COVID-19 Vaccine Responsiveness in Patients with Multiple Myeloma and Waldenström Macroglobulinemia
Authors: Branagan Andrew R. , Lei Matthew M , Maron Jenny S , Yee Andrew J , O'Donnell Elizabeth , Castillo Jorge J. , Raje Noopur S. , Treon Steven P , Flynn Catherine A , Mo Clifton C. , Nadeem Omar , Richardson Paul G. , Panaroni Cristina , Meid Kirsten , Bernstein Zachary S. , Lyons Rebecca T. , Hunter Zachary R , Guerrera Maria Luisa , Gammon Marilyn T. , Lively Kathleen J. , Packer Lisette , Waterman Matthew , Gallagher Raquel , Juleg Boris , Alter Galit , Sarosiek Shayna 
Published: November 2021

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 &gt; 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 &gt;250 U/mL were 47.3% (43/91) in MM and 26.1% (12/46) in WM. In patients ³75 years, responses &gt;250 u/mL were 13.3% (2/15; p&lt;0.05). Vaccine-specific S Ab responses &gt;250 u/mL following mRNA-1273, BNT162b2, and JNJ-78436735 were 67.6% (23/34; p&lt;0.05), 38.3% (18/47; p=NS), and 20% (2/10; p=NS) in MM and 50.0% (8/16; p&lt;0.05), 14.8% (4/27; p&lt;0.05), and 0% (0/3; p=NS) in WM.
Among MM patients with progressive disease, S Ab response &gt;250 u/mL occurred in 30% (6/20) as opposed to 55.6% (30/54) for VGPR+ (p&lt;0.05). MM patients having autologous stem cell transplant within 12 months demonstrated 100% (5/5; p&lt;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&lt;0.05).
Among WM patients, S Ab responses &gt;250 U/mL occurred in 63.6% (7/11; p&lt;0.05) previously untreated; 0% (0/9; p&lt;0.05) who received rituximab within 12 months; 10% (2/20); p&lt;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&lt;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 incomplete 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 1 Figure 1.

Disclosures
Branagan: Adaptive Biotechnologies: Consultancy; BeiGene: Consultancy; CSL Behring: Consultancy; Karyopharm: Consultancy; Pharmacyclics: Consultancy; Sanofi Genzyme: Consultancy. Lei: AbbVie: Honoraria; Epizyme: Honoraria; Fresenius Kabi: Consultancy; Intervention Insights: Consultancy. Yee: Amgen: Consultancy; Bristol Myer Squibb: Consultancy; Adaptive: Consultancy; GSK: Consultancy; Janssen: Consultancy; Oncopeptides: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Karyopharm: Consultancy. O'Donnell: Adaptive: Consultancy; Bristol Myer Squibb: Consultancy; Janssen: Consultancy; Karyopharm: Consultancy; Onocopeptide: Consultancy; Takeda: Consultancy. Castillo: Abbvie: Consultancy, Research Funding; BeiGene: Consultancy, Research Funding; Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding. Raje: Celgene, Amgen, Bluebird Bio, Janssen, Caribou, and BMS: Other. Treon: BeiGene: Consultancy, Research Funding; Eli Lily: Research Funding; Abbvie/Pharmacyclics: Consultancy, Research Funding. Mo: GSK: Consultancy, Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Epizyme: Consultancy; Eli Lilly: Consultancy; Janssen: Honoraria; Karyopharm: Honoraria, Membership on an entity's Board of Directors or advisory committees; Sanofi: Honoraria, Membership on an entity's Board of Directors or advisory committees. Nadeem: Takeda: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees. Richardson: Oncopeptides: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Protocol Intelligence: Consultancy; Janssen: Consultancy; Sanofi: Consultancy; Secura Bio: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; AstraZeneca: Consultancy; AbbVie: Consultancy; Jazz Pharmaceuticals: Consultancy, Research Funding. Juleg: Leyden Labs: Current Employment; Amsterdam: Current Employment; Netherlands: Current Employment.