SUMMARY  

• Use With non-Janssen Coronavirus Disease 2019 (COVID-19) Vaccines
  • Clinicians should use clinical judgement based on local/institutional guidelines, standards of care, and individual patient risk/benefit assessment when considering concomitant use of DARZALEX-based therapy and a non-Janssen COVID-19 vaccine.
  • For additional information regarding the use of non-Janssen COVID-19 vaccines, please refer to the manufacturer of the specific vaccine.
• General Vaccination Information
  • Refer to the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices COVID-19 Vaccine Recommendations and General Best Practice Guidelines for Altered Immunocompetence.^1,2
  • It is generally recommended that live viral or live bacterial vaccines should not be given concurrently with monoclonal antibodies (MAbs).³
  • Country-specific health authority and medical society recommendations may be available regarding the use of COVID-19 vaccines in oncology patients, including information regarding additional mRNA COVID-19 vaccine dose recommendations for patients with hematologic malignancies receiving active treatment. Relevant content from the most-recognized organizations is listed below. However, this list is not a complete list of publicly available resources. The content is subject to change as evidence evolves.
    • For information from the World Health Organization, visit: COVID-19 Vaccines
    • For information from the Centers for Disease Control and Prevention Advisory Committee on Immunization Practices, visit: COVID-19 Vaccine Recommendations, General Best Practice Guidelines for Altered Immunocompetence, and Interim Clinical Considerations for Use of COVID-19 Vaccines Currently Authorized in the United States
    • For information from the American Society for Hematology, visit: COVID-19 Resources
    • For information from the British Society for Haematology, visit: COVID-19 Vaccines in Patients with Haematologic Disorders
    • For information from the European Hematology Association, visit: EHA Statement on COVID-19 Vaccines
    • For information from the European Society for Blood and Marrow Transplantation, visit: COVID-19 and BMT
    • For information from the National Comprehensive Cancer Network, visit: Coronavirus Disease 2019 (COVID-19) Resources for the Cancer Care Community
    • For information from the International Myeloma Society (IMS), visit: Recommendations for the Management of Myeloma Patients During the COVID19 Pandemic
• Abdallah et al (2022)⁴ evaluated the antibody responses against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) after vaccination with mRNA-1273 and BNT162b2 in a retrospective study on patients with plasma cell disorders (PCD; including multiple myeloma [MM], light-chain [AL]-amyloidosis, and smoldering MM) who were receiving ongoing treatment. Among patients receiving any DARZALEX-based therapy (n=72), an adequate neutralizing antibody (NAb) response (≥250 U/mL) was reported in 22 (31%) patients, an intermediate response (250 U/mL to ≥50 U/mL) was reported in 28 (31%) patients, and no response (<5 U/mL) was reported in 22 (31%) patients. The NAb response levels according to the treatment regimen received have been summarized in Table: NAb Response as per Treatment Received.
• Kastritis et al (2022)⁵ conducted a prospective study to evaluate the NAb response against SARS-CoV-2 after vaccination with BNT162B2 in patients with AL amyloidosis or transthyretin-related (ATTR) amyloidosis. The level of NAb titers in patients receiving DARZALEX-based vs non-DARZALEX-based therapy was 52.1% vs 46.4% (P=0.486), and the level of NAb titers in patients with vs without prior exposure to DARZALEX was 92.1% vs 91.2% (P=0.966), respectively.
• Nooka et al (2022)⁶ evaluated the development of anti-SARS-CoV-2 NAbs after vaccination with the Pfizer/BioNTech vaccine (BNT162b2), Moderna vaccine (mRNA-1273), or Janssen COVID-19 Vaccine (Ad26.COV2.S) in patients with MM and identified the factors affecting antibody response. Anti-cluster of differentiation 38 (CD38) antibody treatment was identified as a factor related to low anti-SARS-CoV-2 receptor-binding domain (RBD) specific antibody and NAb responses in the multivariable analysis (P=0.012).
• Haggenburg et al (2022)⁷ conducted a prospective, observational, multicenter, cohort study assessing the immunogenicity of 2 doses of mRNA-1273 in patients with hematological malignancies. Overall, 70% of previously uninfected patients achieved seroconversion and 55% achieved adequate vaccine response after 2 doses. An adequate vaccine response was achieved in 68.8% (95% confidence interval [CI], 53.781.3) of patients with MM on DARZALEX-based therapy.
• Terao et al (May 2022)⁸ conducted a prospective, observational study investigating the seropositivity and clinically protective titer after 2 doses of BNT162b2 or mRNA-1273 in patients with PCD. In the univariate analysis, anti-CD38 antibody use was associated with seronegativity (P=0.021) and insufficient antibody production (P=0.006). In the multivariable analysis, anti-CD38 antibody use was associated with seronegativity (P=0.031).
• Terao et al (February 2022)⁹ conducted an observational study evaluating the association between CD38+ regulatory T cell (Treg) count and duration of maintenance of vaccine response after 2 doses of BNT162b2 or mRNA-1273 in patients with PCD. Anti-spike immunoglobulin G (S-IgG) levels remained unchanged at 4 and 12 weeks after the second vaccination in patients who received anti-CD38 antibody (P=0.54) and significantly decreased by 44 U/mL from week 4 to week 12 in those who did not receive anti-CD38 antibody (P=0.001).
• Ramasamy et al (2022)¹⁰ reported results from an ongoing, prospective, observational cohort study evaluating the humoral and cellular responses after 2 doses of BNT162b2 or the Oxford/AstraZeneca vaccine (AZD1222) in patients with MM. The number of patients with MM with suboptimal S-IgG levels (<50 IU/mL) was numerically higher in patients receiving therapy (anti-CD38/anti-B-cell maturation antigen [BCMA] antibody, n=3; other, n=5) than in those not receiving therapy (8 [9.6%] vs 1 [2.2%]; P=0.16). Anti-CD38/anti-BCMA antibody exposure was determined to be an independent predictor of suboptimal S-IgG levels (odds ratio [OR], 5.03; 95% CI, 0.63-56.42; not statistically significant).
• Greenberg et al (2021)¹¹ evaluated the safety outcomes and antibody response after 2 doses of mRNA-1273 or BNT162b2 in patients with MM. Median anti-SARS-CoV-2 RBD antibody titer was above the upper limit of the assay (>250 U/mL) in all 7 patients who were on DARZALEX-based therapy.
• Ghandili et al (November 2021)¹² reported results from an ongoing, single-center, prospective, observational study (COVIDOUT; clinicaltrials.gov identifier: NCT04779346) evaluating the development of SARS-CoV-2 spike protein antibody titer (SP-AbT) after the first and second vaccine doses in patients with PCD. Patients receiving anti-CD38 therapy reported a significantly lower median SP-AbT (62 vs 1085 binding antibody unit [BAU]/mL; P=0.002) than those not receiving anti-CD38 therapy. Ghandili et al (July 2021)¹³ reported SP-AbT after the first dose of mRNA vaccines and vector-based vaccine in patients with PCD.
• Terpos et al (August 2021)¹⁴ reported the results from an ongoing, large, prospective study evaluating the development of anti-SARS-CoV-2 NAbs after administration with either BNT162b2 or AZD1222 vaccine in patients with plasma cell neoplasms. Four weeks after the second dose of BNT162b2 or 7 weeks after the first dose of AZD1222, patients who were receiving anti-CD38-based combinations achieved significantly lower NAb responses (mean±standard deviation [SD], 45.4%±29.4%) compared to patients not receiving treatment (mean±SD, 66%±25.4%; P=0.013). Treatment with anti-CD38 combinations was a significant predictive factor for lower antibody response (OR, 2.9; 95% CI, 1.2-7.1; P=0.002). Terpos et al (April 2021)¹⁵ evaluated the development of anti-SARS-CoV-2 NAbs after administration after the first dose of the BNT162b2 vaccine in MM patients. Twenty-two days after the first dose of the BNT162b2 vaccination, MM patients presented with lower median NAb titers compared to the control arm of healthy volunteers (20.6% vs 32.5%; P<0.01).
• Avivi et al (2021)¹⁶ reported the results from a single-center, prospective study evaluating serological response of MM patients compared to healthy volunteers
  14-21 days post second dose of BNT162b2. Univariate analyses showed time on DARZALEX-based therapy was not related to seropositive response. Lower response rates (69% vs 81%) were observed in patients receiving DARZALEX-containing regimens (OR, 0.52; 95% CI, 0.25-1.02; P=0.08).
• Pimpinelli et al (2021)¹⁷ evaluated the immunogenicity of BNT162b2 in a prospective, cohort study by measuring antibody titers, seroconversion rates, and trend in patients with solid cancers and hematological malignancies (including MM), elderly subjects over 80 aged and health workers. DARZALEX in combination with lenalidomide was significantly associated with a lower response rate compared to patients on active treatment with proteasome inhibitor (PI)-based and immunomodulatory imide drugs (IMiDs)- based therapies, alone or in combination (without DARZALEX) (50% [7/14] vs 92.9% [26/28]; P=0.003).
• Other relevant literature describing the concomitant use of anti-CD38 antibodies with non-Janssen COVID-19 Vaccines has been referenced in addition to the data summarized below.^18-23

