Abstract
Patients with multiple myeloma (MM) have a lower efficacy from COVID‐19 vaccination and a high rate of mortality from COVID‐19 in hospitalized patients. However, the overall rate and severity of COVID‐19 infection in all settings (including non‐hospitalized patients) and the independent impact of plasma cell‐directed therapies on outcomes needs further study. We reviewed the medical records of 9225 patients with MM or AL amyloidosis (AL) seen at Mayo Clinic Rochester, Arizona, and Florida between 12/01/2019 and 8/31/2021 and identified 187 patients with a COVID‐19 infection (n = 174 MM, n = 13 AL). The infection rate in our cohort was relatively low at 2% but one‐fourth of the COVID‐19 infections were severe. Nineteen (10%) patients required intensive care unit (ICU) admission and 5 (3%) patients required mechanical ventilation. The mortality rate among hospitalized patients with COVID‐19 was 22% (16/72 patients). Among patients that were fully vaccinated at the time of infection (n = 12), two (17%) developed severe COVID‐19 infection, without any COVID‐related death. On multivariable analysis, treatment with CD38 antibody within 6 months of COVID‐19 infection [Risk ratio (RR) 3.6 (95% CI: 1.2, 10.5), p = .02], cardiac [RR 4.1 (95% CI: 1.3, 12.4), p = .014] or pulmonary comorbidities [RR 3.6 (95% CI 1.1, 11.6); p = .029] were independent predictors for ICU admission. Cardiac comorbidity [RR 2.6 (95% CI: 1.1, 6.5), p = .038] was an independent predictor of mortality whereas MM/AL in remission was associated with lower mortality [RR 0.4 (95% CI: 0.2–0.8); p = .008].
1. INTRODUCTION
We are midway into the third year of the coronavirus disease 2019 (COVID‐19) pandemic, caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). 1 As of June 2022, there have been 84.5 million confirmed cases in the United States (US) alone, with a death toll of over 1 million people. 2 During this time, progress has been made and we have medications that have shown efficacy in controlling the virus including broad‐spectrum antivirals such as Ritonavir‐Boosted Nirmatrelvir (Paxlovid) 3 or Molnupiravir 4 for nonhospitalized patients with mild–moderate COVID‐19, and Remdesivir 5 for hospitalized patients with moderate‐to‐severe COVID‐19. Most importantly, vaccines have been instrumental in reducing COVID‐19 disease severity. 6
The three COVID‐19 vaccines approved in the United States are the Pfizer‐BioNTech messenger RNA (mRNA) vaccine, the Moderna mRNA vaccine, and the Johnson & Johnson virus vector. 7 High vaccine efficacy rate of about 95% were reported in phase 3 clinical data for both mRNA vaccines, 8 , 9 and high seroconversion rates were demonstrated in the Pfizer vaccine. 10 However, these studies excluded immunocompromised patients and specifically, patients with hematologic malignancies. A recent meta‐analysis of 19 studies comparing the vaccine seroconversion rates between immunocompromised patients with hematologic malignancies (n = 2436) and immunocompetent controls (n = 1896) reported significantly lower seroconversion rates in immunocompromised patients. 11 Poor COVID‐19 vaccine efficacy is also seen in patients with multiple myeloma (MM), especially in patients with immunoparesis (i.e., subnormal concentrations of uninvolved immunoglobulins) and/or those being treated with anti‐CD38 or anti‐B‐cell maturation antigen (BCMA) therapies which target the B‐cells and plasma cells responsible for generating the antibody responses. 12
Patients with MM and a COVID‐19 infection have a more prolonged course of illness with higher mortality, 13 with CD38 and BCMA directed therapies being associated with increased severity of infections. There is a paucity of large studies in MM exploring these therapies as independent risk factors for severe disease and death while considering other medical comorbidities. In addition, vast majority of the studies that are currently available on COVID‐19 and MM mainly include hospitalized patients, creating a selection bias. In this study, we report the outcomes of patients MM and AL amyloidosis (AL) who developed COVID‐19 infection and the factors associated with severe infection, intensive care unit (ICU) admission, and mortality.
