ABSTRACT
BACKGROUND: Multiple myeloma (MM) and Waldenström macroglobulinemia (WM) are associated with significant immunoparesis. Based on the ongoing COVID-19 pandemic, there is an urgent need to understand whether patients are able to mount a sufficient response to COVID-19 vaccines. METHODS: MM and WM patients are vaccinated with mRNA-1273 (Moderna), BNT162b2 mRNA (Pfizer/BioNTech), or JNJ-78436735 (Johnson & Johnson) in a prospective clinical trial. Primary endpoint is SARS-CoV-2 spike protein (S) antibody (Ab) detection 28 days after final vaccination. Secondary endpoints include functional serologic assessments and T-cell responses at 28 days, 6 months, 9 months, and 12 months following vaccination. S Abs were detected by Elecsys assay (Roche Diagnostics), with 3 0.80 U/mL defined as positive and titers > 250 U/mL considered stronger correlates of neutralization. SARS-CoV-2 wildtype and variant S-specific Ab isotypes and FcγR binding profiles were quantified by custom Luminex assay. Antibody-dependent neutrophil and cellular phagocytosis (ADNP and ADCP) were assessed using flow cytometry. RESULTS: To date 141 patients have been enrolled, 137 (91 MM and 46 WM) of whom had an S Ab assessment. Median Ab titer was 178.0 (IQR, 16.10-1166.0) for MM and 3.92 (IQR, 0-278.9) for WM. S Ab response rate was 91% (83/91) in MM and 56% (27/46) in WM. However, responses achieving S Ab >250 U/mL were 47.3% (43/91) in MM and 26.1% (12/46) in WM. In patients 375 years, responses >250 u/mL were 13.3% (2/15;p<0.05). Vaccine-specific S Ab responses >250 u/mL following mRNA-1273, BNT162b2, and JNJ-78436735 were 67.6% (23/34;p<0.05), 38.3% (18/47;p=NS), and 20% (2/10;p=NS) in MM and 50.0% (8/16;p<0.05), 14.8% (4/27;p<0.05), and 0% (0/3;p=NS) in WM. Among MM patients with progressive disease, S Ab response >250 u/mL occurred in 30% (6/20) as opposed to 55.6% (30/54) for VGPR+ (p<0.05). MM patients having autologous stem cell transplant within 12 months demonstrated 100% (5/5;p<0.05) S Ab responses. For MM patients actively receiving an anti-CD38 monoclonal Ab or an immunomodulatory drug, S Ab response occurred in 38.9% (14/36;p=NS) and 50.9% (28/55;p<0.05). Among WM patients, S Ab responses >250 U/mL occurred in 63.6% (7/11;p<0.05) previously untreated;0% (0/9;p<0.05) who received rituximab within 12 months;10% (2/20);p<0.05) on an active Bruton Tyrosine Kinase (BTK) inhibitor;and 20% (3/15;p=NS) who received other therapies. Functional Ab studies were performed on 14 MM patients, 14 WM, patients, and 14 healthy donors (HD) (Figure 1). All patients were assessed 28 days following their final vaccination and myeloma patients had an additional assessment 28 days following initial vaccination. MM and WM patients demonstrated less IGG1 and IGG3 S Ab production than HD. MM patients showed increased IgA and IgM S Ab production as well as increased FcgR2A binding following a second vaccine in contrast to HD. Both ADNP and ADCP were reduced in MM and WM patients. MM patients demonstrated improved ADCP in SARS-CoV-2 variants B.1.351, B.1.117, and P.1 versus wildtype (p<0.05). CONCLUSIONS: We report the first known evidence of impaired functional humoral responses following COVID-19 vaccines in patients with MM and WM. Overall, WM patients showed more severe impairment of COVID-19 S Ab responses. Most previously untreated WM patients achieved S Ab responses, however the most significant reduction in S Ab responses were seen in WM patients who received rituximab within 12 months or active BTK inhibitors. For MM patients, being in disease remission associated with improved S Ab response. Among MM and WM patients, age 375 years associated with significantly lower rates and vaccination with MRNA-1273 (Moderna) elicited significantly higher S Ab response rates than other vaccines. A defect in ADNP and more profound defect in ADCP suggests overall compromised opsinophagocytic activity among MM and WM patients. Data comparing first and second vaccine responses in MM patients, suggest less efficient class switching to IGG as well as incomple e maturation of their FcgR2A binding profiles but normal maturation of FcgR3A. Interestingly, ADCP was improved in several emerging SARS-CoV-2 variants. T-cell studies are pending and will be updated. Further understanding of the immunological response to COVID19 vaccination is needed to clarify patients risks, and necessity for booster or alternative protective measures against COVID-19. (Figure Presented).