PRODUCT LABELING

• DARZALEX (daratumumab) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.;  www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX-pi.pdf
• DARZALEX FASPRO (daratumumab and hyaluronidase-fihj) [Prescribing Information]. Horsham, PA: Janssen Biotech, Inc.; www.janssenlabels.com/package-insert/product-monograph/prescribing-information/DARZALEX+Faspro-pi.pdf

CLINICAL DATA

Anti-SARS-CoV-2 NAbs After 2 Doses of mRNA-1273 or BNT162b2 in Patients with Plasma Cell Disorders

Abdallah et al (2022)⁴ evaluated the antibody responses after vaccination with mRNA-1273 and BNT162b2 in a retrospective study on patients with PCD (including MM, ALamyloidosis, and smoldering MM) who were receiving ongoing treatment.

Study Design/Methods

• Inclusion criteria: presence of PCD (MM, AL-amyloidosis, or smoldering MM) with ongoing treatment, received two doses of either mRNA-1273 or BNT162b2, and measurement of NAb levels against SARS-CoV-2 taken after 30 days from the second dose of the vaccine
• Exclusion criteria: <2 doses of the aforementioned vaccines, or vaccination with Ad26.COV2.S
• Response was classified according to NAb levels after 30 days from the second dose:
  • Adequate response (≥250 U/mL)
  • Intermediate response (250 U/mL to ≥50 U/mL)
  • No response (<5 U/mL)

Results

Patient Characteristics

• Overall, 149 patients were included. The baseline patient and disease characteristics are summarized in Table: Baseline Patient and Disease Characteristics.

Efficacy

• The median time between the second dose of the vaccine and the assessment of NAb levels was 104 days (range, 30-196).
• Adequate NAb response was reported in 63 (42%) patients, intermediate response was reported in 47 (32%) patients, and no response was reported in 39 (26%) patients.
• Treatment with anti-CD38-based regimen was associated with a lower odd (OR, 0.39; 95% CI, 0.20-0.76) of achieving adequate NAb response (P<0.005).
• The NAb response statuses as per the treatment received are summarized in Table: NAb Response as per Treatment Received.

Anti-SARS-CoV-2 NAbs After 2 Doses of BNT162b2 in Patients with AL or ATTR Amyloidosis

Kastritis et al (2022)⁵ conducted a prospective study to evaluate the NAb response against SARS-CoV-2 after vaccination with BNT162B2 in patients with AL or ATTR amyloidosis.

