High Humoral Response after Anti-Sars-Cov-2 mRNA-Based Vaccines in Patients with Active Multiple Myeloma (MM) and Relationship with Disease Status/Line of Therapy
Authors: Mancuso Katia , Zamagni Elena , Solli Vincenza , Gabrielli Liliana , Pantani Lucia , Rocchi Serena , Rizzello Ilaria , Tacchetti Paola , Fusco Alessio , De Cicco Gabriella , Ursi Margherita , Talarico Marco , Favero Emanuele , Nepoti Giuliana , Ruffini Barbara , Terragna Carolina , Lazzarotto Tiziana , Zinzani Pier Luigi , Cavo Michele 
Published: November 2021

Abstract
mRNA vaccines BNT162b2 and mRNA1273 are highly effective in preventing SARS-CoV-2 infection and mortality in healthy adults. However, their immunogenicity in immunocompromised Multiple Myeloma (MM) patients is less clear.
We performed an observational prospective study of 96 MM patients (pts) treated at our centre, aimed at assessing the humoral and cell-mediated immune (CMI) response following the full immunization schedule. To this aim, we measured serum levels of neutralizing IgG anti Spike-protein (IgG anti S-RBD) at 1, 3, 6, 9 and 12 months after the 2 nd dose of vaccination, using the electrochemiluminescence (ECLIA) platform (Elecsys® Anti-sars-Cov-2 ECLIA assay) and evaluated CMI response in terms of pts with a SARS-CoV-2 specific IFNγ T cell response by IGRA (Interferon-Gamma Release Assays) test at 3 and 12 months after 2 nd dose. A concentration level of IgG anti S-RBD ≥0.80 U/ml was considered a seropositive result. Herein, we report preliminary data on the development of humoral response in 96 MM pts who reached the first study timepoint (1 month after 2 nd dose), compared to 54 health-care workers as controls.
At vaccination, the median age of the 96 patients (51 males/45 females) was 66.5 (range 47-83) years. The median number of previous lines of therapy was 1 (range 1-11) and only 7 (7.3%) pts were not receiving active treatment. 44.8% (n=43) pts had relapse/refractory MM. Among 72 (75%) transplant-eligible pts, 63 patients had previously received autologous stem-cell transplantation (ASCT) with a median time between ASCT and vaccine of 31 (range 3-274) months.
70 (72.9%) pts had received immunomodulatory drugs (IMIDs) containing regimens, 30 (31.3%) proteasome inhibitors (PIs), 11 (11.5%) IMIDs + PIs, 32 (33.3%) anti-CD38 monoclonal antibodies (anti-CD38 moAbs). 33 (34.4%) pts were in lenalidomide (R) maintenance therapy.
At vaccination, 67 (68.8%) pts were in VGPR or higher, 18 (18.7%) in PR and 11 (11.3%) in SD or PD. Immunoparesis (≥1 uninvolved Ig below lower level limit) was observed in 78 (88.6%) pts, of whom 59 (67.1%) showed a reduction of two Ig classes.
All pts had completed the 2 planned doses of BNT162b2 (40.6%) or mRNA1273 (59.4%) vaccine 3 or 4 weeks apart, respectively. Control cohort (n=54; median age of 51 [range 40-66] years) received mRNA vaccine during the same period. People with previous SARS-CoV-2 infection (positive IgG anti S-RBD or anti-nucleocapsid N antibody titer before vaccines) were excluded from the analysis.
At 1 month post 2 nd dose, (median 30 days, IQR 28-32) seropositive response rate to vaccination was 91.7% (n=88) for MM pts vs 100% for controls, p=0.05; the median IgG anti S-RBD titer was 435 (range 0.4-2500) vs 1040.5 U/ml (range 160-2500), respectively; p=0.008.
No difference in the rate of seropositive response between those who received the 2 type of vaccines was found (p=0.09).
