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Patients with multiple myeloma frequently present with substantial immune impairment and an increased risk for infections and infection-related mortality. The risk for infection with SARS-CoV-2 virus and resulting mortality is also increased, emphasising the importance of protecting patients by vaccination. Available data in patients with multiple myeloma suggest a suboptimal anti-SARS-CoV-2 immune response, meaning a proportion of patients are unprotected. Factors associated with poor response are uncontrolled disease, immunosuppression, concomitant therapy, more lines of therapy, and CD38 antibody-directed and B-cell maturation antigen-directed therapy. These facts suggest that monitoring the immune response to vaccination in patients with multiple myeloma might provide guidance for clinical management, such as administration of additional doses of the same or another vaccine, or even temporary treatment discontinuation, if possible. In those who do not exhibit a good response, prophylactic treatment with neutralising monoclonal antibody cocktails might be considered. In patients deficient of a SARS-CoV-2 immune response, adherence to measures for infection risk reduction is particularly recommended. This consensus was generated by members of the European Multiple Myeloma Network and some external experts. The panel members convened in virtual meetings and conducted an extensive literature research and evaluated recently published data and work presented at meetings, as well as findings from their own studies. The outcome of the discussions on establishing consensus recommendations for COVID-19 vaccination in patients with multiple myeloma was condensed into this Review., Competing Interests: Declaration of interests HL declares research funding from Amgen and Takeda, and speaker's honoraria from and participation on advisory boards for Amgen, Takeda, Sanofi, Janssen, Celgene-Bristol Myers Squibb, and Seattle Genetics. PS declares research funding from Amgen, Celgene-Bristol Myers Squibb, Janssen, SkylineDx, and Takeda, and honoraria from and participation on advisory boards for Amgen, Celgene-Bristol Myers Squibb, Janssen, SkylineDx, and Takeda. TF declares participation on advisory boards for Janssen, Bristol Myers Squibb, Takeda, Amgen, Roche, Karyopharm, Oncopeptides, and Abbvie, and speaker's honoraria from Janssen and Bristol Myers Squibb. JS-M declares consulting fees from and participation on advisory boards for Amgen, Celgene-Bristol Myers Squibb, Janssen, MSD, Novartis, Takeda, Sanofi, Roche, Abbvie, GlaxoSmithKline, Regeneron, SecuraBio, and Karyopharm. M-VM declares honoraria from and participation on advisory boards for Janssen, Celgene-Bristol Myers Squibb, Takeda, Amgen, Sanofi, Oncopeptides, GlaxoSmithKline, Adaptive, Pfizer, Regeneron, Roche, Sea-Gen, and Blu Bird bio. PM declares honoraria from and participation on advisory boards for Janssen, Celgene-Bristol Myers Squibb, Amgen, Sanofi, and Abbvie. MC declares honoraria from Janssen, Celgene-Bristol Myers Squibb, GlaxoSmithKline, Amgen, Takeda, AbbVie, and Sanofi, and participation on advisory boards for Janssen, Celgene-Bristol Myers Squibb, GlaxoSmithKline, Amgen, Takeda, AbbVie, and Sanofi. CP declares consultancy fees from Amgen, Takeda, Celgene-Bristol Myers Squibb, and Sanofi; travel support from Amgen, Takeda, Janssen, and Celgene-Bristol Myers Squibb; and honoraria from Janssen, Celgene-Bristol Myers Squibb, and Sanofi. SZ declares research funding from Takeda and Janssen, and participation on advisory boards for Takeda, Janssen, Sanofi, Bristol Myers Squibb, and Oncopeptides. ME declares honoraria from and participation on advisory boards for Amgen, Celgene-Bristol Myers Squibb, GlaxoSmithKline, Janssen, Karyopharm, Sanofi, and Takeda, and research funding from Amgen, Celgene-Bristol Myers Squibb, Janssen, Karyopharm, and Takeda. GC declares honoraria from and participation on advisory boards for Celgene-Bristol Myers Squibb, Takeda, GlaxoSmithKline, Sanofi, Amgen, Janssen, and Oncopeptides, and research funding