Introduction
The severe acute respiratory syndrome coronavirus 2 (SARS-COV-2) has profound effects on patients with Multiple myeloma (MM). 1 Infections are a leading cause of morbidity and mortality in MM patients. 2 This increased risk of infections is predominately due to underlying immune dysfunction affecting both humoral and cellular immunity from their underlying plasma cell dyscrasia. 3 Additionally, the use of anti-myeloma therapies predispose patients to infections through immune-cell suppression, hypogammaglobinemia, and poorer responses to vaccinations. 4 Further, MM is predominately a disease of the elderly- population more likely to have associated comorbidities such as diabetes (DM), hypertension (HTN), and chronic kidney disease (CKD). 5
The clinical presentations early in the COVID-19 pandemic were highly variable; ranging from mild symptoms such as cough and coryza to severe disease associated with pneumonia, hypoxia, respiratory failure, acute respiratory distress syndrome (ARDS), thromboembolism, multi-organ failure, immune dysregulation, and multisystem complications related to cytokine release syndrome. 6 The reports during the early phase of the COVID-19 pandemic showed a high overall risk of morbidity and mortality due to COVID-19 infection in MM patients. Specifically, rate of hospitalization was 56% in patients with COVID-19 pneumonia, with 20% of patients requiring ICU-level care and nearly 18% risk of death. 7 The case fatality rate was 22% to 29%. 1 MM patients with symptomatic COVID-19 infections who were also undergoing systemic antimyeloma therapy were reported to have a much higher mortality, up to 55%. 8
This data led to the implementation of screening protocols including routine COVID-19 testing of all patients (regardless of symptoms) before each treatment. In addition, the treatment paradigm was modified to minimize the exposure by having fewer infusions and injections, a preference for oral therapies, efforts to limit office visits, and selecting therapies that mitigate the risk of immune dysfunction. 9 , 10 Here, we aim to investigate the effects of rigorous COVID-19 screening on outcomes of COVID-19 infection in patients with MM.
Methods
After obtaining institutional review board (IRB) approvals from each participating institution, we retrospectively collected data from MM patients diagnosed with SARS-CoV-2 infection between March 1, 2020 and October 30, 2020, from 2 myeloma centers (Levine Cancer Institute (LCI) & the University of Kansas medical center (KUMC)). Contributing institutions independently identified consecutive patients and reported information through de-identified variables. Due to possible confounding by other infections, patients without laboratory-confirmed COVID-19 infection were excluded. Patients with any other malignancy along with MM were also excluded from the analysis. The data was obtained on patient characteristics, comorbidities, symptoms, laboratory findings, treatments, and outcomes. Hypogammaglobinemia was defined as IgG levels < 400 mg/dL. Quantitative variables were presented with their median and interquartile (IQ) range; groups were compared via the Kruskal test. In addition to descriptive statistics, logistic regression was used to estimate risk factors associated with adverse outcomes. We estimated odds ratios (ORs) with 95% confidence intervals (CIs). Multivariate analysis was performed to assess the effects of independent factors on hospitalization and survival. The study was approved by local IRBs at participating sites per institutional policy, according to the principles of the Declaration of Helsinki.
Results
We identified a total of 162 MM patients who had COVID-19 infection (LCI n = 132, KUMC n = 30). Patient Characteristics are listed in ( Table 1 ). The majority of patients were male (n = 93,57%). The median age at the time of COVID-19 infection was 64 years (IQ: 56-72). Most patients were white (n = 90, 56%), with all remaining patients being African American, (n = 72, 44%). Current or former smoking or vaping history was reported in (n = 65, 40%) patients.
