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A randomized phase 2 trial of idiotype vaccination and adoptive autologous T-cell transfer in patients with multiple myeloma
Qazilbash, M. H., Saini, N. Y., Cha, S. C., Wang, Z., Stadtmauer, E. A., Baladandayuthapani, V., Lin, H., Tross, B., Honhar, M., Rao, S. S., et al
Blood. 2022;139(9):1289-1301
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Editor's Choice
Abstract
We hypothesized that combining adoptively transferred autologous T cells with a cancer vaccine strategy would enhance therapeutic efficacy by adding antimyeloma idiotype (Id)-keyhole limpet hemocyanin (KLH) vaccine to vaccine-specific costimulated T cells. In this randomized phase 2 trial, patients received either control (KLH only) or Id-KLH vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine. In 36 patients (KLH, n = 20; Id-KLH, n = 16), no dose-limiting toxicity was seen. At last evaluation, 6 (30%) and 8 patients (50%) had achieved complete remission in KLH-only and Id-KLH arms, respectively (P = .22), and no difference in 3-year progression-free survival was observed (59% and 56%, respectively; P = .32). In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH. In conclusion, in this combination immunotherapy approach, we observed significantly more robust IR in CD4+ and CD8+ T cells in the Id-KLH arm, supporting further investigation of vaccine and adoptive immunotherapy strategies. This trial was registered at www.clinicaltrials.gov as #NCT01426828.
PICO Summary
Population
Patients with newly diagnosed symptomatic MM with immunoglobulin G monoclonal protein, age ≤70 years, in two centres in USA (n=36)
Intervention
antimyeloma idiotype (Id)-keyhole limpet hemocyanin (KLH) vaccine vaccine, autologous transplantation, vaccine-specific costimulated T cells expanded ex vivo, and 2 booster doses of assigned vaccine (Id-KLH arm, n=16)
Comparison
Keyhole limpet hemocyanin (KLH) vaccine alone (KLH only arm, n=20)
Outcome
In a 594 Nanostring nCounter gene panel analyzed for immune reconstitution (IR), compared with patients receiving KLH only, there was a greater change in IR genes in T cells in those receiving Id-KLH relative to baseline. Specifically, upregulation of genes associated with activation, effector function induction, and memory CD8+ T-cell generation after Id-KLH but not after KLH control vaccination was observed. Similarly, in responding patients across both arms, upregulation of genes associated with T-cell activation was seen. At baseline, all patients had greater expression of CD8+ T-cell exhaustion markers. These changes were associated with functional Id-specific immune responses in a subset of patients receiving Id-KLH.
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Serological Response to Vaccination after Autologous Transplantation for Multiple Myeloma Is Associated with Improved Progression-Free and Overall Survival
Merz, A. M. A., Merz, M., Zhang, Y., Stecklein, K., Pleskow, J., Chen, G. L., Buck, D. A., Mohammadpour, H., Herr, M. M., Elshoury, A., et al
Transplantation and cellular therapy. 2021;27(3):245.e1-245.e8
Abstract
Revaccination after autologous hematopoietic cell transplantation (AHCT) is recommended in post-HCT survivorship guidelines to restore humoral immunity. Data on seroconversion after AHCT and vaccination in multiple myeloma (MM) patients are limited. We investigated the feasibility and effectiveness of vaccination post-AHCT and analyzed the restoration of humoral immunity and patient prognosis. Anti-pathogen titers were measured within a median of 2 days before and 96 days after AHCT and following revaccination in 139 MM patients who had a first AHCT from 2013 to 2016. Most (84%) patients received at least one dose of any planned vaccines. High-dose melphalan with AHCT restored measurable immunity in 18% of patients. In an additional >60% of patients, seroconversion occurred after vaccination; however, despite vaccination, 20% of patients remained seronegative for most pathogens. Attainment of MM complete response post-AHCT was associated with higher rates of seroconversion which yielded significantly longer progression-free and overall survival. Our study demonstrates the feasibility of post-AHCT vaccination, supporting measurement of post-vaccination titers to determine which patients should be considered for antimicrobial prophylaxis, as seroconversion does not occur in all patients. Titer seroconversion is a potential indicator of the immunological effects of AHCT, with restoration of humoral immunity demonstrating improved survival.