Study Design/Methods

• Inclusion criteria: patients with prior diagnosis of AL or ATTR amyloidosis and eligibility for vaccination with BNT162B2 were included.
  • The control group was defined as an age and gender-matched population of volunteers with no autoimmune or active malignant disease, human immunodeficiency virus (HIV) infection, or active hepatitis B or C infection (patient to control ratio, 1:2).
• Samples were collected at day 1 (D1; first vaccine dose), day 22 (D22; second vaccine dose), and day 50 (D50; 4 weeks after the second vaccine dose).
• Primary endpoint: NAb titers at D50

Results

Patient Characteristics

• Overall, 126 patients were included in the patient group (male, n=68; median age, 66 years [range, 35-86]) and 252 individuals were included in the control group (male, n=136; median age, 66 years [range, 35-86]).
• Prior to D1, the median NAb titer levels in the patient vs control group was 14.9% (interquartile range [IQR], 7.8-23.1) vs 14% (IQR, 6.8-22.9%; P=0.439), respectively. A baseline NAb of ≥30% was reported in 8 (6.5%) individuals (of which 5 had a history of COVID-19 infection) in the patient group and in 24 (9.9%) individuals in the control group.
• At the time of vaccination, 29 (24%) patients were on DARZALEX-based therapy, 33 (27%) patients had prior exposure to DARZALEX (last dose ≥3 months prior to vaccination), and 92 (75%) patients were in hematologic remission (complete response [CR] or very good partial response [VGPR]).

Efficacy

• On D22, a significant increase from baseline in NAb titers was observed in both the patient and control group (P<0.001).
  • In the patient vs control group, the median NAb titer level was 23.6% (IQR, 12.437.7) vs 47.5% (IQR, 32.1%-62.7%; P<0.001), and the rate of developing clinically relevant level of NAb titers (≥50%) was 18% vs 44.7% (P<0.001), respectively.
• On D50, a further significant increase in NAb titers was observed in both the groups (P<0.001).
  • In the patient vs control group, the median NAb titer level was 83.1% (IQR, 41.594.9) vs 95.6% (IQR, 91.7-97.2; P<0.001) and the rate of developing clinically relevant level of NAb titers was 71% vs 98% (P<0.001), respectively.
• Therapy with DARZALEX did not affect NAb titers among patients who had ongoing therapy. The level of NAb titers in patients receiving DARZALEX-based vs non-DARZALEX-based therapy was 52.1% vs 46.4% (P=0.486), respectively.
• Prior exposure to DARZALEX did not affect NAb titer levels at D50 among patients who were not on active therapy. The level of NAb titers in patients with vs without prior exposure to DARZALEX was 92.1% vs 91.2% (P=0.966), respectively.

Anti-SARS-CoV-2 NAbs After Vaccination With BNT162b2, mRNA-1273, or Ad26.COV2.S in Patients With MM

Nooka et al (2022)⁶ evaluated the development of anti-SARS-CoV-2 NAbs after vaccination with BNT162b2, mRNA-1273, or Ad26.COV2.S in patients with MM and identified the factors affecting antibody response.

Study Design/Methods

• Patients with MM who received BNT162b2, mRNA-1273, or Ad26.COV2.S were included.
• The serologic response to vaccines was measured using enzyme-linked immunoassay (ELISA) to detect antibodies against SARS-CoV-2 spike RBD. NAbs were evaluated using pseudovirus and live virus neutralization assays against the initial Wuhan SARS-CoV-2 strain (WA1) and B1.617.2 (Delta) variant.
• Antibodies against nucleocapsid (NC) were monitored to evaluate previous environmental exposure to the virus.

Results

Patient Characteristics

• Overall, 238 patients were included (median age at vaccination [range],
  67.26 [38.44-90.08] years; median time from diagnosis to vaccination [range],
  51.91 [1.15-376.94] months; male, n=124).

Efficacy

• After the second vaccination, RBD-specific antibodies and NAbs were detected in 208 (87%) and 128 (54%) patients, respectively. Both anti-RBD and NAb titers peaked at 12 weeks after the second vaccination and declined by 3 months. Select patient characteristics and anti-RBD and NAb responses are presented in Table: Patient Characteristics and Responses.

• Overall, patients receiving anti-CD38 antibody treatment developed low levels of antiRBD antibodies and NAbs after vaccination. NC-negative patients with ≥2 previous lines of therapy (LOTs) with anti-CD38 MAbs or their combinations reported significantly reduced vaccine-induced NAbs in the univariate analyses. Two or more previous LOT with anti-CD38 MAb or their combinations were reported as independent predictors of reduced NAb responses in the multivariable analysis. See Table: Predictors of Antibody Response.

Immunogenicity of 2 Doses of mRNA-1273 in Patients With Hematological Malignancies

Haggenburg et al (2022)⁷ conducted a prospective, observational, multicenter, cohort study to assess the immunogenicity of 2 doses of mRNA-1273 in patients with hematological malignancies.

Study Design/Methods

• Patients were stratified into 17 predefined cohorts based on their diagnosis and treatment status. The MM cohort included the following subgroups based on treatment status:
  • First-line therapy
  • DARZALEX
  • IMiDs
  • Less than 9 months after autologous hematopoietic stem cell transplantation (HSCT) and exposure to high-dose melphalan
• Inclusion criteria: adults ≥18 years old with a diagnosis of lymphoma, MM, chronic lymphocytic leukemia, acute myeloid leukemia, myelodysplastic syndrome, myeloproliferative disease, or sickle cell disease and currently receiving or received immunochemotherapy in the past 6-12 months prior to vaccination or those who received targeted agents, autologous or allogeneic HSCT within 6-12 months prior to vaccination, or CD-19-directed chimeric antigen receptor (CAR)-T cell therapy
• Exclusion criteria: known allergy to one of the components of the vaccine, and a life expectancy of <12 months
• All patients received 2 doses of mRNA-1273 28 days apart.
• Humoral responses against spike subunit 1 (S1-IgG), spike RBD (S-IgG), and NC antigen domain (N-IgG) were determined quantitatively and centrally using a beadbased multiplex immunoassay.