2. METHODS
After Mayo Clinic institutional review board approval, medical records of patients with a diagnosis of multiple myeloma or AL evaluated at Mayo Clinic Rochester, Arizona, and Florida between 12/01/2019 and 8/31/2021 were screened (n = 9225) (Figure S1). Diagnosis of a COVID‐19 infection was established by a positive polymerase chain reaction (PCR) testing performed either at Mayo Clinic or an external center with report available for review in the electronic health record (EHR). From the initial cohort, we identified 187 patients with MM and AL who also had at least one positive COVID‐19 PCR test between 12/01/2019 and 8/31/2021. Patient with suggestive symptoms but no documented PCR positivity were not included in the final cohort. Cardiac comorbidity included structural or ischemic heart disease, and arrythmias. Pulmonary comorbidities included a diagnosis of obstructive airway disease, interstitial lung disease or obstructive sleep apnea. Renal impairment was defined as estimated glomerular filtration rate of <60 ml/min. As of 8/31/2021, the United States was experiencing the peak of the COVID‐19 Delta variant (Figure S2A). Our study therefore only includes patients infected during the first four COVID‐19 waves (12/2019–8/31/2021). During the timeframe of study, the Center for Disease Control and Prevention (CDC) recommended 2 doses of either the Pfizer or Moderna vaccine or 1 dose of the Janssen vaccine to complete the primary vaccine series. For this study, we therefore defined “fully vaccinated” as 2 doses of Pfizer or Moderna vaccine or 1 dose of Janssen vaccine. Severe COVID‐19 was defined by the National Institutes of Health as an SpO2 < 94% on room air at sea level, a ratio of arterial partial pressure of oxygen to fraction of inspired oxygen (PaO2/FiO2) <300 mm Hg, a respiratory rate >30 breaths/min, or lung infiltrates >50%. 14 All statistical analyses were performed using SPSS (version 19; SPSS Inc., Chicago, IL, USA).
3. RESULTS
3.1. Patient characteristics
One‐hundred‐eighty‐seven patients with MM and AL, who also had at least one documented positive COVID‐19 PCR test between 12/01/2019 and 08/31/2021, were included in this study (Figure S1). The cross‐sectional prevalence of COVID‐19 in MM and AL patients in our cohort was 2%. One‐hundred‐seventy‐four patients had MM (93%), and 13 patients had AL not meeting criteria for MM (7%) (Table 1). The characteristics of patients with AL are summarized in Table 2. The first positive COVID‐19 PCR test was recorded on 03/27/2020. Most patients (n = 136; 73%) in this study developed COVID‐19 between 10/1/2020 to 03/1/2021 (Figure S2B), which correlates to the third COVID‐19 wave that occurred over the winter months of 2020–21 (Figure S2A).
TABLE 1.
Patient characteristics
| Median (range) or N (%) | |
|---|---|
| Total number of patients | 187 (100%) |
| MM | 174 (19%) |
| AL amyloidosis without coexisting MM | 13 (7%) |
| Age at time of COVID‐19 diagnosis, years | 67 (35–92) |
| Female sex | 64 (34%) |
| High‐risk FISH in patients with MM | 70/147 (48%) |
| ISS stage in patients with MM | |
| Stage 1 | 58/150 (39%) |
| Stage 2 | 50/150 (33%) |
| Stage 3 | 42/150 (28%) |
| Number of lines of treatment prior to COVID‐19 diagnosis | |
| MM | 2 (0–13) |
| AL amyloidosis | 2 (0–4) |
| Anti‐CD38 therapy at any time prior to COVID‐19 diagnosis | 98/184 (53%) |
| Anti‐CD38 therapy within 6 months of COVID‐19 diagnosis | 64/184 (35%) |
| ASCT at any time prior to COVID‐19 diagnosis | 99/184 (54%) |
| ASCT within 6 months of COVID‐19 diagnosis | 17/184 (9%) |
| CAR‐T cell therapy any time prior to COVID‐19 diagnosis | 8/184 (4%) |
| CAR‐T cell therapy within 6 months of COVID‐19 diagnosis | 2/184 (1%) |
| Immunoparesis within 3 months of COVID‐19 diagnosis | 146/164 (89%) |
| Severity of COVID‐19 infection | |
| Asymptomatic | 31/186 (17%) |
| Mild | 83/186 (45%) |
| Moderate | 28/186 (15%) |
| Severe | 44/186 (24%) |
| Deceased at follow‐up | 24 (13%) |
| Death from COVID‐19 | 9 (5%) |
| Disease progression | 7 (4%) |
| Non‐COVID‐19 infection | 4 (2%) |
| Cardiac complications | 3 (2%) |
| GI bleed | 1 (0.5%) |
| Hospitalization needed during COVID‐19 infection | 72/186 (39%) |
| ICU admission during COVID‐19 infection | 19/186 (10%) |
| Mechanical ventilation required | 5/186 (3%) |
| VTE during COVID‐19 infection | 11/187 (6%) |
| Number of COVID‐19 infections | |
| One | 177 (95%) |
| Two | 10 (5%) |
Abbreviations: ASCT: autologous stem cell transplantation; AL: light chain amyloidosis; CAR‐T: chimeric antigen receptor T cell therapy; ICU: intensive care unit; ISS: international staging system; MM: multiple myeloma; VTE: venous thromboembolism.
TABLE 2.