from GlaxoSmithKline and Takeda. MAD declares participation on advisory boards for Amgen, Takeda, Bristol Myers Squibb, Janssen, and Beigene. FG declares honoraria from Amgen, Janssen, Takeda, Celgene-Bristol Myers Squibb, AbbVie, and GlaxoSmithKline, and participation on advisory boards for Amgen, Celgene-Bristol Myers Squibb, Janssen, Takeda, AbbVie, GlaxoSmithKline, Roche, Adaptive Biotechnologies, Oncopeptides, and Bluebird Bio. HE declares honoraria from Amgen, Celgene-Bristol Myers Squibb, Janssen, Takeda, GlaxoSmithKline, Sanofi, Novartis; consultancy fees from and participation on advisory boards for Amgen, Celgene-Bristol Myers Squibb, Janssen, Takeda, GlaxoSmithKline, Sanofi, and Novartis; and research funding from Amgen, Celgene-Bristol Myers Squibb, Janssen, Sanofi, and GlaxoSmithKline. MD declares speaker's honoraria and research funding from Amgen, Celgene-Bristol Myers Squibb, Janssen, Sanofi, and Takeda. KW declares research funding from Amgen, Celgene-Bristol Myers Squibb, Janssen, and Sanofi, and honoraria from Amgen, Abbvie, Adaptive Biotech, Celgene-Bristol Myers Squibb, Janssen, Karyopharm, Novartis, Oncopeptides, Roche Pharma, Takeda, and Sanofi. GJ declares speaker's honoraria from and participation on advisory boards for Celgene-Bristol Myers Squibb, Takeda, GlaxoSmithKline, Sanofi, Amgen, Johnson & Johnson, and Oncopeptides, and research funding from Celgene-Bristol Myers Squibb and Takeda. LG declares participation on advisory boards for Amgen, Takeda, Celgene-Bristol Myers Squibb, and Janssen. NvdD declares research funding from Janssen Pharmaceuticals, Amgen, Celgene-Bristol Myers Squibb, Novartis, and Cellectis, and participation on advisory boards for Janssen Pharmaceuticals, Amgen, Celgene-Bristol Myers Squibb, Takeda, Roche, Novartis, Bayer, Servier, GlaxoSmithKline, and Sanofi. XL declares honoraria from Janssen-Cilag, Celgene-Bristol Myers Squibb, Amgen, Novartis, Takeda, Sanofi, Abbvie, Merck, Roche, Karyopharm Therapeutics, Carsgen Therapeutics, Oncopeptides, and GlaxoSmithKline; consulting and advisory roles for Janssen-Cilag, Celgene-Bristol Myers Squibb, Amgen, Takeda, Novartis, Merck, Gilead Sciences, Abbvie, Roche, Karyopharm Therapeutics, Oncopeptides, Carsgen Therapeutics, and GlaxoSmithKline; travel fees from Accommodations; and expenses from Takeda. HG declares grants and provision of Investigational Medicinal Product Amgen, Celgene-Bristol Myers Squibb, Chugai, Janssen, and Sanofi; research support from Amgen, Celgene-Bristol Myers Squibb, Chugai, Janssen, Incyte, Molecular Partners, MSD, Sanofi, Mundipharma GmbH, Takeda, and Novartis; participation on advisory boards for Adaptive Biotechnology, Amgen, Celgene-Bristol Myers Squibb, Janssen, Sanofi, and Takeda; and honoraria from Amgen, Celgene-Bristol Myers Squibb, Chugai, GlaxoSmithKline, Janssen, Novartis, and Sanofi. MeB declares participation on advisory boards for Amgen, Celgene-Bristol Myers Squibb, Janssen, Sanofi, Takeda, and Oncopeptides, and speaker's honoraria from Amgen, Celgene-Bristol Myers Squibb, Janssen, Sanofi, and Takeda. IN declares Advisory Boards and Honoraria: Amgen, Janssen, Celgene-Bristol Myers Squibb. MS declares speaker's honoraria and participation on advisory boards for Celgene-Bristol Myers Squibb, Amgen, Takeda, Janssen, and GlaxoSmithKline. NA declares research funding from Celgene-Bristol Myers Squibb, Amgen, Janssen, and Takeda. RH declares consultancy fees from and participation on advisory boards for Janssen, Amgen, AbbVie, Bristol Myers Squibb, Novartis, PharmaMar, and Takeda; honoraria from Janssen, Amgen, Bristol Myers Squibb, PharmaMar, and Takeda; and research funding from Janssen, Amgen, Bristol Myers Squibb, Novartis, and Takeda. NZ declares speaker's honoraria and participation on advisory boards for Celgene-Bristol Myers Squibb, Amgen, Takeda, Janssen, and Sanofi. EK declares consultancy fees and honoraria from and participation on advisory boards for Amgen, Genesis Pharma, Takeda, Janssen, and Pfizer Sanofi. AB declares honoraria from and participation on advisory boards for Amgen, Janssen, Celgene-Bristol