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Recommendations for vaccination in multiple myeloma: a consensus of the European Myeloma Network
Ludwig, H., Boccadoro, M., Moreau, P., San-Miguel, J., Cavo, M., Pawlyn, C., Zweegman, S., Facon, T., Driessen, C., Hajek, R., et al
Leukemia. 2020
Abstract
Vaccination is one of the most successful medical interventions that has saved the life of millions of people. Vaccination is particularly important in patients with multiple myeloma, who have an increased risk of infections due to the disease-inherent immune suppression, and because of the immune suppressive effects of therapy. Hence, all appropriate measures should be exploited, to elicit an effective immune response to common pathogens like influenza, pneumococci, varicella zoster virus, and to those bacteria and viruses (haemophilus influenzae, meningococci, and hepatitis) that frequently may pose a significant risk to patients with multiple myeloma. Patients after autologous, and specifically after allogeneic transplantation have severely reduced antibody titers, and therefore require a broader spectrum of vaccinations. Response to vaccination in myeloma often is less vigorous than in the general population, mandating either measurement of the postvaccination antibody titers and/or repeating the vaccination. Here, we compile the existing data on vaccination in multiple myeloma and provide recommendations for clinical practice.
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Revaccination after Autologous Hematopoietic Stem Cell Transplantation Is Safe and Effective in Patients with Multiple Myeloma Receiving Lenalidomide Maintenance
Palazzo, M., Shah, G. L., Copelan, O., Seier, K., Devlin, S. M., Maloy, M., Kenny, S., Hassoun, H., Korde, N. S., Lendvai, N., et al
Biology of blood and marrow transplantation : journal of the American Society for Blood and Marrow Transplantation. 2018;24(4):871-876
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Abstract
Guidelines recommend vaccination starting 12 months after autologous hematopoietic stem cell transplant (aHCT), but there is varying practice for patients on maintenance therapy, with some centers not immunizing at all. Because of decreased vaccine rates among the general population causing loss of herd immunity, we aimed to establish the safety and efficacy of revaccinating multiple myeloma patients on lenalidomide maintenance (LM). Of the 122 patients who were vaccinated after aHCT between 2010 and 2014 at Memorial Sloan Kettering Cancer Center, 91 (75%) were on LM. Vaccine responses were defined by increases between pre- and postvaccination titers. Reponses varied by vaccine type with 76% responding to pertussis, 70% diphtheria, 60% tetanus, 71% Haemophilus influenzae, and 58% pneumococcal. All patients retained minimal levels of polio immunity, but 27% responded with increased titers. Fewer patients received hepatitis A and B, but of those who did, 30% responded to hepatitis A and 40% to hepatitis B. No differences were seen in rates of response for those on LM at time of vaccination compared with those who were not. There were no vaccine-related adverse effects. Reimmunization with inactivated vaccines in patients on LM is therefore both safe and effective, offering this population immunity to vaccine-preventable diseases.
Clinical Commentary
What is known?
NIHMS1533942
What did this paper set out to examine?
What did they show?
What are the implications for practice and for future work?
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Safety of live-attenuated measles-mumps-rubella and herpes zoster vaccination in multiple myeloma patients on maintenance lenalidomide or bortezomib after autologous hematopoietic cell transplantation
Pandit, A., Leblebjian, H., Hammond, S. P., Laubach, J. P., Richardson, P. G., Baden, L. R., Marty, F. M., Issa, N. C.
Bone marrow transplantation. 2018
Abstract
Attenuated live virus vaccinations are generally recommended 24 months following hematopoietic cell transplantation (HCT) in patients not receiving immunosuppressive therapy. To date, there are no data regarding the safety of live-attenuated herpes zoster or measles-mumps-rubella (MMR) vaccinations in multiple myeloma patients on maintenance lenalidomide or bortezomib following autologous HCT. One hundred thirty-seven multiple myeloma patients on maintenance lenalidomide or bortezomib post-auto-HCT who received either MMR or herpes zoster vaccine were analyzed and any adverse events documented in the medical record in the 42 days following vaccination were recorded. Patients were vaccinated a median of 25 months (range, 18-62) post transplant. The most common post-vaccination adverse event was upper respiratory tract infection (18/137 patients); no rash attributed to vaccine strains or other adverse outcomes potentially related to the vaccines were identified. MMR and herpes zoster vaccination were safe and well-tolerated in this cohort.