Results

Patient Characteristics

• Overall, 695 patients were included. The baseline characteristics of patients with MM are summarized in Table: Patient Baseline Characteristics.

• N-IgG >14.3 BAU/mL was detected at baseline in 4.9% of patients who were excluded from the analyses.

Efficacy

• Overall, 70% of previously uninfected patients achieved seroconversion (S1-IgG >10 BAU/mL) and 55% achieved adequate vaccine response (S1-IgG ≥300 BAU/mL) after 2 doses of the vaccine.
• In the MM cohort, an adequate vaccine response was achieved in 52.2% of patients on the first-line remission induction therapy, 68.8% of patients on DARZALEX, 77.1% of patients on IMiDs, and 88.9% of patients who received autologous HSCT and high-dose melphalan within the last 9 months.⁷ See Table: S1-IgG Levels After 2 Vaccine Doses in the MM Cohort.

SARS-CoV-2 Spike and Nucleocapsid Antibody Responses After 2 Doses of BNT162b2 or mRNA-1273 in Patients With PCD

Terao et al (May 2022)⁸ conducted a prospective, observational study investigating the seropositivity and clinically protective titer after 2 doses of BNT162b2 or mRNA-1273 in patients with PCD.

Study Design/Methods

• Prospective, observational, multicenter study
• Study arms included the following:
  • Patients with PCD
  • Healthy volunteers previously uninfected with COVID-19 aged >60 years without active cancer or immunosuppression therapy as controls
• Inclusion criteria: Adults ≥18 years old with a diagnosis of PCD (symptomatic MM, smoldering MM [sMM], or monoclonal gammopathy of undetermined significance [MGUS]) and no known history of COVID-19 onset
• Primary endpoints: Anti-SARS-CoV-2 antibody levels (immunoglobulin G [IgG] against spike RBD and NC) and seropositivity
• Antibody response was analyzed using Elecsys^® Anti-SARS-CoV-2 on Cobas 8000 e801 module from serum samples collected on day 1 (before the first vaccination [T0]), day 15-28 (before the second vaccination [T1]), and day 36-85 (T2), if available.

Results

Patient Characteristics

• Overall, 269 patients (symptomatic MM, n=206; sMM, n=31; MGUS, n=32) were included.
  • Serum samples were obtained from 78, 94, and 194 patients with symptomatic MM at T0, T1, and T2, respectively, and from the control group at T2.
  • Patients with symptomatic MM received PIs (n=55; 26.7%), IMiDs (n=121; 58.7%), anti-CD38 antibody (n=83; 40.3%), elotuzumab (n=16; 7.8%), and autologous stem cell transplantation (ASCT; n=2; 1.0%) 6 months before their first vaccination and immunoglobulin replacement (n=21; 10.2%) 2 months before or after their first vaccination.
  • Select baseline and disease characteristics are summarized in Table: Patient Baseline Characteristics.

• Overall, 257 patients were included in the analyses, excluding those with sMM or MGUS who were treated with DARZALEX for concomitant AL amyloidosis (sMM, n=6; MGUS, n=6).

Efficacy

• S-IgG seropositivity (≥0.8 U/mL) was achieved in 172 (88.7%) patients with symptomatic MM, 25 (100%) patients with sMM, 24 (96%) patients with MGUS, and all controls at T2.
• Clinically protective S-IgG (≥200 U/mL) was achieved in 75 (38.3%) patients with symptomatic MM, 18 (72.0%) with sMM, 19 (76.0%) with MGUS, and 87 (92.6%) controls at T2.
• N-IgG seropositivity was reported in 1 patient with asymptomatic onset of COVID-19.
• In the univariate analysis, anti-CD38 antibody use was associated with seronegativity and insufficient antibody production. In the multivariable analysis, anti-CD38 antibody use was associated with seronegativity. See Table: Effect of Anti-CD38 Antibody on Vaccine Response.

• Patients who received anti-CD38 antibody had lower levels of polyclonal IgG
  (421 vs 796 mg/dL; P<0.001), similar absolute lymphocyte count (1200 vs 1301/µL; P=0.22), and similar treatment response (≥very good partial response [VGPR]; 88.2% vs 82.1%; P=0.30) vs those who did not.
• Patients receiving anti-CD38 antibody within 30 days before the first vaccine had significantly lower median S-IgG levels at T2 than those not receiving anti-CD38 antibody (36.9 vs 191.0 U/mL; P<0.001). Effect of duration from the last administration of anti-CD38 antibody on vaccine response is summarized in Table: Effect of Duration From the Last Anti-CD38 Antibody Administration on Vaccine Response.

• In patients with vs without clinically protective S-IgG levels, the percentage of patients receiving anti-CD38 antibody was 11.1% vs 42.9% (P=0.2), respectively.

Terao et al (February 2022)⁹ conducted an observational study evaluating the association between CD38+ T-reg count and duration of maintenance of vaccine response after 2 doses of BNT162b2 or mRNA-1273 in patients with PCD.

Study Design/Methods

• Patients with PCD (MM, sMM, or MGUS) who received 2 doses of an mRNA-based vaccine (BNT162b2 or mRNA-1273) were included.
• Serum samples were collected at 4 weeks (T1; median [range], 31.5 [10-65] days; n=60) and 12 weeks (T2; median [range], 89 [60-133] days; n=53) after the second vaccination and were analyzed for antibody response using Elecsys^® Anti-SARS-CoV-2 on Cobas 8000 e801 module.

Results

Patient Characteristics

• Overall, 60 patients were included in this study. Select baseline and disease characteristics are summarized in Table: Patient Baseline Characteristics.

Efficacy

• At T1 and T2, 90.0% and 94.3% of patients were seropositive (S-IgG, ≥0.8 U/mL), 35.0% and 30.2% of patients had clinically protective responses (S-IgG, ≥200 U/mL), and median (range) S-IgG levels were 74.4 (0.47171) U/mL and 77.4 (0.4-3530) U/mL, respectively.
• Late responders (n=18; 34.0%) included a higher percentage of patients who received anti-CD38 antibody 3 months before T0 (66.7% vs 31.4%; P=0.020) and had lower median polyclonal IgG (4.23 vs 6.72 g/L; P=0.014) vs non-late responders.
• At T1 and T2, antibody titers in patients who received anti-CD38 antibody were significantly lower vs those who did not receive anti-CD38 antibody (T1, 26.2 vs 201 U/mL, P=0.002; T2, 35.8 vs 122 U/mL, P=0.023).
• S-IgG levels remained unchanged at T1 and T2 in patients who received anti-CD38 antibody (P=0.54) and significantly decreased by 44 U/mL from T1 to T2 in those who did not receive anti-CD38 antibody (P=0.001).
• In patients who received anti-CD38 antibody 3 months at T0 vs those who did not receive anti-CD38 antibody, the following changes were noted:
  • Median CD8+ (546 vs 296/µL; P=0.004) and human leukocyte antigen-DR isotype (HLA-DR)+ T cell (609 vs 304/µL; P=0.002) counts were higher.
  • Median CD19+ (31 vs 100/µL; P=0.064) and CD56+ (22 vs 283/µL; P<0.001) counts were lower.
  • CD38+ T-reg counts (1.0 vs 13.5/µL; P<0.001) were lower.
  • Total T-reg counts (57.1 vs 56.8/µL; P=0.72) were similar.
• CD38+ T-reg counts (2.5 vs 10.3/µL; P=0.023) and CD19+ counts (28 vs 103/μL, P=0.021) were significantly lower in late responders vs non-late responders.
• At T1, patients with low CD38+ T-reg counts (≤4.8/µL; n=25) reported lower median SIgG levels compared with those with high CD38+ T-reg counts (≥4.8/µL; n=35; 29.7 vs 176.0 U/mL; P=0.016).
• At T2, no significant difference in median S-IgG was reported between patients with low vs high CD38+ T-reg counts (71.9 vs 77.4 U/mL; P=0.61).
• Median S-IgG level decreased significantly from T1 to T2 in patients with high CD38+ Treg counts (176.0 vs 77.4 U/mL; P<0.001) and remained unchanged in patients with low CD38+ T-reg counts (29.7 vs 71.9 U/mL; P=0.53).
• The relationship between anti-CD38 antibody and IMiD usage and vaccine response is summarized in Table: Effect of Anti-CD38 Antibody and IMID Usage on Vaccine Response.

Humoral and Cellular Responses After 2 Doses of BNT162b2 or AZD1222

Ramasamy et al (2022)¹⁰ reported results from an ongoing, prospective, observational cohort study evaluating the humoral and cellular responses after 2 doses of BNT162b2 or AZD1222 in patients with MM.

Study Design/Methods

• Patients with MM or sMM who received the first and the second doses of BNT162b2 or AZD1222 were included.
• Serum samples were collected at the following intervals:
  • Before the second or first vaccinations
  • Three or more weeks after the second vaccination
  • Planned to be collected before the third vaccination and/or after >3 weeks of the third vaccination
• Samples were analyzed for S-IgG or N-IgG using turbidimetry. Cellular responses were analyzed by quantifying SARS-CoV-2-specific effector T cells using the Oxford Immunotec T interferon gamma release assay (IGRA).

Results

Patient Characteristics

• Overall, 214 patients (MM, n=204; sMM, n=10) were included in this study. Median interval between the first and second vaccinations was 11 weeks (range, 2-12.7). Select baseline and disease characteristics are summarized in Table: Patient Baseline Characteristics.

Efficacy

• Positive S-IgG level (≥50 IU/mL) was reported in 67.6% and 92.5% of patients after the first and second vaccinations, respectively. Patients with positive N-IgG (≥1.5 IU/mL) at the second vaccination achieved significantly higher S-IgG levels (P=0.002) vs those without. See Table: Humoral Responses After the First and Second Vaccinations.

• The number of patients with MM with suboptimal S-IgG levels (<50 IU/mL) was numerically higher in patients receiving therapy (anti-CD38/anti-BCMA antibody, n=3; other, n=5) vs those not receiving therapy (8 [9.6%] vs 1 [2.2%]; P=0.16).
• Anti-CD38 antibody/BCMA exposure was reported as an independent predictor of suboptimal S-IgG levels (OR, 5.03; 95% CI, 0.63-56.42; not statistically significant) and negative IGRA reactivity (<8 interferon gamma releasing cells/10⁶ peripheral blood mononuclear cells; OR, 4.80; 95% CI, 1.09-21.02; statistically significant) vs no chemotherapy.

Safety Outcomes and Antibody Response After 2 Doses of mRNA-1273 or BNT162b2

Greenberg et al (2021)¹¹ evaluated the safety outcomes and antibody response after 2 doses of mRNA-1273 or BNT162b2 in patients with MM.

Study Design/Methods

• Prospective cohort study
• Adult patients (≥18 years old) with MM without prior SARS-CoV-2 infection who received the first and the second vaccine doses were included.
• Serum samples were analyzed for antibodies against the SARS-CoV-2 RBD 1 month after the second vaccination using Elecsys^® Anti-SARS-CoV-2.

Results

Patient Characteristics

• Overall, 44 patients were included. Select patient and disease characteristics are summarized in Table: Patient Characteristics.

