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Bispecific antibody therapies targeting BCMA (B-cell maturation antigen) represent a novel therapeutic approach for patients with multiple myeloma. They are currently used in cases of refractory multiple myeloma but are also being investigated in earlier lines of treatment. However, these new therapies can lead to deeper immunosuppression and exacerbate an underlying immunosuppressive state in patients with multiple myeloma. As a result, infectious complications are common with these therapies and are a significant concern. Therefore, preventing infections in this population is crucial. However, data on the best strategies for prevention are currently lacking.
Although the effectiveness of immunoglobulins (Ig) has been demonstrated, it remains to be determined whether immunoglobulin administration is necessary for all patients receiving these therapies or only for those with low serum immunoglobulin G (IgG) levels. Furthermore, the optimal target IgG level to achieve in order to reduce the risk of infections is also unknown in this specific population of multiple myeloma patients. Guidance needs to be provided to the clinicians to better support MM patients undergoing this novel therapy by addressing the hypogammaglobulinemia and therefore limiting and ideally avoiding the high risk of infections.
In this prospective, randomized, unblinded, multicenter study, as per the standard of care approach, every patient with relapsed refractory MM receiving a BCMA-directed TCE with history of recurrent or severe infections and/or total IgG level less than 4 g/L will receive Ig support (intravenous ou subcutaneous). Once on Ig supplementation, the optimal target trough IgG level to achieve is not well established. The goal of this study is therefore to better define, in this patient population , the target trough IgG level to achieve a reduction in the incidence of severe infections.
The primary objective is to demonstrate the non-inferiority in the cumulative incidence of severe infections at 3 months between patients on Ig support with a target trough IgG level of 4-6 g/L (experimental group) versus a target trough IgG level of 8-10 g/L (standard of care (SOC) group).
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| Label | Type | Description | Intervention Names |
|---|---|---|---|
| Group A IgG level 8-10 g/L | Active Comparator | Immunoglobulin support (subcutaneous or intravenous) |
|
| Group B IgG level 4-6 g/L | Experimental | Immunglobulin support (subcutaneous or intravenous) |
|
| Group C | Other | No immunoglobulin support. If pre specified conditions are met, crossover to Group A or B. |
|
| Name | Type | Description | Arm Group Labels | Other Names |
|---|---|---|---|---|
| Target trough IgG level of 8-10 g/L | Drug | Target trough IgG level of 8-10 g/L |
|
| Measure | Description | Time Frame |
|---|---|---|
| Severe infections | Non-inferiority in the cumulative incidence of severe infections at 3 months between patients on Ig support with a target trough IgG level of 4-6 g/L (experimental group) versus a target trough IgG level of 8-10 g/L (standard of care group) | From enrollment to 3 months after time of randomization |
| Measure | Description | Time Frame |
|---|---|---|
| Minor/Moderate infections rate | Rates of minor/moderate infection rates | From enrollment to 12 monts after randomization |
| All infection rate | All infections rate |
| Measure | Description | Time Frame |
|---|---|---|
| Vaccinal response (optional) | For patients with no previous Ig support, we will examine the vaccinal response with specific antibody titers to tetanus. | From vaccination (at enrollment) to 1 month after vaccination. |
| CM reactivation and infection rate |
Inclusion Criteria:
Exclusion Criteria:
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| Name | Role | Phone | Extension | |
|---|---|---|---|---|
| Philippe Nadeau, PhD | Contact | 1-418-525-4444 | 67324 | philippe.nadeau@chudequebec.ca |
| Name | Affiliation | Role |
|---|---|---|
| Dr Julie Côté, MD,FRCPC | CHU de Québec-Université Laval | Study Chair |
| Dr Julie Côté, MD,FRCPC | CHU de Québec-Université Laval | Principal Investigator |
| Dr Vincent Laroche, MD,FRCPC |
| Facility | Status | City | State | ZIP | Country | Contacts |
|---|---|---|---|---|---|---|
| Centre Intégré de Cancérologie | Recruiting | Québec | Quebec | Canada |
| PubMed Identifier | Type | Citation | Retractions |
|---|---|---|---|
| 38443345 | Background | Mohan M, Monge J, Shah N, Luan D, Forsberg M, Bhatlapenumarthi V, Balev M, Patwari A, Cheruvalath H, Bhutani D, Thanendrarajan S, Dhakal B, Zangari M, Al-Hadidi S, Cooper D, Lentzsch S, van Rhee F, D'Souza A, Szabo A, Schinke C, Chakraborty R. Teclistamab in relapsed refractory multiple myeloma: multi-institutional real-world study. Blood Cancer J. 2024 Mar 5;14(1):35. doi: 10.1038/s41408-024-01003-z. | |
| 24682509 |
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Of note, patients in Group C will crossover to Group A or B once meeting the pre specified conditions.
Stratified randomization with block design by site.