Characteristics of patients with AL amyloidosis
| Gender | Age at COVID | Deceased | Cause of death | Organ involved | IV Septum thickness | Mayo 2012 Cardiac staging | Renal impairment | Severe COVID | |
|---|---|---|---|---|---|---|---|---|---|
| 1 | F | 74 | N | Cardiac | 10 mm | 3 | Y | N | |
| 2 | M | 57 | Y | Cardiac arrest | Cardiac | 14 mm | 3 | N | N |
| 3 | F | 56 | N | Cardiac | 13 mm | 2 | N | N | |
| 4 | M | 47 | N | Cardiac, Kidney, GI | 13 mm | 2 | Y | N | |
| 5 | M | 61 | N | Kidney | 11 mm | Y | N | ||
| 6 | F | 82 | N | Kidney | 11 mm | Y | N | ||
| 7 | M | 73 | N | Kidney | 11 mm | Y | N | ||
| 8 | F | 57 | Y | Cardiac arrest | Cardiac | 15 mm | 3 | N | N |
| 9 | M | 61 | N | Cardiac, Kidney, GI, Spleen, BM | 14 mm | 2 | Y | N | |
| 10 | M | 61 | N | Lung | 8 mm | N | N | ||
| 11 | M | 80 | Y | Septic shock | Cardiac, Kidney | 14 mm | 3 | Y | Y |
| 12 | M | 60 | N | Cardiac | 17 mm | 3 | N | Y | |
| 13 | M | 75 | N | Cardiac, Kidney, Hepatic | 11 mm | 2 | Y | Y |
The median age at the time of COVID‐19 diagnosis was 67 (range 35–92) years and 64 patients (34%) were female. Fluorescent in situ hybridization (FISH) data was available for 147 patients with MM and 70 patients (48%) were high‐risk (i.e., del17, t(4;14), t(14;16), t(14;20), gain 1q) according to the mSMART 3.0 (www.msmart.org) classification. Quantitative immunoglobulin levels were available for 164 patients at the time of COVID‐19 diagnosis and 146 patients (89%) had immunoparesis defined as suppression of ≥1 uninvolved immunoglobulin(s). 15 One‐hundred‐fifteen patients (24%) had severe COVID‐19. Data regarding hospitalization was available for 186 patients. Seventy‐two patients (39%) were admitted to the hospital for COVID‐19 infection, 19 patients (10%) required ICU admission, and 5 patients (3%) required mechanical ventilation. Immunoparesis was not a significant risk factor for mortality COVID‐19 infection (Figure S3), severe COVID‐19 infection (Figure S4), or ICU admission (Figure S5).
At the time of COVID‐19 diagnosis, 170 patients (91%) were unvaccinated, 5 patients (3%) were partially vaccinated, and 12 patients (6%) had completed the initial vaccine series (Table 3). At time of follow‐up, 58 patients (31%) were unvaccinated, 12 patients (6%) had received one dose of vaccine, 40 patients (21%) had received two doses, 64 (34%) had received three doses, and 13 (7%) had received four doses. Ten (5%) patients had 2 separate COVID‐19 infections. The median duration of follow‐up from COVID‐19 diagnosis was 12.5 (95% CI: 11.3, 13.6) months as estimated by the reverse Kaplan–Meier method.
TABLE 3.
COVID vaccination status
| Median (range) or n (%) | |
|---|---|
| COVID vaccine status at time of COVID‐19 infection | |
| Unvaccinated | 170 (91%) |
| Partially vaccinated | 5 (3%) |
| Pfizer (1 dose) | 4 (2%) |
| Moderna (1 dose) | 1 (0.5%) |
| Fully vaccinated | 12 (6%) |
| Pfizer (at least 2 doses) | 8 (4%) |
| Moderna (at least 2 doses) | 4 (2%) |
| COVID‐19 vaccine status at time of follow‐up | |
| Unvaccinated | 58 (31%) |
| 1 dose of vaccine | 12 (6%) |
| Pfizer | 5 (3%) |
| Moderna | 4 (2%) |
| J&J | 3 (2%) |
| 2 doses of vaccine | 40 (21%) |
| Pfizer | 30 (16%) |
| Moderna | 10 (5%) |
| 3 doses of vaccine | 64 (34%) |
| Pfizer | 33 (18%) |
| Moderna | 30 (16%) |
| Pfizer, Moderna | 1 (0.5%) |
| 4 doses of vaccine | 13 (7%) |
| Pfizer | 10 (5%) |
| Moderna | 3 (2%) |
3.2. Factors predicting survival after COVID‐19
Twenty‐four (13%) patients were deceased (all‐cause mortality) at the time of follow‐up, of which 21 had MM (12% of patients with MM), and 3 had AL (23% of patients with AL) (Table 4). Nine patients (5%) died because of COVID‐19 infection with a median time to death of 15 (range 4–94) days from diagnosis of COVID‐19; all of the patients that died from COVID‐19 infection had underlying MM and were unvaccinated at time of COVID‐19 infection. The 3 patients with AL who were deceased at time of follow‐up all had underlying cardiac amyloidosis and died from non‐COVID‐related causes: two as a result of cardiac arrest and one from septic shock (Table 2). The remaining 15 non‐COVID related deaths were due to MM disease progression (n = 7), other infections (n = 4), cardiovascular complications (n = 3), and GI complication (n = 1).