Table 1
Patient Characteristics of Study Participants: COVID-19 Infection Variables.
| Total ( n = 162) | |
| Age | 64 (56-72) |
| Male | 93 (57%) |
| Female | 69 (43%) |
| Smoking | 65 (40%) |
| Ethnicity | |
| White | 90 (56%) |
| African American | 72 (44%) |
| Type of Symptoms | |
| Fatigue | 90 (56%) |
| Cough | 86 (53%) |
| Fever | 65 (40%) |
| SOB | 61 (38%) |
| Myalgias | 48 (30%) |
| Severity of Symptoms | |
| Mild (with no Hospitalization) | 113 (69.7%) |
| Moderate (Need for Hospitalization) | 33 (20.3%) |
| Severe (ICU) | 16 (9.8%) |
| Need for Oxygen | |
| Oxygen less than 6L | 31 (19%) |
| Invasive Oxygen support | 6 (3.7%) |
| Associated Comorbid Conditions | |
| HTN | 72 (44.4%) |
| CKD | 48 (29.6%) |
| DM | 36 (22.2 %) |
| Obesity | 27 (16.6%) |
| CHD | 23 (14.1%) |
| CAD | 22 (13.5%) |
Patients reported a myriad of symptoms including fatigue (n = 90, 56%), cough (n = 86, 53%), fever (n = 65, 40%), shortness of breath (n = 61, 38%), and myalgias (n = 48, 30%). A substantial population (n = 46, 28%) of patients were asymptomatic. The median duration of COVID-19-related symptoms was 15 days (IQ:12-30). Most patients had mild symptoms with no need for hospitalization (n = 113, 69.7%), only 33 patients (20.3%) had symptoms requiring hospitalization, and 16 (9.8%) had severe symptoms requiring ICU-level care. There were 31 patients (19%) who required some degree of oxygen support, with only 6 patients (3.7%) requiring invasive ventilation and 3 patients (1.8%) requiring vasopressors. The case fatality was 6%, with 10 deaths related to COVID-19 infection in the entire cohort.
Most patients had associated comorbid conditions; the most frequent were HTN (n = 72, 44.4%), hypogammaglobinemia (n = 52,32%), CKD (n = 48, 29.6%), DM (n = 36, 22.2%), and obesity (n = 27, 16.6%). In addition, congestive heart failure (CHF) was reported in 14.1% (n = 23), coronary artery disease in 13.5% (n = 22), and other heart disease in 16% of patients.
Baseline myeloma disease characteristics are listed in ( Table 2 ). Ongoing Myeloma treatment during the last 3 months before infection included immunomodulatory drug (IMiD) containing regimens in 35.1% (n = 57) of patients, followed by proteasome inhibitor-containing regimens in 28.3% (n = 46) and daratumumab-containing regimens in 26.5% (n = 43) of patients. One-third of patients (n = 54,33.3%) had relapsed and refractory MM, while 29.6% (n = 48) were receiving maintenance therapy, and only 11.7% (n = 19) on induction therapy. There were 77 (47.5%) patients with a history of autologous stem cell transplant (ASCT) before COVID-19 infection; only 3 patients had ASCT within 1 year of their infection, and 3 patients within 6 months of COVID-19 infection. Regarding MM disease status at the time of infection, most patients (n = 53, 32.7%) were in complete response (CR), while 13.5% (n = 22) were in very good partial response (VGPR), 12.3% (n = 20) were in partial response (PR), 14.8% (n = 24) with stable disease (SD) and 17.2% (n = 28) with progressive disease (PD).
Table 2
Patient Characteristics of Study participants: Multiple Myeloma Variables.