ABSTRACT
Background: There is growing evidence to suggest that continuous monitoring and a proper use of patient-reported outcomes (PROs) in the clinical setting may improve patient care by facilitating doctor-patient communication, promoting individualized supportive care, and increasing patient satisfaction (Velikova, J Clin Oncol. 2004;22(4):714-24;Yang, Support Care Cancer. 2018 Jan;26(1):41-60). This may be of particular importance for patients with MM, a condition characterized by considerable heterogeneity in PROs at different timepoints within a patient's disease journey (TA King et al, Semin Oncol Nurs. 2017;33(3):299-315;R Abonour et al, Ann Hematol. 2018;97(12):2425-36). There is also a growing body of evidence to support that digital platforms in healthcare can have an impact on patients' lives and improve the patient care experience across diverse medical settings. Web-based platforms that provide education and allow patients to track data have demonstrated improvement across a range of PROs measuring empowerment, self-efficacy, and mastery when compared against standard of care in a variety of disease states (MR Fu et al, Internet Interv. 2016;5:56-64;G Bouma et al, Support Care Cancer. 2017;25(7):2075-2083). This may be particularly relevant in light of the current coronavirus disease 2019 (COVID-19) global pandemic. Patient-reported outcome data (e.g., symptoms) that can be readily shared with healthcare professionals (HCPs) can support clinical decision making and impact patient outcomes (E Basch et al, JAMA. 2017 Jul 11;318(2):197-8). Data collected through wearables (such as emoji scales and activity) have been shown to be correlated with traditional, validated PRO measures in patients with cancer (CA Thompson et al, Blood. 2017;130(Suppl 1):2179). Digital medication tracking has led to better medication adherence, increased prescription refills, and better clinical outcomes. Centralized disease management digital platforms have shown potential to reduce patients’ risk of complications (S Kumar et al, Abstract for the 77th American Diabetes Association. 2017). Despite this body of evidence supporting the potential impact of the use of digital platforms, there is little evidence specifically in MM. The MyHOPE™ for MM Solution is a validated investigational digital technology platform designed to provide patients with a comprehensive set of tools and resources to support the patient throughout their overall experience with MM and to collect biometrics and self-reported data such as symptom tracking, medication adherence, and health-related quality of life (HRQoL) with the ability to share this data with the patient's care team. MyHOPE™ for MM is the first prospective study evaluating the impact of a digital intervention for patients with hematological malignancies. Study Design and Methods: This is a multi-center, randomized, pilot trial of the MyHOPE™ for MM Solution. Approximately 126 adult patients (≥ 18 years of age) with a diagnosis of MM and who reside in the USA will be recruited from approximately 30 study sites within the USA, reflecting both community and academic centers. Patients will be stratified according to disease status (newly-diagnosed multiple myeloma transplant-eligible or ineligible, newly-diagnosed multiple myeloma in patients undergoing their first autologous stem cell transplant, or relapsed and/or refractory) and will be randomized in a 2:1 manner to either the Patient App + HCP Portal (Cohort 1) or Patient App Alone (Cohort 2). Primary objectives include feasibility of the platform and patient empowerment and self-efficacy. Other objectives include user satisfaction with the platform, health-related quality of life, and clinical outcomes. Enrolled patients will receive MM-treament regimen according to their physician's care plan. The study is in start-up and recruitment is expected through 2021. Disclosures: Raje: Celgene: Consultancy. Nadeem: Amgen: Membership on an entity's Board of Directors or advisory committees;Adaptive: Membership on an entity's Board of Direct rs or advisory committees;Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees;Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES;Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES;Janssen: Consultancy, Honoraria, Other: TRAVEL, ACCOMMODATIONS, EXPENSES. Mikhael: Amgen, Celgene, GSK, Janssen, Karyopharm, Sanofi, Takeda: Honoraria. Ludwig: Bristol Myers Squibb: Consultancy. Agarwal: Bristol-Myers Squibb Company: Current Employment, Current equity holder in publicly-traded company. Inumerable: Bristol Myers Squibb: Current Employment. Ong: Bristol Myers Squibb: Current Employment. Jagannath: BMS, Janssen, Karyopharm, Legend Biotech, Sanofi, Takeda: Consultancy.