TABLE 4.
Breakdown of clinical events by type of monoclonal gammopathy
| Clinical events | Number of patients | ||
|---|---|---|---|
| Total (n = 187) | MM (n = 174) | AL (n = 13) | |
| Mortality; n (%) | 24 (13%) | 21 (12%) | 3 (23%) |
| Death from COVID‐19; n (%) | 9 (5%) | 9 (5%) | 0 (0%) |
| Severe COVID‐19; n (%) | 44 (24%) | 41 (24%) | 3 (23%) |
| Hospitalization; n (%) | 72 (39%) | 68 (39%) | 4 (31%) |
| ICU admission; n (%) | 19 (10%) | 18 (10%) | 1 (8%) |
| VTE during COVID‐19; n (%) | 11 (6%) | 11 (6%) | 0 (0%) |
Abbreviations: ICU: intensive care unit; VTE: venous thromboembolism.
Overall, 8 patients (4%) died within a month of infection, 10 (5%) died within 2 months of infection, and 11 patients (6%) died within 3 months of COVID‐19 diagnosis. Of these 11 deaths, 8 were COVID‐19 related deaths, and all were unvaccinated at time of COVID‐19 infection. Seventy‐two patients were hospitalized during COVID‐19 infection, of which 68 had MM and 4 had AL (Table 4). Sixteen out of the 72 patients who were hospitalized were deceased at time of follow‐up (mortality rate of hospitalized patients: 22%). Of these 16 patients, 14 patients had MM (mortality rate of hospitalized MM patients: 21%), and 2 patients had AL.
Multivariable analysis identified comorbid cardiac disease (RR: 2.6; 95% CI: 1.1, 6.5; p = .038) as a significant risk factor for mortality after COVID‐19 diagnosis (Table 5). On the other hand, mortality was lower if MM or AL was in remission at time of COVID‐19 diagnosis (RR: 0.4; 95% CI: 0.2, 0.8; p = .008) (Table 5). Results of univariable analysis are shown in Figure S3 and Table 5.
TABLE 5.
Univariable and multivariable analysis of factors associated with mortality, severe COVID‐19 infection, hospitalization, ICU admission, and VTE in patients with MGUS and COVID‐19
| Dependent variables | Variables significant on univariable analysis | Univariable analysis | Multivariable analysis | Risk ratio (95% CI) | p‐value |
|---|---|---|---|---|---|
| Risk ratio (95% CI) | p‐value | ||||
| Mortality | Cardiac disease | 3.1 (1.3, 7.5) | .011 | 2.6 (1.1, 6.5) | .038 |
| Pulmonary disease | 3.1 (1.3, 7.8) | .013 | 2.5 (1, 6.4) | .055 | |
| Myeloma in remission at time of COVID‐19 | 0.5 (0.3, 1) | .049 | 0.4 (0.2, 0.8) | .008 | |
| Severe COVID | Age ≥ 65 years at COVID diagnosis | 3.2 (1.5, 7) | .003 | 2.3 (1, 5.2) | .049 |
| Cardiac disease | 3.9 (1.9, 7.9) | <.0001 | 3 (1.5, 6.4) | .003 | |
| Pulmonary disease | 3.2 (1.5, 6.9) | .002 | 2.1 (0.9, 4.7) | .08 | |
| ICU admission | Cardiac disease | 3.8 (1.4, 10.1) | .009 | 4.1 (1.3, 12.4) | .014 |
| Pulmonary disease | 5 (1.9, 13.5) | .001 | 3.6 (1.1, 11.6) | .029 | |
| α‐CD38 within 6 months | 3.3 (1.2, 9) | .019 | 3.6 (1.2, 10.5) | .02 | |
| VTE | Hospitalization | 8 (1.7, 38.2) | .009 | ||
| ICU admission | 6.1 (1.6, 23.2) | .008 |
Note: Un‐bolded rows highlight variables that are statistically significant on univariable analysis only; bolded rows highlight variables that are statistically significant on both univariable and multivariable analyses.
Abbreviations: ICU: intensive care unit; VTE: venous thromboembolism.