| Total ( n = 162) | |
| Myeloma status | |
| Complete remission | 53 (32.7%) |
| Very good Partial Response | 22 (13.5%) |
| Partial remission | 20 (12.3%) |
| Stable disease | 24 (14.8%) |
| Progressive disease/relapse | 28 (17.2%) |
| Myeloma Therapy in the Last 3 mo | |
| Immunomodulators (IMiDs) | 57 (35.1%) |
| Proteasome Inhibitors (PIs) | 46 (28.3%) |
| Anti-CD38 Antibody | 43 (26.5%) |
| Maintenance Therapy | 48 (29.6%) |
| Induction Therapy | 19 (11.7%) |
| Relapsed Refractory MM | 54 (33.3%) |
| H/o of ASCT | 77 (47.5%) |
Interestingly, myeloma disease status at the time of infection had no impact on hospitalization. The odds ratio (OR) for hospitalization compared with CR/VGPR were: MR/SD 1.1, (95% CI 0.4-3); OR for PD 1.8, (95% CI 0.7-4) or mortality (OR for MR or SD 3.2, (95% CI 0.4-24); OR for PD 4, (95% CI 0.6-25). Prior ASCT did not affect the risk of hospitalization (OR = 0.7, 95% CI 0.3-1.4) or mortality (OR = 0.53, 95% CI 0.1-2.4). In univariate analysis, CKD, hepatic dysfunction, DM, and HTN were associated with an increased risk of hospitalization. However, in multivariate analysis, only CKD, hepatic dysfunction, and hypogammaglobinemia significantly increased the risk of admission, as shown in Figure 1 . In a multivariate analysis regarding survival, increased age and lymphopenia were associated with increased COVID-19-related mortality, as shown in Figure 2 .
Discussion
This analysis includes 162 MM patients with COVID-19 infection early in the course of the COVID-19 pandemic. This represents the time just before the implementation of vaccinations but around the time of large-scale enactment of regular screening processes across institutions. Only 10 deaths were reported in the entire cohort, with a case fatality rate of 6%. Early reports, especially in blood cancer patients, noted higher mortality rates, risk of hospitalization with severe disease, and complications compared to our cohort. 11 , 12 , 13 A study from New York City by Hultcrantz et al reported a mortality rate of 24% in MM patients admitted to hospitals with COVID-19 infection, which was significantly higher than the general population. 1
Our study's primary purpose was to better understand the risk factors associated with poor outcomes from COVID-19 infection in MM patients and the effectiveness of implemented screening protocols and regular testing in this high-risk population. There were more COVID-19 infections noted in men as compared to women, which is consistent with trends noted in the general population. 14 The OR for increased risk of hospitalization was higher in patients with associated comorbid conditions, especially HTN, DM, CKD, and hepatic dysfunction. Similar disease characteristics were also reported in the earlier studies in the general population cohort. 11 , 15 There was an increased risk of severe infection that required hospitalization in patients with hypogammagloblinemia. 2 In studies, hypogammaglobinemia was associated with severe COVID-19 infection, high viral replication intensity, and prolonged virus carrier status duration in nasopharyngeal swabs. 16 There was an increased risk of COVID-19-related mortality in older adults and lymphopenic patients. In earlier studies to identify the risk factors associated with death in cancer patients with COVID-19 infection, the age over 65 was an independent risk factor. 17 The lymphopenia is associated with increased severity of COVID-19 infection, need for hospitalization, admission to ICU, oxygen requirement, and higher mortality. 18 It is well known that cytotoxic lymphocytes, including cytotoxic T lymphocytes and natural killer cells, are essential to maintaining immune homeostasis and inflammatory response to control viral infections. 19
Interestingly the prior ASCT was not associated with an elevated risk of severe COVID-19 infection that requires hospitalization, oxygenation, or elevated mortality risk. Even though in this study, 77 of 162 MM patients had been treated with autologous stem cell transplant, including 6 patients within the 12 months before contracting the SARS-CoV-2 Infection, which is consistent with earlier studies as well. 1 Similarly, no relationship was observed between the prior lines of therapy, type of therapy, active MM therapy, or maintenance therapy with severity and outcomes associated with COVID-19 infection. This finding reinforced the notion of safely continuing the MM therapies during the COVID-19 pandemic in patients without evidence of COVID-19 infection with focusing on better control of MM disease burden for better overall outcomes rather than delaying the therapies for MM.
