Variation in Use of Immunoglobulin and Impact on Survival in Multiple Myeloma: A Report from the Australian and New Zealand Myeloma and Related Diseases Registry (MRDR)
Authors: Chai Khai Li , Wellard Cameron , Moore Elizabeth M. , Augustson Bradley , Bapat Akshay , Blacklock Hilary Anne , Cooke Rachel Elizabeth , Forsyth Cecily , Hamad Nada , Harrison Simon J , Ho Phoebe Joy , Hocking Jay , Kerridge Ian H. , King Tracy , McCaughan Georgia J , Mollee Peter , Morrissey Orla , Murphy Nicholas E. , Quach Hang , Tan Xuan Ni , Wong Kimberly , Spencer Andrew , Wood Erica M. , McQuilten Zoe 
Published: November 2021

Abstract
Introduction
Serious infection is common in patients with multiple myeloma (MM), and associated with major morbidity and mortality. Immunoglobulin (Ig) replacement is frequently used to reduce frequency and severity of infections, however evidence is based on small trials conducted &gt;20 years ago. Ig utilisation and associated costs in this patient cohort are rising worldwide.
In Australia (Aus), Ig for secondary hypogammaglobulinaemia is funded if total IgG is below lower limit of reference range with a history of recurrent or severe bacterial infection, or in severe hypogammaglobulinaemia (IgG &lt; 4 g/L excluding paraprotein). In New Zealand (NZ), patients generally require a history of recurrent infections and trial of oral antibiotics before commencing Ig.
This study aims to outline Ig use in the "real-world" MM setting, identify variation in and predictors of use, and describe association of Ig with survival outcomes.
Methods
Retrospective review of patients registered on the MRDR, a prospective registry established in 2012, currently open at &gt;60 sites across Aus/NZ.
Patients with a diagnosis of MM or plasma cell leukaemia with verifiable data regarding Ig use were included in this analysis. Ig use was confirmed using medical/laboratory records, national Aus Ig dispensing tool or the NZ Blood Service portal. Quality of survival outcomes and cause of death data was augmented via linkage with national death registries.
Baseline patient/disease characteristics, therapy and survival outcomes were compared between patients who received any Ig within 24 months of MM diagnosis and non-recipients using chi-square tests for categorical variables and rank sum tests for continuous variables. Variation in Ig use across sites were compared. Kaplan-Meier survival analysis was used to estimate time to Ig and duration of use. A time-dependent Cox analysis was used to compare survival for patients whilst on and off Ig therapy. All statistical analysis was completed on STATA/IC statistical software v16.1 (College Station, TX, USA).
Results
As of July 2021, &gt;4600 patients with plasma cell dyscrasias are registered on the MRDR. Of these, 2025 patients from 13 sites (12 Aus across five states/territories and one NZ) with verifiable data on Ig were included. 242 (12.0%) received Ig during follow-up, with a median time from MM diagnosis to Ig use of 14.2 months, median duration of Ig use of 54.9 months, and median patient follow-up time of 23 months (Figure 1). At 24 months following MM diagnosis, 14.9% (160 of 1075 patients reaching 24-month follow up) received Ig, and a further 7.6% (82 patients) received Ig later, after 24 months.
Administration of Ig within 24 months post-MM diagnosis varied widely across Aus states and territories (2.7%-29.6%), and was 2.0% from one NZ site.
Patients administered Ig within 24 months post-MM diagnosis had lower baseline IgG (3.7 vs. 5.6 g/L, p&lt;0.001), IgA (0.3 vs. 0.5 g/L, p=0.027), IgM (0.20 vs. 0.21 g/L, p=0.019) and total serum Ig levels (28.0 vs 56.0 g/L, p&lt;0.001), were more likely to have abnormal Fluorescence in situ hybridization (FISH) results (83.5% vs. 62.7%, p&lt;0.001) and receive immunomodulatory drugs (IMiDs) (28% vs. 12.3%, p&lt;0.001) or anti-CD38 therapy (4.5% vs. 1.2%, p=0.004) first-line compared with patients not administered Ig (Tables 1, 2).
Ig use was not associated with an overall survival benefit (HR=0.79, 0.50-1.24, p=0.3). At time of last follow-up, there were 577 deaths (28.5%). Available data on cause of death was available for 175 deaths (30.3%). Of these, 65 deaths (37.1%) had infection listed as primary/secondary cause of death (COD). 64 of 65 infection-related deaths occurred in non-Ig recipients. In patients who received Ig (at any time), 12.5% had infection as primary/secondary COD, compared to 38.5% in non-recipients (p=0.14).
Conclusion
This Aus/NZ analysis found that 14.9% of MM patients received Ig by 24 months post-MM diagnosis with wide variation in practice. Ig use was associated with lower baseline Ig levels (all subtypes), abnormal FISH and first-line IMiD/anti-CD38 therapy. In this "real-world" cohort, Ig use was not associated with survival, highlighting the need for well-designed contemporary studies to inform evidence-based patient selection, especially with increasing use of Ig and targeted anti-myeloma therapies, and a high burden of infection-related mortality.
Figure 1 Figure 1.

Disclosures
Hamad: Novartis: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Harrison: Haemalogix: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Roche/Genentech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Novartis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Janssen Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene/ Juno/ BMS: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Abbvie: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Eusa: Consultancy, Honoraria, Speakers Bureau; Sanofi: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; GSK: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Terumo BCT: Consultancy, Honoraria. Mollee: Janssen, Pfizer: Research Funding; Amgen, BMS, Janssen, Caelum, EUSA, Pfizer, SkylineDx, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: No personal fees received. Quach: GlaxoSmithKline: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Antengene: Consultancy, Membership on an entity's Board of Directors or advisory committees; CSL: Consultancy, Membership on an entity's Board of Directors or advisory committees; Bristol Myers Squibb: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Janssen/Cilag: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Takeda: Consultancy, Membership on an entity's Board of Directors or advisory committees; Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Amgen: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Karyopharm: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding. Spencer: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Amgen: Honoraria, Research Funding; Bristol Myers Squibb: Research Funding; Takeda: Honoraria, Research Funding, Speakers Bureau; STA: Honoraria. Wood: Amgen, Celgene, Gilead, Janssen, Novartis, Sanofi, Takeda: Research Funding; Abbvie, Amgen, Antengene, Bristol-Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi, and Takeda.: Other: The Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) has received funding from Abbvie, Amgen, Antengene, Bristol-Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi, and Takeda. . McQuilten: Amgen, Celgene, Gilead, Janssen, Novartis, Sanofi, Takeda: Research Funding; Abbvie, Amgen, Antengene, Bristol-Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi, and Takeda.: Other: The Australian and New Zealand Myeloma and Related Diseases Registry (MRDR) has received funding from Abbvie, Amgen, Antengene, Bristol-Myers Squibb, Celgene, Gilead, GSK, Janssen, Novartis, Sanofi, and Takeda. .