3.3. Factors predicting development of severe COVID‐19
Forty‐four patients (24%) had severe COVID‐19, of which 41 had MM (24% of patients with MM), and 3 had AL (23% of patients with AL). Forty‐one (93%) of patients with severe COVID‐19 were unvaccinated at time of COVID‐19 infection, 1 patient (2%) was partially vaccinated (Pfizer x 1), and 2 patients (5%) were fully vaccinated (1 patient received Moderna x 2; 1 patient received Pfizer x 2). Multivariable analysis identified age ≥ 65 years at COVID‐19 diagnosis (RR: 2.3; 95% CI: 1, 5.2; p = .049) and comorbid cardiac disease (RR: 3; 95% CI: 1.5, 6.4; p = .003) as risk factors for developing severe COVID‐19 (Table 5). Results of univariable analysis are shown in Figure S4 and Table 5.
Of the 44 patients who had severe COVID‐19, 19 patients (43%) received convalescent plasma (Table S1). The use of convalescent plasma in patients with severe COVID‐19 did not significantly impact mortality from COVID‐19 (RR: 0.6; 95% CI: 0.1, 2.8; p = .51).
3.4. Factors predicting ICU stay during COVID‐19 hospitalization
Nineteen patients (10%) required ICU admission during the course of COVID‐19 infection, of which 18 had MM (10% of patients with MM), and 1 had AL (8% of patients with AL). Eighteen (95%) of these ICU patients were unvaccinated at time of COVID‐19 and 1 patient (2%) was partially vaccinated (Pfizer x 1). Multivariable analysis showed that anti‐CD38 therapy within 6 months of COVID‐19 diagnosis (RR: 3.6; 95% CI: 1.2, 10.5; p = .02), comorbid cardiac disease (RR: 4.1; 95% CI: 1.3, 12.4; p = .014), and pulmonary disease (RR: 3.6; 95% CI: 1.1, 11.6; p = .029) were significant risk factors for ICU stay (Table 5). Results of univariable analysis are shown in Figure S5 and Table 5.
3.5. Vaccine efficacy in patients who completed the primary vaccination series
Of the 187 patients, 170 (91%) were unvaccinated, 5 (3%) were partially vaccinated and 12 (6%) were fully vaccinated at time of COVID‐19 diagnosis (Table 3). The median time from completion of primary vaccination series to testing positive for COVID‐19 was 89 (range: 10–176) days. Six fully vaccinated patients (50%) developed COVID‐19 more than 90 days from time of completion of primary vaccination series, while the remaining 6 patients developed COVID‐19 within 90 days. Two out of the 12 fully vaccinated patients (17%) developed severe COVID‐19 infection, without any COVID‐related death. Of note, patients who received daratumumab within 6 months of COVID‐19 infection were not at increased risk of developing COVID‐19 within 90 days of completion of primary vaccination series (RR: 0.5 [95% CI: 0.08, 3.2]; p = .46).
3.6. Venous thromboembolism during COVID‐19 infection
Eleven patients (6%) developed venous thromboembolism (VTE) during COVID‐19 infection, of which all had MM (6% of patients with MM) (Table 4). Univariable analysis identified hospitalization (RR: 8; 95% CI: 1.7, 38.2; p = .009) and ICU admission during COVID‐19 (RR: 6.1; 95% CI: 1.6, 23.2; p = .008) as risk factors associated with development of VTE during COVID‐19 infection (Table 5).
4. DISCUSSION
A number of retrospective studies reporting on the outcomes of COVID‐19 infection in mainly hospitalized patients with MM have been published and the mortality rate following COVID‐19 infection ranged from 22% to 54.8%. 13 , 16 , 17 , 18 , 19 , 20 Although not consistent across the different studies, risk factors for mortality included symptomatic COVID‐19 infection, age, high‐risk cytogenetics, renal disease, and active or progressive MM. 11 In our study, all‐cause mortality rate was 13% and 9 patients (5%) died because of COVID‐19. Comorbid cardiac disease was the only independent predictor of higher mortality after COVID‐19 infection whereas patients with their underlying MM or AL in remission at time of COVID‐19 diagnosis had a lower risk for mortality. Importantly, prior autologous stem cell transplant, CD38 directed therapy, high‐risk cytogenetics, immunoparesis, or renal disease were not significant predictors of mortality in our cohort of patients. 21 , 22 Use of CD38‐directed monoclonal antibodies administered within 6 months of COVID‐19 diagnosis (RR: 3.6; 95% CI: 1.2, 10.5; p = .02) was a significant risk factor for ICU stay during COVID‐19 admission, in addition to patients with underlying cardiac or pulmonary comorbidities, possibly due to the poor seroconversion with vaccination in patients receiving daratumumab. 23 , 24