Efficacy

• Anti-SARS-CoV-2 RBD antibody was detected in 41 of 44 (93%; 95% CI, 81-99) patients overall, 25 of 27 (93%; 95% CI, 76-99) patients who were on therapy, and 16 of 17 (94%; 95% CI, 71-99) patients who were not on therapy.
• Median titer was above the upper limit of the assay (>250 U/mL) for both patients who were on therapy and those who were not on therapy.
• Median anti-SARS-CoV-2 RBD antibody titer was >250 U/mL (IQR, >250 to >250) in all 7 patients on DARZALEX-based therapy.¹¹

Safety

• Overall, 80% of all local reactions and 71% of all systemic reactions were mild.
• The most common local and systemic reactions are summarized in Table: Systemic and Local Reactions.

• Since vaccination, no patient developed anaphylaxis, new neurologic condition, SARSCoV-2 incidence, or infection.

Development of SARS-CoV-2 SP-AbT After the First and the Second Vaccine Doses

Ghandili et al (November 2021)¹² reported results from an ongoing, single-center, prospective, observational study (COVIDOUT; clinicaltrials.gov identifier: NCT04779346) evaluating the development of the SARS-CoV-2 SP-AbT after the first and the second vaccine doses in patients with PCD. Ghandili et al (July 2021)¹³ reported the SP-AbT after the first dose of mRNA vaccines and vector-based vaccine in patients with PCD.

Study Design/Methods

• Study arms included the following:
  • Patients with PCD
  • Health care workers with matched gender and vaccination regime as controls
• Inclusion criteria: Adults ≥18 years old with a confirmed diagnosis of MM, sMM, monoclonal gammopathy of clinical significance (MGCS), and systematic light-chain (AL) amyloidosis and eligible for anti-SARS-CoV-2 vaccination according to IMS recommendations
• Exclusion criteria: SARS-CoV-2 infection prior to immunization
• Primary objectives included the following:
  • To evaluate the correlation between SP-AbT after the second vaccine dose and CD19+ B cell count
  • To compare the number of patients with PCD who developed SP-AbT after second dose, and compare the SP-ABT levels between patients with PCD and healthy controls.
• Blood samples were analyzed quantitatively for S-IgG and qualitatively for N-IgG using Elecsys^® Anti-SARS-CoV-2.

Results

Patient Characteristics

• Overall, 82 patients were included, of whom 37 (45.1%) received anti-CD38 therapy. Select baseline and disease characteristics are summarized in Table: Patient Baseline Characteristics and Table: Baseline Characteristics of Patients With Myeloma and Controls, respectively.

• Anti-SARS-CoV-2 antibody titers were analyzed at a mean of 24 days (SD, ±11.2) after the first vaccination and 21 days (SD, ±9.4) after the second vaccination.

Efficacy

• After the first vs second vaccinations, positive SP-AbT was reported in 31.9% vs 88.9% of evaluable patients, and median SP-AbT was 0 BAU/mL (range, 0-10328) vs
  216.87 BAU/mL (range, 0-25,720), respectively.
• Positive SP-AbT was reported after the second vaccination in 80.9% of patients with myeloma who did not develop SP-AbT after the first vaccination.
  • Median SP-AbT titer was significantly lower (51.04 vs 2191.87 BAU/mL; P<0.0001) in patients reporting positive SP-AbT after the second vaccination vs those reporting positive SP-AbT after the first vaccination.
• Positive SP-AbT was reported in a significantly lower number of patients with myeloma after the second vaccination vs the control group (89.9% vs 100%; P=0.008).
  • Median SP-AbT titer was similar in patients with myeloma and the control group (878 BAU/mL [range, 0-25,720] vs 938 BAU/mL [range, 0.3-22,287]; P=0.64) after the second vaccination.
• Patients receiving anti-CD38 therapy reported a significantly lower median SP-AbT (62 vs 1085 BAU/mL, P=0.002) vs those not receiving anti-CD38 therapy.
• Patients receiving quadruplet therapies (containing a combination of DARZALEX, bortezomib, thalidomide, and dexamethasone [DaraVTD] or isatuximab, carfilzomib, lenalidomide, and dexamethasone [IsaKRD] as the first-line therapy for newly diagnosed MM or a combination of elotuzumab, pomalidomide, cyclophosphamide, and dexamethasone [Elo-PCd] for relapsed/refractory [R/R] MM) reported a significantly lower median SPAbT titer (7 vs 565 BAU/mL; P<0.001) vs those not receiving quadruplet therapy.
• In the multiple linear regression analysis, quadruplet therapy was negatively correlated with SP-AbT titer (coefficient, -1.44 [95% CI, -2.75 to -0.13]; P=0.032).
• Among 9 patients who did not develop SP-AbT after the second vaccination, 4 patients (MM, n=3; MM+AL, n=1) received anti-CD38 therapy (DARZALEX, lenalidomide, and dexamethasone [DRd], n=2; IsaKRD, n=2).

Ghandili et al (July 2021)¹³ reported the SP-AbT after the first dose of mRNA vaccines and vector-based vaccine in patients with PCD from the COVIDOUT study.

Study Design/Methods

• Primary endpoint: level of post-vaccination SARS-CoV-2 SP-AbT after first vaccination based on CD19+B lymphocyte count
• Secondary endpoints: number of patients with plasma cell neoplasia showing anti-SARS-CoV-2-antibodies at least seven days after first immunization; development of anti-SARS-CoV-2-antibodies under CD38-directed treatment; relationship of remission status, disease, and patient characteristics to development of anti-SARS-CoV-2-antibodies; relationship between B and T cell status and anti-SARS-CoV-2-antibody titer.
• Vaccines that could be used included mRNA-vaccines (BNT162b2 and mRNA-1273), and vector-based vaccine (AZD1222).
• SP-AbT were measured by LIAISON SARS-CoV-2 spike trimeric IgG and Elecsys Anti-SARS-CoV-2.

Results

Patient Characteristics

• The study evaluated 82 patients from January 2021 to 21 May 2021.
• Baseline patient and disease characteristics are summarized in Table: Patient Baseline Characteristics.