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| Target trough IgG level 4-6 g/L | Drug | Target trough IgG level of 4-6 g/L |
|
|
| No history of recurrent or severe infections and total IgG level higher or equal at 4 g/L | Drug | If, during follow-up, the patient presents recurrent or severe infections and/or total IgG level less 4 g/L, crossover to group A or B |
|
|
| From enrollment to 12 months after randomization |
CMV reactivation and infection
| From enrollment to 12 months after randomization |
| Adverse events related to the administration of the Ig product | Adverse events related to the administration of the Ig product | From enrollment to 12 months after randomization |
| Quality of life assessment, according to the EORTC-QLQ-C30 | Quality of life assessment (SC and IV) | From enrollment to 12 months after randomization |
| CHU de Québec-Université Laval |
| Principal Investigator |
| Background |
| Compagno N, Cinetto F, Semenzato G, Agostini C. Subcutaneous immunoglobulin in lymphoproliferative disorders and rituximab-related secondary hypogammaglobulinemia: a single-center experience in 61 patients. Haematologica. 2014 Jun;99(6):1101-6. doi: 10.3324/haematol.2013.101261. Epub 2014 Mar 28. |
| 15480339 | Background | Gardulf A, Nicolay U, Math D, Asensio O, Bernatowska E, Bock A, Costa-Carvalho BT, Granert C, Haag S, Hernandez D, Kiessling P, Kus J, Matamoros N, Niehues T, Schmidt S, Schulze I, Borte M. Children and adults with primary antibody deficiencies gain quality of life by subcutaneous IgG self-infusions at home. J Allergy Clin Immunol. 2004 Oct;114(4):936-42. doi: 10.1016/j.jaci.2004.06.053. |
| 23040368 | Background | Ducruet T, Levasseur MC, Des Roches A, Kafal A, Dicaire R, Haddad E. Pharmacoeconomic advantages of subcutaneous versus intravenous immunoglobulin treatment in a Canadian pediatric center. J Allergy Clin Immunol. 2013 Feb;131(2):585-7.e1-3. doi: 10.1016/j.jaci.2012.08.022. Epub 2012 Oct 2. No abstract available. |
| 23167310 | Background | Martin A, Lavoie L, Goetghebeur M, Schellenberg R. Economic benefits of subcutaneous rapid push versus intravenous immunoglobulin infusion therapy in adult patients with primary immune deficiency. Transfus Med. 2013 Feb;23(1):55-60. doi: 10.1111/j.1365-3148.2012.01201.x. Epub 2012 Nov 20. |
| 28041678 | Background | Perez EE, Orange JS, Bonilla F, Chinen J, Chinn IK, Dorsey M, El-Gamal Y, Harville TO, Hossny E, Mazer B, Nelson R, Secord E, Jordan SC, Stiehm ER, Vo AA, Ballow M. Update on the use of immunoglobulin in human disease: A review of evidence. J Allergy Clin Immunol. 2017 Mar;139(3S):S1-S46. doi: 10.1016/j.jaci.2016.09.023. Epub 2016 Dec 29. |
| 17402794 | Background | Gardulf A. Immunoglobulin treatment for primary antibody deficiencies: advantages of the subcutaneous route. BioDrugs. 2007;21(2):105-16. doi: 10.2165/00063030-200721020-00005. |
| 23835249 | Background | Stiehm ER. Adverse effects of human immunoglobulin therapy. Transfus Med Rev. 2013 Jul;27(3):171-8. doi: 10.1016/j.tmrv.2013.05.004. Epub 2013 Jul 6. |
| 33453130 | Background | Jolles S, Michallet M, Agostini C, Albert MH, Edgar D, Ria R, Trentin L, Levy V. Treating secondary antibody deficiency in patients with haematological malignancy: European expert consensus. Eur J Haematol. 2021 Apr;106(4):439-449. doi: 10.1111/ejh.13580. Epub 2021 Feb 2. |
| 35176351 | Background | Otani IM, Lehman HK, Jongco AM, Tsao LR, Azar AE, Tarrant TK, Engel E, Walter JE, Truong TQ, Khan DA, Ballow M, Cunningham-Rundles C, Lu H, Kwan M, Barmettler S. Practical guidance for the diagnosis and management of secondary hypogammaglobulinemia: A Work Group Report of the AAAAI Primary Immunodeficiency and Altered Immune Response Committees. J Allergy Clin Immunol. 2022 May;149(5):1525-1560. doi: 10.1016/j.jaci.2022.01.025. Epub 2022 Feb 14. |
| 29951056 | Background | Guo Y, Tian X, Wang X, Xiao Z. Adverse Effects of Immunoglobulin Therapy. Front Immunol. 2018 Jun 8;9:1299. doi: 10.3389/fimmu.2018.01299. eCollection 2018. |