Compared to the Pfizer and Moderna vaccine approval studies which reported 0% severe infection in individuals who completed the primary 2‐dose vaccine series at a median follow‐up time of about 2 months, 8 , 9 the severe infection rate was 17% in fully vaccinated patients in our study and the median time from completion of primary vaccination series to testing positive for COVID‐19 in our study was 89 (range: 10–176) days. However, it is important to note that the severe infection rate in unvaccinated patients in our study was 24%; much higher than the severe infection rate in the placebo groups of the vaccine trials (both <0.5%). This discrepancy is most likely due to the difference in study population (immunocompromised patients with monoclonal gammopathy, frequently with other systemic comorbidities versus general population), reasons for COVID‐19 PCR testing (mostly targeted testing in our study versus routine screening in the vaccine studies), as well as different timepoints in the COVID‐19 pandemic and different vaccine efficacy rates against different SARS‐CoV‐2 strains. A subsequent study of Moderna vaccine efficacy against the delta COVID‐19 variant in the general population reported a hospitalization rate of 2% (5 out of 232) in fully vaccinated individuals versus 8% (136 out of 1795) in unvaccinated individuals. 25 In our study, 25% (3 out of 12) fully vaccinated patients were hospitalized versus 40% (68 out of 169) unvaccinated patients. There was no significant difference in RR for hospitalization [0.5 (95% CI: 0.1, 1.9); p = .31] between fully vaccinated versus unvaccinated patients. The rates of hospitalization are much higher in our study, which could again be explained by the same reasons as above. Fifty percent (n = 6) of the COVID‐19 infections in fully vaccinated patients were beyond 90 days from completion of initial vaccination series.
Our study is limited by its retrospective nature and the inherent biases this introduces in the interpretation of these results. In addition, the study population inclusion was censored at the peak of the Delta wave (8/31/21), meaning that our study only captures patients who developed COVID‐19 on or before 8/31/21, and conclusions from this study may not be generalizable to future variants such as Omicron. Data on spike antibody levels after vaccination were patchy and highly variable regarding timing of testing, and hence not included in this study. The strengths of our study lie in its large size, inclusion of patients with asymptomatic MM, and inclusion of a good proportion of outpatient COVID‐19 cases, considerations that were lacking in prior COVID‐19 studies in patients with MM. This study therefore provides valuable information on the outcomes and risk factors for mortality in patients with COVID‐19 and underlying monoclonal gammopathy.
5. CONCLUSION
Although the overall COVID‐19 infection rate in patients with MM and AL is low, a fair proportion of these infections were severe. Exposure to CD38‐directed therapy was associated with a higher rate of ICU admission whereas underlying MM or AL in remission was associated with lower mortality from COVID‐19. Pre‐existing cardiac and pulmonary comorbidities continue to be important predictors of the clinical course with COVID‐19 infections.
AUTHOR CONTRIBUTIONS
Matthew Ho, Saurabh Zanwar, and Shaji Kumar conceived the project and contributed to the design of the study. Matthew Ho, Saurabh Zanwar, and Shaji Kumar collected the data, performed the analysis, and wrote the paper. Francis K. Buadi, Sikander Ailawadhi, Jeremy Larsen, Leif Bergsagel, Moritz Binder, Asher‐Chanan‐Khan, David Dingli, Angela Dispenzieri, Rafael Fonseca, Morie A. Gertz, Wilson Gonsalves, Ronald S. Go, Suzanne Hayman, Prashant Kapoor, Taxiarchis Kourelis, Martha Q. Lacy, Nelson Leung, Yi Lin, Eli Muchtar, Vivek Roy, Taimur Sher, Rahma Warsame, Amie Fonder, Matthew Ho, Yi L. Hwa, Robert A. Kyle, S. Vincent Rajkumar, and Shaji Kumar contributed data and reviewed the paper.
CONFLICT OF INTEREST
Morie A. Gertz reports personal fees from Ionis/Akcea, personal fees from Prothena, personal fees from Sanofi, personal fees from Janssen, personal fees from Aptitude Healthgrants and personal fees from Ashfield Meetings personal fees from Juno, personal fees from Physicians Education Resource, personal fees for Data Safety Monitoring board from Abbvie, fees from Johnson & Johnson, and Celgene, personal fees from Research to Practice, Meetings personal fees from Sorrento, Development of educational materials for i3Health.
Rafael Fonseca reports the following conflicts of interest: Consulting: AbbVie, Amgen, Bayer, BMS/Celgene, GSK, H3 Therapeutics, Janssen, Juno, Karyopharm, Kite, Merck, Novartis, Oncopeptides, OncoTracker, Pfizer, Pharmacyclics, Regeneron, Sanofi, Takeda. Scientific Advisory Board: Adaptive Biotechnologies, Caris Life Sciences, OncoMyx and OncoTracker. Rest of the authors do not report any relevant conflicts of interest.