• Sixty-three (76.8%) patients were vaccinated with mRNA-based vaccines and 19 (23.2%) with vector-based vaccines.
• SP-AbT was assessed at a median of 25 days after first vaccination.
• Higher CD19+ B-lymphocyte counts positively correlated with SP-AbT results (Spearman correlation coefficient, r=0.45; P<0.0001).
  • Median CD19+ B lymphocytes were lower in patients under current anti-CD38 treatment vs patients without treatment (20 vs 38; P=0.054).
  • Patients with longer durations of CD38 treatment correlated to lower CD19+ B lymphocyte counts (correlation coefficient, r=-0.173; P=0.06).
• Lower titers were observed in patients with current anti-CD38-antibody treatment (P=0.009).
• Likelihood of positive titer results was lower in patients with current anti-CD38 treatment vs without anti-CD38 treatment.
  • Negative SP-AbT were detected in 29 (93.5%) patients vs 28 (65.1%) receiving current anti-CD38 treatment vs without anti-CD38 treatment, respectively; (P=0.005).
  • Positive SP-AbT were detected in 2 (6.5%) patients vs 15 (34.9%) receiving current anti-CD38 treatment vs without anti-CD38 treatment, respectively; (P=0.005).
• There were no differences in SP-AbTs between DARZALEX- or isatuximab- treated patients.

Anti-SARS-CoV-2 NAbs after BNT162b2 or AZD1222 Vaccine in Patients With Plasma Cell Neoplasms

Terpos et al (August 2021)¹⁴ reported the results from an ongoing, large, prospective study (clinicaltrials.gov identifier: NCT04743388) evaluating the development of anti-SARS-CoV-2 NAbs after vaccination with either BNT162b2 or AZD1222 vaccine in patients with plasma cell neoplasms.

Study Design/Methods

• Prospective, observational, single country (Greece)
• Arms:
  • MM patients
  • Healthy control patients of similar age and gender
• Inclusion criteria: ≥18 years; presence of MGUS; active MM or sMM; vaccination eligibility as determined by the IMS.
• Exclusion criteria: end stage renal disease; HIV or active hepatitis B and C infection; an autoimmune disorder or active malignant disease, previous hospitalization due to allergy (anaphylaxis); prior diagnosis of COVID-19.
• Primary endpoint: NAb development against SARS-CoV-2 on day 22 (D22) and on day 50 (D50)
• NAbs were measured by ELISA from serum collected on day 1 (D1; before first BNT162b2 dose or AZD1222 dose), D22 (before second BNT162b2 dose or 3 weeks after the first AZD1222 dose), and D50 (4 weeks after the second dose of the BNT16b2 or 7 weeks after the first AZD1222 dose).

Results

Patient Characteristics

• The study population included 276 patients with plasma cell neoplasms and 226 healthy controls who were matched for age and gender.
  • In the MM patient arm, 215 (77.8%) received the BNT162b2 vaccine and 61 (22.1%) received the AZD1222 vaccine.
  • In the control arm, 171 (75.66%) received the BNT162b2 vaccine and 55 (24.34%) received the AZD1222 vaccine (P=0.56).
• Baseline MM patient and disease characteristics are summarized in Table: Patient Baseline Characteristics.

Efficacy

• At baseline on D1, there were no differences in NAb titers between MM patients and healthy controls (P=0.7).
• On D22, there was no difference between patients who were vaccinated with BNT162b2 or AZD1222 in NAb titer values or the number of patients who developed NAb titers ≥30% (positive titer) or ≥50% (clinically relevant viral inhibition).
• On D22 and D50, MM patients presented with lower NAb titers compared to healthy controls. NAb results are summarized in Table: NAb Titers on Day 22 and Day 50.

• Of the 158 MM patients who developed clinically relevant responses at D50 (NAb titer ≥50%), 114 had symptomatic MM (on treatment, n=91; in remission and not receiving treatment, n=23).
• Of the 65 symptomatic MM patients with low response at D50 (NAb titer <30%), 63 were on treatment and 2 were off treatment. Type of treatment and NAb titer response rates are presented in Table: MM Treatment for NAb Responders and Non-responders at Day 50.

• There was no significant difference in NAb production among treatment types on D22.
• On D50, patients who were receiving anti-CD38-based combinations achieved significantly lower NAb responses (mean±SD, 45.4%±29.4%) compared to patients not receiving treatment (mean±SD, 66%±25.4%; P=0.013).
• Median NAb titer on day 50 for patients receiving belantamab/anti-CD38 treatment (31.9%; IQR, 18.9-69) was lower compared to those receiving other treatment regimens (62.8%; IQR, 26-88.3) and those who were not receiving treatment (64.6%; IQR, 47.6-90.8).
• Treatment with anti-CD38 combinations was a significant predictive factor for lower antibody response (OR, 2.9; 95% CI, 1.2-7.1; P=0.002).
• There was a non-significant increased risk for poor NAb response after COVID-19 vaccination with anti-CD38-based regimens (OR, 2.4; 95% CI 2.9-6.2; P=0.07).

Safety

• Presence of adverse events (AEs) was independent of disease status or active treatment.
• Seventy-one (33%) and 68 (31.6%) patients experienced mild reactions after the first and second dose of the BNT162b2 vaccine, respectively.
  • Twenty-eight (13%) and 45 (21%) patients experienced grade 1/2 systemic adverse reactions which included fatigue, fever, lymphadenopathy, muscle pain, arthralgias, and headache.  
• Twenty (32.8%) patients experienced local reactions after the first dose of AZD1222, with the most frequent being pain at injection site, erythema, and/or swelling.

Anti-SARS-CoV-2 NAbs after the First Dose of the BNT162b2 Vaccine in Patients With MM

Terpos et al (April 2021)¹⁵ reported the results from an ongoing, large, prospective study (clinicaltrials.gov identifier: NCT04743388) evaluating the development of anti-SARS-CoV-2 NAbs after the first dose of the BNT162b2 vaccination in MM patients.  

