Antibody Response to COVID-19 mRNA Vaccine in Patients with Multiple Myeloma and Waldenstrom's Macroglobulinemia after Primary Immunization and Booster: Reactivity to the Sars-Cov-2 WT Virus, Delta and Omicron Variants

Patients with multiple myeloma (MM) or Waldenstrom's Macroglobulinemia (WM) present low humoral and cytokine responses to vaccination against SARS-CoV-2. The aim of this study was to evaluate magnitude and breadth of binding and neutralizing Ab induced upon vaccination in patients with MM and WM and to compare the ranking of the responses to the health care workers cohort comparing the vaccine effect after primary and first booster vaccinations.

This is a prospective study to monitor the kinetics and breadth of anti-SARS-CoV-2 humoral immune responses upon SARS-CoV-2 BNT162b2 (Pfizer/BioNtech) mRNA vaccination (NCT04743388) in MM and WM patients. Βlood was collected on day of 1st (D1) and 2nd (D22) vaccination, at one month after the 2nd vaccination (D50), day of 3rd (M9) vaccination, and one month later (M10). In-house ELISA assays using a panel of purified trimeric complete Wuhan strain (WA1) Spike and Spike-RBD and a panel of Variant of Concern (VOC) Spike proteins (Delta B.1.617.2, Omicron BA.1 (B.1.1.529) and BA.2) were used. The ACE2 binding competition neutralization assay was performed using a US FDA-approved ELISA (cPass SARS-CoV-2 NAbs Detection Kit; Gen-Script, Piscataway, NJ). Pseudotype neutralization was performed with a using a HIV_NLDEnv-Nanoluc assay carrying WA1 D616G, Delta, BA.1, BA.2 and BA.4 Spike proteins (AA 1-1254).

Five patient cohorts, including 80 patients with MM [n=80: treated with anti-CD38 (n=17), BCMA (belantamab mafodotin; n=3), other therapies (n=20) and off therapy (n=20)] and 16 with WM (off therapy n=7; on active therapy with rituximab-based regimens n=9) were evaluated. The MM and WM cohorts were compared to a cohort of BNT162b2 mRNA vaccinated health care workers (HCW, n=37).

After the 2^nd dose (D50), a 95-100% response rate in terms of anti-Spike Ab was found in the MM off therapy cohort as well as in MM patients on active therapy except of anti-CD38 and anti-BCMA-based regimens and in the WM off therapy cohort. Similar high response rate was found in the HCW cohort. On the other hand, several patients failed to respond in cohorts undergoing active therapies with rituximab (7/9, 77%), anti-CD38 (6/18, 33%) or anti-BCMA (1/3, 33%), indicating the negative effect of these therapies on vaccine response even after the 2^nd vaccination (D50). The response rate improved after the 3^rd dose for the anti-CD38 treated MM cohort (M10), supporting the importance of continued vaccination, even if the initial response rate was low under this treatment. In contrast, thebooster vaccination did not improve the response rate in patients who received rituximab- or anti-BCMA-based regimens. We further noted a wider range in magnitude of Spike Ab response in the patient cohorts compared to the HCW cohort at all three time points analyzed. All patient cohorts and HCW benefited from the booster vaccination with median increase from ~20- to ~50-fold increase at M10, except for the WM cohort on therapy which showed a heterogenous response with only few patients (3 of 9) and the BCMA-treated MM (2 of 3), showing booster immune responses.

Comparison of the patient cohorts showed similar responses breadth and ranking with strong recognition of WA1 and Delta but significantly lower binding to BA.1, BA.2 and BA.4, respectively. These data showed that the magnitude, but not the cross-reactivity of the Spike Ab was affected by certain anti-cancer treatments (anti-CD38, anti-CD20 and anti-BMCA). In general, we found good correlations between binding Ab to Spike-RBD and neutralization capability (ID50) across the panel analyzed in the WM and MM cohorts irrespective of the therapy status.

Overall, the 3rd BNT162b2 mRNA vaccination increased the anti-Spike Ab levels in the majority of MM and WM patient cohorts showing a benefit of the booster, with exceptions in patients treated with anti-CD20, anti-DC38 and anti-BCMA monoclonal antibodies (MAbs). The response to omicron variants is much lower compared to WA1 and delta variants. Our data show that strong ELISA Ab titers in all patient cohorts and HCW were good predictors for the ability to neutralize not only WA1 but also Delta and the Omicron variants. However, the response to the later is low and it seems to offer low protection, supporting the use of protective measures, such as the use of anti-SARS-CoV-2 MAbs, especially in patients under treatment with anti-CD20, anti-DC38 and anti-BCMA MAbs.

Terpos:Janssen: Honoraria, Research Funding; GSK: Honoraria, Research Funding; Genesis: Honoraria, Research Funding; EUSA Pharma: Honoraria, Other: Travel Expenses; BMS: Honoraria; Amgen: Honoraria, Other: Travel Expenses, Research Funding; Novartis: Honoraria; Takeda: Honoraria, Other: Travel Expenses, Research Funding; Sanofi: Honoraria, Research Funding. Gavriatopoulou:Karyopharm: Consultancy, Honoraria; GSK: Consultancy, Honoraria; Janssen Cilag: Honoraria; Sanofi: Honoraria; Genesis Pharma: Honoraria; Takeda: Consultancy, Honoraria; Amgen: Consultancy, Honoraria. Kastritis:Janssen: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Genesis Pharma: Honoraria; GSK: Honoraria; Pfizer: Honoraria, Research Funding; Takeda: Honoraria. Dimopoulos:BeiGene: Honoraria; Amgen: Honoraria; Jannsen: Honoraria; BMS: Honoraria; TAKEDA: Honoraria.