Supporting information
Appendix S1 Table S1 COVID‐directed treatments administered
Figure S1 Study design. The Mayo Clinic (Rochester, Arizona, and Florida) electronic health record was screened and 9,225 consecutive patients with MM and AL amyloidosis who were seen between 12/01/2019 and 08/31/2021 were identified. From this initial cohort, we identified 187 patients who also had at least one positive SARS‐COV2 PCR test between 12/01/2019 and 08/31/2021 to be included in subsequent analyses
Figure S2 Daily trends in number of COVID‐19 cases. (a) Daily trends in the number of COVID‐19 cases in the United States (Graph obtained from the CDC's COVID‐19 data tracker website). (b) Number of COVID‐19 infections per day in patients with MM and AL amyloidosis in our study. One‐hundred‐thirty‐six (73%) of patients in our study developed COVID‐19 between 10/1/2020 to 03/1/2021
Figure S3 Risk ratios (RR) for mortality after COVID‐19 infection. Univariate logistic regression was used to estimate risk ratios with 95% confidence intervals (CI) for these risk factors associated with mortality after COVID‐19 infection in patients with monoclonal gammopathy of undetermined significance
Figure S4 Risk ratios (RR) for severe COVID‐19 infection. Univariate logistic regression was used to estimate risk ratios with 95% confidence intervals (CI) for these risk factors associated with severe COVID‐19 infection in patients with monoclonal gammopathy of undetermined significance
Figure S5 Risk ratios (RR) for ICU admission. Univariate logistic regression was used to estimate risk ratios with 95% confidence intervals (CI) for these risk factors associated with ICU admission in patients with monoclonal gammopathy of undetermined significance
Ho M, Zanwar S, Buadi FK, et al. Risk factors for severe infection and mortality In patients with COVID‐19 in patients with multiple myeloma and AL amyloidosis. Am J Hematol. 2023;98(1):49‐55. doi: 10.1002/ajh.26762
Matthew Ho and Saurabh Zanwar contributed equally to this study.
DATA AVAILABILITY STATEMENT
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.
REFERENCES
- 1. Liu YC, Kuo RL, Shih SR. COVID‐19: the first documented coronavirus pandemic in history. Biom J. 2020;43(4):328‐333. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 2. COVID Data Tracker. Centers for Disease Control and Prevention. Accessed June 5, 2022. https://covid.cdc.gov/covid-data-tracker
- 3. Hammond J, Leister‐Tebbe H, Gardner A, et al. Oral Nirmatrelvir for high‐risk, nonhospitalized adults with Covid‐19. N Engl J Med. 2022;386(15):1397‐1408. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4. Jayk Bernal A, Gomes da Silva MM, Musungaie DB, et al. Molnupiravir for Oral treatment of Covid‐19 in nonhospitalized patients. N Engl J Med. 2021;386(6):509‐520. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5. Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid‐19—final report. N Engl J Med. 2020;383(19):1813‐1826. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6. Mohammed I, Nauman A, Paul P, et al. The efficacy and effectiveness of the COVID‐19 vaccines in reducing infection, severity, hospitalization, and mortality: a systematic review. Hum Vaccin Immunother. 2022;18(1):2027160. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7. Lee A, Wong SY, Chai LYA, et al. Efficacy of Covid‐19 vaccines in immunocompromised patients: systematic review and meta‐analysis. BMJ. 2022;376:e068632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8. Polack FP, Thomas SJ, Kitchin N, et al. Safety and efficacy of the BNT162b2 mRNA Covid‐19 vaccine. N Engl J Med. 2020;383(27):2603‐2615. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 9. Baden LR, El Sahly HM, Essink B, et al. Efficacy and safety of the mRNA‐1273 SARS‐CoV‐2 vaccine. N Engl J Med. 2020;384(5):403‐416. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10. Eyre DW, Lumley SF, Wei J, et al. Quantitative SARS‐CoV‐2 anti‐spike responses to Pfizer‐BioNTech and Oxford‐AstraZeneca vaccines by previous infection status. Clin Microbiol Infect. 2021;27(10):1516.e1517‐1516.e1514. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 11. Lee ARYB, Wong SY, Chai LYA, et al. Efficacy of covid‐19 vaccines in immunocompromised patients: systematic review and meta‐analysis. BMJ (Clinical Research Ed). 2022;376:e068632. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12. Terpos E, Rajkumar SV, Leung N. Neutralizing antibody testing in patients with multiple myeloma following COVID‐19 vaccination. JAMA Oncol. 2022;8(2):201‐202. [DOI] [PubMed] [Google Scholar]
- 13. Ludwig H, Sonneveld P, Facon T, et al. COVID‐19 vaccination in patients with multiple myeloma: a consensus of the European myeloma network. Lancet Haematol. 2021;8(12):e934‐e946. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 14. COVID‐19 Treatment Guidelines Panel. Coronavirus Disease 2019 (COVID‐19) Treatment Guidelines. 2021; https://www.covid19treatmentguidelines.nih.gov/.