Based on the emerging information early in the pandemic, institutions around the country initially implemented strict screening and testing protocols and modification of treatment pathways. This resulted in more options that can be safely administrated with minimal health care exposure in these high-risk MM patients. Our study showed that these screening and treatment protocols led to better outcomes and a decrease in morbidity & mortality associated with COVID-19 infection in MM patients. The studies showed these efforts provided safe and effective care to MM patients without any evidence of delay or determinantal effects on the outcome. 20
The main limitation of our study is its retrospective design with data collection from 2 myeloma centers. The second limitation is the small number of highly heterogeneous populations. We note a higher representation of African American population in our study than in average US studies. This heterogeneity allows for better generalizability of our reported outcomes. The difference between our reported outcomes and other centers could be due to the difference in reporting time with more vaccination availability and better treatment options. Finally, regional variations in screening methods, resources, and treatment modalities may impact the primary and secondary outcomes.
Conclusions
In summary, this study of MM patients with COVID-19 infection reinforces the infection mitigation measures and adjustment of clinical care pathways to support those practices. In addition, a better understanding of the disease process and implementing center-specific disease control measures with universal screening improved morbidity and mortality. Our data support this notion of screening all patients during the pandemic, which helps close monitoring and implementing an early temporary hold of MM therapies at an early asymptomatic stage to provide appropriate supportive care in COVID-19-infected MM patients. Also, our data suggest that myeloma therapy should not be compromised during the COVID-19 pandemic in patients without any concern of COVID-19 infection.
Clinical Practice Point
COVID-19 has profound effects on patients with MM mainly due to underlying immune dysfunction and associated therapies make patients susceptible to infections.
There was an increased risk of COVID-19-related mortality in older adults and lymphopenic patients.
The myeloma disease status and prior ASCT at the time of infection had no impact on hospitalization or mortality.
The prior ASCT was not associated with an elevated risk of severe COVID-19 infection that requires hospitalization, oxygenation, or elevated mortality.
Similarly, no relationship was observed between the prior lines of therapy, type of therapy, active MM therapy, or maintenance therapy with severity and outcomes associated with COVID-19 infection.
Our study findings reinforced the notion of continuing the MM therapies during the COVID-19 pandemic and focusing on better control of MM disease burden for better overall outcomes rather than delaying the therapies for MM.
With the better understanding of the disease process and implementing center-specific disease control measures with universal screening improved morbidity and mortality in these high-risk patients.
Disclosure
Peter M. Voorhees: Consulting or Advisory Role-Abbvie/Genentech; Bristol-Myers Squibb; GlaxoSmithKline; Janssen; Karyopharm Therapeutics; Oncopeptides; Pfizer; Sanofi; Secura Bio; Research Funding-Abbvie (Inst); GlaxoSmithKline (Inst); Janssen (Inst); TeneoBio (Inst); Travel, Accommodations, Expenses-Sanofi (OPTIONAL) Uncompensated Relationships - GlaxoSmithKline.
Barry Paul: Stock and Other Ownership Interests - Bristol-Myers Squibb; Consulting or Advisory Role Celgene/Bristol-Myers Squibb; Janssen Oncology; Speakers' Bureau - Amgen.
Manisha Bhutani: Research Funding - Amgen (Inst); Bristol-Myers Squibb/Celgene (Inst); C4 Therapeutics (Inst); Celularity (Inst); Cerecor (Inst); Janssen Research & Development (Inst); MedImmune (Inst); Millenium Pharmaceuticals (Inst).
Cindy Varga: Honoraria-Adaptive Biotechnologies.
Al-Ola A. Abdallah: Research Funding-Abbvie (Inst); Bristol-Myers Squibb/Medarex (Inst); Celgene (Inst); GlaxoSmithKline (Inst); Sanofi (Inst); Seattle Genetics (Inst); Patents, Royalties, Other Intellectual Property-PSA vaccine patent.
Shebli Atrash: Honoraria-Janssen; Speakers' Bureau - Celgene; Janssen; Research Funding - Amgen; Celgene/Bristol-Myers Squibb (Inst); GlaxoSmithKline; Janssen Oncology (Inst); Karyopharm Therapeutics.
The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
References
1. 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: 10.1158/2643-3230.BCD-20-0102.