Pts with response level ≥ CR had a median antibody (Ab) titer (1242 U/ml, range 0.4-2500) significantly higher than those with ≤CR (221.5 U/ml, range 0.4- 2500), p&lt;0.001.
Pts receiving PI (median Ab titer 156; range 0.4- 2500) and anti-CD38 MoAbs (median titer 265 U/ml; 0.4- 2500) containing regimens had a lower Ab titer than all the other pts (p=0.003 and p&lt;0.001, respectively). Median Ab titer was higher in pts who received ASCT vs others (1042, range 0.4- 2500 vs 160 U/ml, range 228-2500, p&lt;0.001) and in pts receiving R maintenance (1681.2, range 0.4-2500 vs 529.5 U/ml, range 0.4-2500, p&lt;0.001). In pts with 2-Ig immunoparesis, the median Ab titer was 272 (range 0.4-2500) vs 2500 U/ml (range 228-2500) for no immunoparesis (p= 0.0037).
A distribution analysis of the Ab titer revealed a significant correlation between better humoral response and hematological response ≥ CR (p&lt;0.001), being in first-line treatment (p=0.039), having received ASCT (p=0.001) and receiving R maintenance (p=0.001).
Multivariate analysis confirmed ≥ CR [OR 2.54, 95% CI 93-756], being in first line treatment [OR 2.10, CI 22-722] and R maintenance therapy [OR 4.53, CI 484-1233] as independent predictors of better humoral response at 1 month after 2 nd vaccine dose.
In conclusion, mRNA vaccines provided a high seropositivity rate in pts in active MM treatment, with a better humoral response in pts achieving CR, those who received ASCT and receiving R maintenance. Immunoparesis was confirmed to be an unfavourable factor for the development of humoral response, as well as treatment with anti-CD-38 moAbs.

Disclosures
Mancuso: Celgene: Honoraria; Takeda: Honoraria; Sanofi: Honoraria; Amgen: Honoraria; Janssen: Honoraria. Zamagni: Takeda: Honoraria; Amgen: Honoraria; Bristol-Myers-Squibb: Honoraria; Janssen: Honoraria. Pantani: Amgen: Honoraria; Janssen: Honoraria. Rocchi: Amgen: Honoraria; GalxoSmithKline: Honoraria; Janssen: Honoraria. Rizzello: Amgen: Honoraria; GlaxoSmithKline: Honoraria; Sanofi: Honoraria. Tacchetti: Amgen: Honoraria; BMS/Celgene: Honoraria; Janssen: Honoraria; Takeda: Honoraria; AbbVie: Honoraria; Sanofi: Honoraria; GlaxoSmithKline: Honoraria; Oncopeptides: Honoraria. Zinzani: JANSSEN-CILAG: Other: Advisory board, Speakers Bureau; MSD: Consultancy, Other: Advisory board, Speakers Bureau; SANDOZ: Other: Advisory board; TG Therapeutics: Other: Advisory board, Speakers Bureau; GILEAD: Other: Advisory board, Speakers Bureau; SERVIER: Other: Advisory board, Speakers Bureau; BMS: Other: Advisory board, Speakers Bureau; CELLTRION: Other: Advisory board, Speakers Bureau; TAKEDA: Other: Advisory board, Speakers Bureau; ROCHE: Other, Speakers Bureau; EUSAPHARMA: Consultancy, Other, Speakers Bureau; KYOWA KIRIN: Other, Speakers Bureau; Incyte: Other, Speakers Bureau; NOVARTIS: Consultancy, Other, Speakers Bureau; ADC Therap.: Other; Beigene: Other, Speakers Bureau; VERASTEM: Consultancy, Other: Advisory board, Speakers Bureau. Cavo: Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: Travel Accommodations, Speakers Bureau; AbbVie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Consultancy, Honoraria; Novartis: Honoraria; Janssen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Other: TRAVEL, ACCOMMODATIONS, EXPENSES, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; GlaxoSmithKline: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers Squib: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau.