Clinical Effectiveness and Long-Term Serologic Responses of COVID-19 Vaccination in Patients with Multiple Myeloma and Waldenström Macroglobulinemia

BACKGROUND: Multiple myeloma (MM) and Waldenström macroglobulinemia (WM) are associated with significant immunoparesis and growing data have demonstrated impaired COVID-19 vaccine responses in this population. However, clinical effectiveness and durability of vaccine response remains largely unknown.

METHODS: MM and WM patients were vaccinated with mRNA-1273 (Moderna), BNT162b2 mRNA (Pfizer/BioNTech), or JNJ-78436735 (Johnson & Johnson) in a prospective clinical trial (NCT04830046). Primary endpoint is SARS-CoV-2 spike protein (S) antibody (Ab) detection 28 days after primary vaccination series. Secondary endpoints include serologic assessments at 28 days following each vaccine, and 12 months following primary vaccination as well as surveillance for SARS-CoV-2 infections. Associations between patient characteristics and SARS-CoV-2 infections and S Ab response were evaluated with Fisher's exact test and Wilcoxon rank sum test.

RESULTS: To date 148 patients have been enrolled since March 2021 (98 MM and 50 WM). Two patients had SARS-CoV-2 infections prior to enrollment and were censored. After primary vaccination, median S Ab titer was 178 U/mL for MM and 2.38 U/mL for WM. S Ab response rates were 91.7% (88/96) in MM and 57.1% (28/49) in WM. However, rates of achieving adequate response (defined as S Ab >250 U/mL) were 45.8% in MM and 26.5% in WM. After initial booster, S Ab >250 U/mL were 81.7% (67/82) in MM and 60.9% (25/41) in WM. After second booster, S Ab >250 U/mL were 90.6% (29/32) in MM and 88.8% (16/18) in WM. 117 patients who had a 12-month S Ab assessment were evaluable. Among these patients, 84.8% (67/79) of MM patients and 86.8% (33/38) of WM patients had an S Ab >250 U/mL. Having any prior S Ab >250 U/mL was the only patient characteristic associated with S Ab >250 U/mL at 12 months, for example after primary vaccination (p<0.001), after 1st booster vaccine (p<0.01) and after 2^ndbooster vaccine (p=0.02).

Surveillance was performed during some of the highest surges of SARS-CoV-2 infections, including early 2021 and recently throughout 2022. After 12-months, SARS-CoV-2 infections were detected in 15% (22/146) of total patients, 18.5% (18/97) with MM and 8.1% (4/49) in WM. Severe infections (defined as leading to hospitalization or death) were detected in 2.7% (4/146) of patients (all MM), including one patient who died who remained unvaccinated after enrollment. All patients who developed SARS-CoV-2 infections had received 3 or fewer COVID-19 vaccinations. A higher risk of SARS-CoV-2 infection was observed among non-Caucasian (4/9; 44%) versus Caucasian (13/104; 12.5%) participants (p=0.02). None of the other baseline or clinical characteristics (including S Ab titer, recent anti-cancer therapy, IVIG therapy, or MM/WM disease response status) significantly impacted acquiring symptomatic SARS-CoV-2 infection (Table 1).

CONCLUSIONS: We report clinical effectiveness of COVID-19 vaccination in patients with MM and WM for the first time in a prospective clinical trial. Although WM patients showed more severe initial impairment of S Ab responses, S Ab levels improved after one and two vaccine boosters. After a second antibody booster, adequate S Ab were achieved in comparable rates between WM and MM, 88.8%, and 90.6%, respectively.

Optimal benefit in preventing SARS-CoV-2 infections was achieved with at least 4 doses of vaccine. No significant differences were observed in S Ab levels between patients who developed SARS-CoV-2 infections and those without, arguing the importance of other factors relating to vaccination such as cellular immunity.

These data demonstrate the importance of COVID-19 vaccination boosting efforts for patients with MM and WM. T-cell studies are ongoing and will be updated. Further understanding of the immunological responses to COVID-19 vaccination as well as identifying those most at risk are needed to inform the timing of boosters and alternative protective measures against SARS-CoV-2 infection in MM and WM patients.

Branagan:Karyopharm Therapeutics: Consultancy; BeiGene: Consultancy; CSL Behring: Consultancy; Adaptive Biotechnologies: Consultancy; Janssen/Pharmacyclics: Consultancy; Genzyme: Consultancy. Lei:TScan Therapeutics: Consultancy; Astrazeneca: Honoraria. Yee:Celgene: Consultancy; GlaxoSmithKline: Consultancy; Janssen: Consultancy, Research Funding; Karyopharm: Consultancy; Oncopeptides: Consultancy; Regeneron: Consultancy; Sanofi: Consultancy; Takeda: Consultancy; Amgen: Consultancy, Research Funding; Bristol Myers Squibb: Consultancy, Research Funding; Adaptive Biotechnologies: Consultancy; AbbVie: Consultancy. O'Donnell:Janssen: Consultancy; BMS: Consultancy, Honoraria. Castillo:Pharmacyclics: Consultancy, Research Funding; Janssen: Consultancy; Cellectar: Consultancy; Roche: Consultancy; TG Therapeutics: Research Funding; Abbvie: Consultancy, Research Funding; Beigene: Consultancy, Research Funding; AstraZeneca: Research Funding. Nadeem:GPCR Therapeutics: Membership on an entity's Board of Directors or advisory committees; Adaptive Biotechnologies: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees, Research Funding; Takeda: Research Funding; GSK: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Membership on an entity's Board of Directors or advisory committees. Raje:Bristol Myers Squibb: Consultancy, Honoraria; Amgen: Consultancy, Honoraria; Medscape: Honoraria; Research to Practice: Honoraria; Two Seventy Bio: Research Funding; Massachusetts General Hospita: Current Employment; Celgene: Honoraria; Janssen: Consultancy, Honoraria. Treon:BMS: Research Funding; BeiGene: Consultancy; X4: Consultancy, Research Funding; Abbvie: Consultancy; Janssen/Pharmacyclics: Consultancy, Research Funding. Richardson:Oncopeptides: Consultancy, Research Funding; Celgene/BMS: Consultancy, Research Funding; Takeda: Consultancy, Research Funding; Karyopharm: Consultancy, Research Funding; Sanofi: Consultancy; Secura Bio: Consultancy; GlaxoSmithKline: Consultancy; Regeneron: Consultancy; AstraZeneca: Consultancy; Protocol Intelligence: Consultancy; Takeda, Abbvie, GSK, and Celgene: Consultancy; Takeda: Research Funding; Takeda, Celgene, and GSK: Honoraria; Takeda and GSK: Other: Travel expenses from Takeda and GSK. Sarosiek:BeiGene: Consultancy; ADC Therapeutics: Research Funding.