- 15. Ho M, Patel A, Goh CY, Moscvin M, Zhang L, Bianchi G. Changing paradigms in diagnosis and treatment of monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM). Leukemia. 2020;34(12):3111‐3125. [DOI] [PubMed] [Google Scholar]
- 16. Cook G, John Ashcroft A, Pratt G, et al. Real‐world assessment of the clinical impact of symptomatic infection with severe acute respiratory syndrome coronavirus (COVID‐19 disease) in patients with multiple myeloma receiving systemic anti‐cancer therapy. Br J Haematol. 2020;190(2):e83‐e86. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17. Wang B, Van Oekelen O, Mouhieddine TH, et al. A tertiary center experience of multiple myeloma patients with COVID‐19: lessons learned and the path forward. J Hematol Oncol. 2020;13(1):94. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18. Martínez‐López J, Mateos M‐V, Encinas C, et al. Multiple myeloma and SARS‐CoV‐2 infection: clinical characteristics and prognostic factors of inpatient mortality. Blood Cancer J. 2020;10(10):103. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 19. Chari A, Samur MK, Martinez‐Lopez J, et al. Clinical features associated with COVID‐19 outcome in multiple myeloma: first results from the international myeloma society data set. Blood. 2020;136(26):3033‐3040. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20. Engelhardt M, Shoumariyeh K, Rösner A, et al. Clinical characteristics and outcome of multiple myeloma patients with concomitant COVID‐19 at comprehensive cancer centers in Germany. Haematologica. 2020;105(12):2872‐2878. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 21. Berlin DA, Gulick RM, Martinez FJ. Severe Covid‐19. N Engl J Med. 2020;383(25):2451‐2460. [DOI] [PubMed] [Google Scholar]
- 22. Hultcrantz M, Richter J, Rosenbaum CA, et al. COVID‐19 infections and clinical outcomes in patients with multiple myeloma in new York City: a cohort study from five academic centers. Blood Cancer Discov. 2020;1(3):234‐243. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23. Terpos E, Gavriatopoulou M, Ntanasis‐Stathopoulos I, et al. The neutralizing antibody response post COVID‐19 vaccination in patients with myeloma is highly dependent on the type of anti‐myeloma treatment. Blood Cancer J. 2021;11(8):138. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24. Frerichs KA, Bosman PWC, van Velzen JF, et al. Effect of daratumumab on normal plasma cells, polyclonal immunoglobulin levels, and vaccination responses in extensively pre‐treated multiple myeloma patients. Haematologica. 2020;105(6):e302‐e306. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25. Bruxvoort KJ, Sy LS, Qian L, et al. Effectiveness of mRNA‐1273 against delta, mu, and other emerging variants of SARS‐CoV‐2: test negative case‐control study. BMJ. 2021;375:e068848. [DOI] [PMC free article] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Supplementary Materials
Appendix S1 Table S1 COVID‐directed treatments administered
Figure S1 Study design. The Mayo Clinic (Rochester, Arizona, and Florida) electronic health record was screened and 9,225 consecutive patients with MM and AL amyloidosis who were seen between 12/01/2019 and 08/31/2021 were identified. From this initial cohort, we identified 187 patients who also had at least one positive SARS‐COV2 PCR test between 12/01/2019 and 08/31/2021 to be included in subsequent analyses
Figure S2 Daily trends in number of COVID‐19 cases. (a) Daily trends in the number of COVID‐19 cases in the United States (Graph obtained from the CDC's COVID‐19 data tracker website). (b) Number of COVID‐19 infections per day in patients with MM and AL amyloidosis in our study. One‐hundred‐thirty‐six (73%) of patients in our study developed COVID‐19 between 10/1/2020 to 03/1/2021
Figure S3 Risk ratios (RR) for mortality after COVID‐19 infection. Univariate logistic regression was used to estimate risk ratios with 95% confidence intervals (CI) for these risk factors associated with mortality after COVID‐19 infection in patients with monoclonal gammopathy of undetermined significance
Figure S4 Risk ratios (RR) for severe COVID‐19 infection. Univariate logistic regression was used to estimate risk ratios with 95% confidence intervals (CI) for these risk factors associated with severe COVID‐19 infection in patients with monoclonal gammopathy of undetermined significance
Figure S5 Risk ratios (RR) for ICU admission. Univariate logistic regression was used to estimate risk ratios with 95% confidence intervals (CI) for these risk factors associated with ICU admission in patients with monoclonal gammopathy of undetermined significance
Data Availability Statement
Data sharing not applicable to this article as no datasets were generated or analysed during the current study.