Myers Squibb, and Sanofi. FS declares honoraria from Amgen, Celgene, Janssen, MSD, Novartis, Oncopeptides, Sanofi, SkyliteDX, and Takeda, and membership on an entity's advisory committees for Amgen, Celgene-Bristol Myers Squibb, Janssen, MSD, Novartis, Oncopeptides, Sanofi, and Takeda. MaB declares honoraria from Sanofi, Celgene-Bristol Myers Squibb, Amgen, Janssen, Novartis, and AbbVie; participation on advisory boards for Janssen and GlaxoSmithKline; and research funding from Sanofi, Celgene-Bristol Myers Squibb, Amgen, Janssen, Novartis, and Mundipharma. ET declares consultancy fees and honoraria from Amgen, Celgene-Bristol Myers Squibb, Janssen, Takeda, Genesis Pharma, GlaxoSmithKline, and Sanofi, and research support from Amgen, Janssen, Celgene-Bristol Myers Squibb, Genesis Pharma, GlaxoSmithKline, and Sanofi. HA-L, MM, CD, and JC declare no competing interests., (Crown Copyright © 2021 Published by Elsevier Ltd. All rights reserved.)

Background: Pomalidomide and dexamethasone is a standard of care for patients with multiple myeloma in whom bortezomib and lenalidomide treatment has failed. KEYNOTE-183 assessed efficacy and safety of pomalidomide and dexamethasone with or without pembrolizumab in patients with relapsed or refractory multiple myeloma. Here, we present the findings of an unplanned, ad-hoc interim analysis at the request of the US Food and Drug Administration (FDA)., Methods: KEYNOTE-183 was a randomised, open-label, phase 3 trial done at 97 medical centres across 11 countries (Australia, Canada, France, Germany, Israel, Italy, Japan, New Zealand, Norway, Spain, and USA). Patients aged at least 18 years with multiple myeloma, an Eastern Cooperative Oncology Group (ECOG) performance status 0 or 1, previously treated with at least two lines of therapy (excluding pomalidomide) and refractory to the last line were randomly assigned 1:1 to the pembrolizumab plus pomalidomide and dexamethasone group or the pomalidomide and dexamethasone group via an interactive voice response or integrated web response system. Patients received oral pomalidomide 4 mg daily on days 1-21 and oral low-dose dexamethasone 40 mg on days 1, 8, 15, and 22 in 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The dual primary endpoints were progression-free survival and overall survival. Efficacy was assessed in all randomly assigned patients and safety was assessed in patients who received at least one dose of study treatment. The trial is registered at ClinicalTrials.gov, number NCT02576977, and it is closed for accrual., Findings: Between Jan 18, 2016, and June 7, 2017, 249 patients were randomly assigned to either the pembrolizumab plus pomalidomide and dexamethasone group (n=125) or the pomalidomide and dexamethasone group (n=124). On July 3, 2017, the FDA established that risks associated with the triple combination outweighed benefits and halted the study. Median follow-up was 8·1 months (IQR 4·5-10·9). Median progression-free survival was 5·6 months (95% CI 3·7-7·5) in the pembrolizumab plus pomalidomide and dexamethasone group versus 8·4 months (5·9-not reached) in the pomalidomide and dexamethasone group; progression-free survival estimates at 6 months were 48% (95% CI 37-58) versus 60% (49-69) at 6 months (hazard ratio [HR] 1·53; 95% CI 1·05-2·22; p=0·98). Median overall survival was not reached (95% CI 12·9-not reached) versus 15·2 months (12·7-not reached; HR 1·61; 95% CI 0·91-2·85; p=0·95); overall survival estimates at 6 months were 82% (95% CI 74-88) versus 90% (82-95). Serious adverse events occurred in 75 (63%) of 120 patients in the pembrolizumab plus pomalidomide and dexamethasone group versus 56 (46%) of 121 patients in the pomalidomide and dexamethasone group. Four (3%) treatment-related deaths occurred in the pembrolizumab plus pomalidomide and dexamethasone group (one each of unknown cause, neutropenic sepsis, myocarditis, and Stevens-Johnson syndrome); myocarditis and Stevens-Johnson syndrome were considered related to pembrolizumab. No treatment-related deaths were reported in the pomalidomide and dexamethasone