of less immunosuppressive therapies, such as proteasome inhibitors, on vaccine response is unknown 6 . To evaluate impact on breakthrough infection risk, we categorized type of systemic anti-MM treatments received and timing of last therapy before vaccination. We defined anti-MM treatments as systemic chemotherapies and MM-specific therapies using a previously validated algorithm 11 . Treatment types were determined by treatments received within 90 days of the initial vaccine dose; patients could have multiple treatment types. All treatment types were combined for subgroup analyses by timing of last dose of systemic therapy prior to vaccination. Chi-square tests were used to determine significance.

A total of 103 MM patients (3.8%) experienced breakthrough infection. Patients with last therapy within 90 days of initial vaccination tended to experience more breakthrough infections. Among patients with last therapy within 90 days, those receiving anti-CD38 therapy, chemotherapy or proteasome inhibitor had significantly higher frequency of breakthrough infection (Table 1) . These data confirm the prior serological data showing decreased antibody response to vaccination in patients on anti-CD38 directed therapies 6 and chemotherapy 7 .

These results suggest that vaccinated patients with MM and MGUS are at increased risk of breakthrough infection relative to the general population. To our knowledge, this study is the first to demonstrate a significant breakthrough risk for patients with MGUS. Patients with MGUS outnumber patients with MM. However, MGUS, unlike MM, is not listed among the CDC COVID-19 high-risk criteria 13 . Indeed, a previous report has suggested that risk of SARS-CoV-2 infection is similar in unvaccinated MGUS patients and general population 9 . Our results suggest a limited vaccine response in MGUS patients compared to general population. Future work is needed to determine how risk of COVID-19 in patients with precancerous states, like MGUS, compares to established CDC risk criteria 13 . Breakthrough incidence increased further in all groups approximately 5 months after vaccination, possibly due to waning immunity, increasing prevalence of vaccine-resistant SARS-CoV-2 variants, or a combination thereof. Future work is needed to determine effective mitigation strategies against waning immunity, such as booster vaccination.

Patients with MM are at higher risk than patients with MGUS, especially for severe COVID-19. This may be partly due to the use of immunosuppressive therapy for MM 8 . Consistent with prior serologic vaccination studies 4,8 , we find the greatest breakthrough infection risk with recent use of immunosuppressive therapy, such as anti-CD38 therapy. However, we find increased risk with proteasome inhibitors, where existing evidence is less clear 8 . Proteasome inhibitors have a complex interaction with the immune system and may impair the innate antiviral immune response 14 . Our study shows that the type and timing of anti-myeloma therapy affects predisposition to breakthrough infection.

Our observations are limited by the retrospective nature of the study, restriction to the VA population, and limitations inherent in EHR data. Specifically, certain predictors, such as antibody titers and COVID variant type, are incompletely captured and have not been included. Also, as many anti-myeloma agents are used in combination, the risk from individual agents cannot be fully ascertained. Despite these limitations, our study represents the largest cohort of vaccinated MM and MGUS patients to date and, as performed on real-world patients, would be expected to have high external validity in clinical practice.

In conclusion, patients with MM, especially those on anti-CD38 therapy, proteasome inhibitors, or chemotherapy, are at high risk of breakthrough COVID-19 infection after vaccination. Patients with MGUS are also at increased risk. Our findings suggest that these vulnerable populations should be considered for additional mitigation strategies, such as pre-exposure prophylaxis. Defined based on all systemic anti-myeloma therapies received within 90 days prior to the first vaccination dose. Patients who received multiple treatment types in this time period are included in multiple treatment type categories. IMiD denotes immunodulatory drugs.

Clinical features associated with COVID-19 outcome in multiple myeloma: first results from the International Myeloma Society data set

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

Low Neutralizing Antibody Responses Against SARS-CoV-2 in Elderly Myeloma Patients After the First BNT162b2 Vaccine Dose

Anti-CD38 therapy impairs SARS-CoV-2 vaccine response against Alpha and Delta variants in Multiple Myeloma patients

Highly variable SARS-CoV-2 spike antibody responses to two doses of COVID-19 RNA vaccination in patients with multiple myeloma

COVID-19 vaccination in patients with multiple myeloma: a consensus of the European Myeloma Network

Association of COVID-19 Vaccination With SARS-CoV-2 Infection in Patients With Cancer: A US Nationwide Veterans Affairs Study

The neutralizing antibody response post COVID-19 vaccination in patients with myeloma is highly dependent on the type of anti-myeloma treatment

Monoclonal gammopathy of undetermined significance and COVID-19: a population-based cohort study

Serological response to the BNT162b2 mRNA or ChAdOx1 nCoV-19 COVID-19 vaccine after first and second doses in patients with plasma cell disorders: influence of host and disease factors

With equal access, African American patients have superior survival compared to white patients with multiple myeloma: a VA study

The COVID-19 Hospitalization Metric in the Pre-and Post-vaccination Eras as a Measure of Pandemic Severity: A Retrospective, Nationwide Cohort Study

COVID-19)

Proteasome Inhibitors Impair the Innate Antiviral Immune Response and Potentiate Pelareorep-Based Viral Therapy in Multiple Myeloma

(A) Cumulative incidence curves of any breakthrough SARS-COV-2 infection by disease state shown using time zero as 14 days after the day of second dose of vaccination. Confidence intervals were calculated by bootstrapping. The number at risk are also shown. (B) Hazard ratios for infection separated by disease state and COVID severity. Hazards are calculated separately for risk of any breakthrough infection and risk of severe breakthrough infection relative to matched controls. All hazards were calculated using Fine-Gray competing risk regression with the competing risk of death. MM denotes multiple myeloma, MGUS monoclonal gammopathy of undetermined significance.

This work is supported by by VA Healthcare System grant No. 5I01BX001584, and NIH/NCI grants SPORE-P50CA100707 and P01CA155258 (NCM).

JTW, JL, NF and NCM designed research. JL and NF collected and analyzed data. JTW, NF, and NCM wrote the manuscript. All authors interpreted data and critically read the manuscript.