Study Design/Methods

• Primary endpoint: NAb development against SARS-CoV-2 on D22  
• NAbs were measured by ELISA from serum collected on D1 (before first BNT162b2 dose) and D22 (before second BNT162b2 dose).

Results

Patient Characteristics

• The study population included 48 MM patients and 104 healthy controls who were vaccinated at the same vaccination center during the same time period.
• Baseline patient demographics and disease characteristics are presented in Table: Patient Baseline Characteristics.

• At baseline on D1, there were no differences in NAb titers between MM patients and healthy controls; all titers were ≤30%.
• On D22, MM patients presented with lower NAb titers compared to the control arm. NAb details are presented in Table: NAb Titers on Day 22.
  • On D22, 28.2% (n=11) of patients with active MM developed NAb titers ≥30% compared to 54.8% healthy controls (n=57)
• Four MM patients developed clinically relevant viral inhibition (NAb titers ≥50%) while in remission without receiving anti-myeloma therapy. These patients had normal levels of uninvolved immunoglobulins after anti-myeloma treatment with bortezomib, lenalidomide and dexamethasone (n=3) and lenalidomide and dexamethasone (n=1).
• No other correlation was observed between anti-myeloma treatment given and NAb titer level on D22.
• Data specifically for DARZALEX-treated patients was not reported.

Seropositivity Rate after Two Doses of BNT162b2 Vaccine in Patients With MM

• Avivi et al (2021)¹⁶ reported the results from a single-center, prospective study evaluating
• serological response of MM patients compared to healthy volunteers 14-21 days post second
• dose of BNT162b2.

Study Design/Methods

• Prospective, single center study in Israel.
• Primary endpoint: The seropositivity rate achieved after BNT162b2 vaccine assessed by measuring the anti-SARS-CoV-2S antibody titer pre- and post-vaccination.
• Inclusion Criteria: active or sMM, >18 years, received 2 consecutive vaccines, and visited the Hematology division at Tel Aviv Sourasky Medical Center (TAMSC) between 23 December 2020 and 17 March 2021.
• Patients treated with DARZALEX single agent or in combination with IMiD and/or PI were advised to have a 14-day gap between their last DARZALEX dose and vaccination (adjusting DARZALEX schedule with possible delays).
• Blood samples for serological test for both patients and healthy controls were drawn 14-21 days after second vaccine and were analyzed using Elecsys^® Anti-SARS-CoV-2S immunoassay.

Results

Patient Characteristics

• The study evaluated 171 MM patients (active MM, n=159; sMM, n=12) and 64 healthy volunteers, from December 30 to March 2021.
• Median follow-up period was 107 (range, 78-121) days from second COVID-19 vaccine, and none of the MM patients developed COVID-19 infection.
• Baseline patient demographics and disease characteristics are presented in Table: Patient Baseline Characteristics.

Efficacy

• Humoral response to BNT162b2 was achieved in 78% (n=133) of MM patients vs 98% (n=63) of healthy volunteers (P=0.000132).
• Univariate analyses showed time on DARZALEX-based therapy was not related to seropositive response.
• Lower response rates (69% vs 81%) were observed in patients receiving DARZALEX-containing regimens (OR, 0.52; 95% CI, 0.25-1.02; P=0.08).
• Seropositive responses by treatment regimens were achieved in 75% (18/24) of patients receiving DARZALEX + lenalidomide + dexamethasone and 63% (12/19) of patients receiving DARZALEX + dexamethasone.

Safety

• All AEs to the vaccine among MM and healthy patients were reported as transient and grade 1/2.
  • Ninety of 161 (53%) MM patients and 29 of 53 (55%) healthy volunteers experienced at least one AE related to the vaccination, with the most frequent AE in both cohorts being pain in the injection site and fatigue.

Immunogenicity of BNT162b2 Vaccine in Patients With MM on Active Treatment

Pimpinelli et al (2021)¹⁷ evaluated the safety and immunogenicity of a BNT162b2 vaccine by measuring antibody titers, seroconversion rates, and trend in patients with solid cancers and hematological malignancies (including MM), elderly subjects aged >80 years and health workers.

Study Design/Methods

• A prospective, cohort study, single-center study
• Neutralizing IgG titers anti-SARS-CoV-2 was evaluated at basal (day 0, first injection, timepoint [TP] 0), after 3 weeks (day 21, second injection, TP1) and 2 weeks post-booster (day 35, TP2). Subsequently, titration TP is expected at 12 (TP3), 24 (TP4), and 52 (TP5) weeks from the first injection.
• All patients were asked to provide nose and throat swabs on each defined TP and in a small sample also peripheral blood mononuclear cells from subsequent studies of T cell response.
• Analysis was focused on patients with MM who received the first vaccine injection on March 2, 9, 16, or 24, 2021 (half-day weekly slots were dedicated to hematological patients) and for whom all tests’ results at each of the first four TPs were available.
• BNT162b2 was given 30 mcg per dose, in 2 doses 3-weeks apart.
• Arms:
  • MM patients (n=42)
  • Patient aged >80 years not suffering from cancer who had completed sampling on TP2 (n=36)
• There were 14 MM patients who received DARZALEX.

Results

• In univariate analysis, patients with MM, on TP2, the likelihood of response was significantly associated with the type of treatment.
  • DARZALEX in combination with lenalidomide was significantly associated with a lower response rate compared to patients on active treatment with PI-based and IMiDs-based therapies, alone or in combination (without DARZALEX) (50% [7/14] vs 92.9% [26/28]; P=0.003).

Literature SearcH

A literature search of MEDLINE^®, Embase^®, BIOSIS Previews^®, and Derwent Drug File (and/or other resources, including internal/external databases) was conducted on 22 January 2025.