2. Blimark C, Holmberg E, Mellqvist UH, et al. Multiple myeloma and infections: a population-based study on 9253 multiple myeloma patients. Haematologica. 2015;100(1):107–113. doi: 10.3324/haematol.2014.107714.
3. Heaney JLJ, Campbell JP, Iqbal G, et al. Characterisation of immunoparesis in newly diagnosed myeloma and its impact on progression-free and overall survival in both old and recent myeloma trials. Leukemia. 2018;32(8):1727–1738. doi: 10.1038/s41375-018-0163-4.
4. Nucci M, Anaissie E. Infections in patients with multiple myeloma in the era of high-dose therapy and novel agents. Clin Infect Dis. 2009;49(8):1211–1225. doi: 10.1086/605664.
5. Chicca IJ, Heaney JL, Iqbal G, et al. Anti-bacterial antibodies in multiple myeloma patients at disease presentation, in response to therapy and in remission: implications for patient management. Blood Cancer J. 2020;10(11):1–12. doi: 10.1038/s41408-020-00370-7.
6. Guan W-j, Ni Z-y, Hu Y, et al. Clinical characteristics of coronavirus disease 2019 in China. N Engl J Med. 2020;382(18):1708–1720. doi: 10.1056/NEJMoa2002032.
7. Krejci M, Pour L, Adam Z, et al. Outcome of COVID-19 infection in 50 multiple myeloma patients treated with novel drugs: single-center experience. Annals of Hematology. 2021;100(10):2541–2546. doi: 10.1007/s00277-021-04594-w.
8. Cook G, Ashcroft AJ, 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. doi: 10.1111/bjh.16874.
9. Terpos E, Engelhardt M, Cook G, et al. Management of patients with multiple myeloma in the era of COVID-19 pandemic: a consensus paper from the European Myeloma Network (EMN) Leukemia. 2020;34(8):2000–2011. doi: 10.1038/s41375-020-0876-z.
10. Malard F, Mohty M. Management of patients with multiple myeloma during the COVID-19 pandemic. Lancet Haematol. 2020;7(6):e435–ee37. doi: 10.1016/S2352-3026(20)30124-1.
11. 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: 10.1182/blood.2020008150.
12. 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):1–11. doi: 10.1038/s41408-020-00372-5.
13. Salje H, Tran Kiem C, Lefrancq N, et al. Estimating the burden of SARS-CoV-2 in France. Science. 2020;369(6500):208–211. doi: 10.1126/science.abc3517.
14. Richardson S, Hirsch JS, Narasimhan M, et al. Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area. JAMA. 2020;323(20):2052–2059. doi: 10.1001/jama.2020.6775.
15. Arentz M, Yim E, Klaff L, et al. Characteristics and outcomes of 21 critically ill patients with COVID-19 in Washington State. JAMA. 2020;323(16):1612–1614. doi: 10.1001/jama.2020.4326.
16. Michot JM, Hueso T, Ibrahimi N, et al. Severe COVID-19 in patients with hematological cancers presenting with viremia. Ann Oncol. 2021;32(10):1297–1300. doi: 10.1016/j.annonc.2021.07.002.
17. Robilotti EV, Babady NE, Mead PA, et al. Determinants of COVID-19 disease severity in patients with cancer. Nat Med. 2020;26(8):1218–1223. doi: 10.1038/s41591-020-0979-0.
18. Lee J, Park SS, Kim TY, Lee DG, Kim DW. Lymphopenia as a biological predictor of outcomes in COVID-19 patients: a nationwide cohort study. Cancers (Basel) 2021;13(3) doi: 10.3390/cancers13030471.
19. Tan L, Wang Q, Zhang D, et al. Lymphopenia predicts disease severity of COVID-19: a descriptive and predictive study. Sign Transduct Target Ther. 2020;5(1):1–3. doi: 10.1038/s41392-020-0148-4.
20. Neparidze N, Wang R, Zeidan AM, et al. Changes in multiple myeloma treatment patterns during the early COVID-19 pandemic period. Leukemia. 2022;36(8):2136–2139. doi: 10.1038/s41375-022-01633-x.