| 20675197 | Background | Orange JS, Grossman WJ, Navickis RJ, Wilkes MM. Impact of trough IgG on pneumonia incidence in primary immunodeficiency: A meta-analysis of clinical studies. Clin Immunol. 2010 Oct;137(1):21-30. doi: 10.1016/j.clim.2010.06.012. Epub 2010 Aug 1. |
| 32417999 | Background | Lee JL, Mohamed Shah N, Makmor-Bakry M, Islahudin FH, Alias H, Noh LM, Mohd Saffian S. A Systematic Review and Meta-regression Analysis on the Impact of Increasing IgG Trough Level on Infection Rates in Primary Immunodeficiency Patients on Intravenous IgG Therapy. J Clin Immunol. 2020 Jul;40(5):682-698. doi: 10.1007/s10875-020-00788-5. Epub 2020 May 16. |
| 37528088 | Background | Raje N, Anderson K, Einsele H, Efebera Y, Gay F, Hammond SP, Lesokhin AM, Lonial S, Ludwig H, Moreau P, Patel K, Ramasamy K, Mateos MV. Monitoring, prophylaxis, and treatment of infections in patients with MM receiving bispecific antibody therapy: consensus recommendations from an expert panel. Blood Cancer J. 2023 Aug 1;13(1):116. doi: 10.1038/s41408-023-00879-7. |
| 38052042 | Background | Frerichs KA, Verkleij CPM, Mateos MV, Martin TG, Rodriguez C, Nooka A, Banerjee A, Chastain K, Perales-Puchalt A, Stephenson T, Uhlar C, Kobos R, van der Holt B, Kruyswijk S, Kuipers MT, Groen K, Vishwamitra D, Skerget S, Cortes-Selva D, Doyle M, Zaaijer HL, Zweegman S, Verona RI, van de Donk NWCJ. Teclistamab impairs humoral immunity in patients with heavily pretreated myeloma: importance of immunoglobulin supplementation. Blood Adv. 2024 Jan 9;8(1):194-206. doi: 10.1182/bloodadvances.2023011658. |
| 37769148 | Background | Lancman G, Parsa K, Kotlarz K, Avery L, Lurie A, Lieberman-Cribbin A, Cho HJ, Parekh SS, Richard S, Richter J, Rodriguez C, Rossi A, Sanchez LJ, Thibaud S, Jagannath S, Chari A. IVIg Use Associated with Ten-Fold Reduction of Serious Infections in Multiple Myeloma Patients Treated with Anti-BCMA Bispecific Antibodies. Blood Cancer Discov. 2023 Nov 1;4(6):440-451. doi: 10.1158/2643-3230.BCD-23-0049. |
| 37582952 | Background | Lesokhin AM, Tomasson MH, Arnulf B, Bahlis NJ, Miles Prince H, Niesvizky R, Rodriotaguez-Otero P, Martinez-Lopez J, Koehne G, Touzeau C, Jethava Y, Quach H, Depaus J, Yokoyama H, Gabayan AE, Stevens DA, Nooka AK, Manier S, Raje N, Iida S, Raab MS, Searle E, Leip E, Sullivan ST, Conte U, Elmeliegy M, Czibere A, Viqueira A, Mohty M. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results. Nat Med. 2023 Sep;29(9):2259-2267. doi: 10.1038/s41591-023-02528-9. Epub 2023 Aug 15. |
| 35661166 | Background | Moreau P, Garfall AL, van de Donk NWCJ, Nahi H, San-Miguel JF, Oriol A, Nooka AK, Martin T, Rosinol L, Chari A, Karlin L, Benboubker L, Mateos MV, Bahlis N, Popat R, Besemer B, Martinez-Lopez J, Sidana S, Delforge M, Pei L, Trancucci D, Verona R, Girgis S, Lin SXW, Olyslager Y, Jaffe M, Uhlar C, Stephenson T, Van Rampelbergh R, Banerjee A, Goldberg JD, Kobos R, Krishnan A, Usmani SZ. Teclistamab in Relapsed or Refractory Multiple Myeloma. N Engl J Med. 2022 Aug 11;387(6):495-505. doi: 10.1056/NEJMoa2203478. Epub 2022 Jun 5. |
| ID | Term |
|---|---|
| D009101 | Multiple Myeloma |
| ID | Term |
|---|---|
| D054219 | Neoplasms, Plasma Cell |
| D009370 | Neoplasms by Histologic Type |
| D009369 | Neoplasms |
| D020141 | Hemostatic Disorders |
| D014652 | Vascular Diseases |
| D002318 | Cardiovascular Diseases |
| D010265 | Paraproteinemias |
| D001796 | Blood Protein Disorders |
| D006402 | Hematologic Diseases |
| D006425 | Hemic and Lymphatic Diseases |
| D006474 | Hemorrhagic Disorders |
| D008232 | Lymphoproliferative Disorders |
| D007160 | Immunoproliferative Disorders |
| D007154 | Immune System Diseases |
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| ID | Term |
|---|---|
| D059039 | Standard of Care |
| D003434 | Crossing Over, Genetic |
| ID | Term |
|---|---|
| D019984 | Quality Indicators, Health Care |
| D011787 | Quality of Health Care |
| D006298 | Health Services Administration |
| D017530 | Health Care Quality, Access, and Evaluation |
| D059765 | Homologous Recombination |
| D011995 | Recombination, Genetic |
| D055614 | Genetic Phenomena |
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