group., Interpretation: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus pomalidomide and dexamethasone is unfavourable for patients with relapsed or refractory multiple myeloma., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co (Kenilworth, NJ, USA)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: Lenalidomide and dexamethasone has been a standard of care in transplant-ineligible patients with newly diagnosed multiple myeloma. The addition of a third drug to the combination is likely to improve treatment efficacy. KEYNOTE-185 assessed the efficacy and safety of lenalidomide and dexamethasone with and without pembrolizumab in patients with previously untreated multiple myeloma. Here, we present the results of an unplanned interim analysis done to assess the benefit-risk of the combination at the request of the US Food and Drug Administration (FDA)., Methods: KEYNOTE-185 was a randomised, open-label, phase 3 trial done at 95 medical centres across 15 countries (Australia, Canada, France, Germany, Ireland, Israel, Italy, Japan, New Zealand, Norway, Russia, South Africa, Spain, UK, and USA). Transplantation-ineligible patients aged 18 years and older with newly diagnosed multiple myeloma, Eastern Cooperative Oncology Group performance status of 0 or 1, and who were treatment naive were enrolled, and randomly assigned 1:1 to receive either pembrolizumab plus lenalidomide and dexamethasone or lenalidomide and dexamethasone alone using an interactive voice or integrated web response system. Patients received oral lenalidomide 25 mg on days 1-21 and oral dexamethasone 40 mg on days 1, 8, 15, and 22 of repeated 28-day cycles, with or without intravenous pembrolizumab 200 mg every 3 weeks. The primary endpoint was progression-free survival, which was investigator-assessed because of early trial termination. Efficacy was analysed in all randomly assigned patients and safety was analysed in all patients who received at least one dose of study drug. This trial is registered at ClinicalTrials.gov, number NCT02579863, and it is closed for accrual., Findings: Between Jan 7, 2016, and June 9, 2017, 301 patients were randomly assigned to the pembrolizumab plus lenalidomide and dexamethasone group (n=151) or the lenalidomide and dexamethasone group (n=150). On July 3, 2017, the FDA decided to halt the study because of the imbalance in the proportion of death between groups. At database cutoff (June 2, 2017), with a median follow-up of 6·6 months (IQR 3·4-9·6), 149 patients in the pembrolizumab plus lenalidomide and dexamethasone group and 145 in the lenalidomide and dexamethasone group had received their assigned study drug. Median progression-free survival was not reached in either group; progression-free survival estimates at 6-months were 82·0% (95% CI 73·2-88·1) versus 85·0% (76·8-90·5; hazard ratio [HR] 1·22; 95% CI 0·67-2·22; p=0·75). Serious adverse events were reported in 81 (54%) patients in the pembrolizumab plus lenalidomide and dexamethasone group versus 57 (39%) patients in the lenalidomide and dexamethasone group; the most common serious adverse events were pneumonia (nine [6%]) and pyrexia (seven [5%]) in the pembrolizumab plus lenalidomide and dexamethasone group and pneumonia (eight [6%]) and sepsis (two [1%]) in the lenalidomide and dexamethasone group. Six (4%) treatment-related deaths occurred in the pembrolizumab plus lenalidomide and dexamethasone group (cardiac arrest, cardiac failure, myocarditis, large intestine perforation, pneumonia, and pulmonary embolism) and two (1%) in the lenalidomide and dexamethasone group (upper gastrointestinal haemorrhage and respiratory failure)., Interpretation: The results from this unplanned, FDA-requested, interim analysis showed that the benefit-risk profile of pembrolizumab plus lenalidomide and dexamethasone is unfavourable for patients with newly diagnosed, previously untreated multiple myeloma. Long-term safety and survival follow-up is ongoing., Funding: Merck Sharp & Dohme, a subsidiary of Merck & Co, Inc (Kenilworth, NJ, USA)., (Copyright © 2019 Elsevier Ltd. All rights reserved.)