Immunoglobulin prophylaxis should be initiated after bispecific antibody therapy in multiple myeloma, regardless of IgG levels Open Access

Bispecific antibodies (bsAbs), which act by redirecting native T cells to eliminate malignant plasma cells, have received several approvals in the United States, Europe, India, Australia, and other countries for the treatment of multiple myeloma (MM). The currently approved bsAbs that target B-cell maturation antigen (BCMA) include teclistamab, elranatamab, and linvoseltamab; other BCMA-targeted bsAbs, such as etentamig, may receive approval in the coming years as well. Talquetamab, which targets G protein–coupled receptor class C group 5 member D (GPRC5D) on MM cells, is commercially available in many countries as well. These drugs have all demonstrated impressive single-agent activity in relapsed/refractory MM,^1-5 and trials of bsAb-based combination therapies are ongoing.^6-8 When compared with autologous chimeric antigen receptor T-cell (CAR-T) therapies, bsAbs can be operationalized more quickly and are more widely available at smaller centers.^9,10 Unlike CAR-T therapy, however, a limitation of bsAb therapy is the general requirement for drug re-administration every 1 to 4 weeks to ensure continued T-cell redirection.

Partly because of this requirement for continued dosing, bsAb therapy recipients are at risk for infections through various mechanisms. Underlying mechanistic causes of infections during bsAb therapy include T-cell exhaustion and hypogammaglobulinemia owing to on-target elimination of normal plasma cells. In various trials of BCMA-targeted bsAbs, ∼70% of patients developed ≥1 infection, whereas more than a quarter developed at least 1 grade ≥3 infection.^11,12 Fatal infections have occurred in 2% to 5% of patients in several bsAb trials, and infections remain the most common cause of nonrelapse mortality even after excluding deaths that occurred in the early years of the coronavirus disease 2019 pandemic.^13,14 Importantly, this cumulative risk of infections does not plateau with continued time on bsAb therapy. In any given month, a de novo grade ≥3 infection can be expected in ∼3% of patients who are receiving BCMA-targeted bsAbs and in 1.5% of patients who are receiving talquetamab.¹¹ 

Immunoglobulin replacement therapy (IgRT) has been studied for >50 years as a strategy to potentially lower infections in MM. Investigations of IgRT in this setting include several randomized controlled trials (RCTs) dating back to 1967 that have studied IgRT via IV, subcutaneous (SC), and even intramuscular routes of administration.^15-18 These RCTs have reached conflicting results regarding the impact of IgRT on severe infections and on health care–related quality of life. However, there is substantial heterogeneity among these RCTs in terms of the exact patient populations. For example, baseline hypogammaglobulinemia, defined by serum IgG levels, was not required for study entry in 2 of the trials.^15,16 In the 2 trials for which hypogammaglobulinemia was required, different IgG thresholds of either 400 or 500 mg/dL were used.^17,18 Nevertheless, based primarily on the high costs of IgRT, most analyses recommend against its routine use in MM or related malignancies such as chronic lymphocytic leukemia.^19-22 

The unique mechanisms of action of bsAb therapy in MM, coupled with their uniquely high infectious risks as described above, call for a careful risk-benefit evaluation of IgRT in this specific setting. Several pertinent guidelines that focus on infection prevention during bsAb therapy for MM have been published in recent years.^23-27 Most guidelines focus on IV immunoglobulin (IVIG, the most commonly used type of IgRT) and recommend what we define as preemptive treatment, namely IVIG initiation regardless of infection history if the serum IgG level is below 400 mg/dL or 4 g/L.^24-27 One set of guidelines recommends primary IgRT prophylaxis in which IVIG is initiated within 1 to 2 cycles of bsAb initiation regardless of the IgG levels or infection history.²⁵ These differences in recommendations are understandable given the lack of high-quality data in this setting, most notably a lack of RCTs. However, this ambiguity has created issues for physicians and health care payers across the world. We have cared for many bsAb recipients for whom the decision to initiate IV or SC immunoglobulin has been dictated by payer policies rather than by clinical benefit-risk evaluations.

To simplify care algorithms and improve patient outcomes, we recommend primary IgRT prophylaxis as the current standard of care (SOC) for all patients with MM who are receiving bsAb therapy. Our recommendation is based on the 3-part framework outlined in Table 1. As we demonstrate in this viewpoint, prescribing IV or SC immunoglobulin, regardless of IgG levels or infection history, is ultimately both the simplest and safest option for patients with MM who are receiving bsAb therapy. As we additionally describe, this strategy will become increasingly cost-effective as patients remain on bsAb therapy for longer with continued per-cycle risks of costly infections. The primary intended audience of our recommendation is physicians who care for patients with MM receiving bsAb therapy. However, our recommendation is applicable to health care payers and trial sponsors as well.

The first rationale for implementing primary prophylaxis, namely reducing the risk of infections with bsAbs, is a critical unmet need for the MM field. For example, cumulative infection rates are even higher with BCMA-targeted bsAbs than with BCMA-targeted CAR-T therapies.³² De novo high-grade infections, which occur in ∼3% of BCMA-directed bsAb recipients per month,¹¹ can cause significant quality-of-life disruptions for patients and hospitalization costs for payers. For patients with MM who reside in low- and middle-income countries, high-grade infections can occur more frequently and are associated with significant morbidity and mortality.^33,34 Even grade 1 infections can sometimes take weeks to months to resolve with bsAb therapy,³⁵ which can place patients at risk of treatment failure if bsAb dosing is interrupted for long periods. Patients who are living with relapsed/refractory MM value the avoidance of serious infections quite highly, even more highly than they value the improved overall response rates or the avoidance of hospitalizations.³⁶ As such, any readily available modality that can lower these infectious risks during bsAb therapy should thus be considered an SOC intervention given the importance of this issue.

To that end, compelling data now exist to support a more expansive approach to IgRT after bsAb therapy.^28,29,37,38 As shown in Table 2, IgG replacement can be characterized as preemptive treatment (withholding IVIG until IgG <400 mg/dL) or primary prophylaxis (initiating IVIG regardless of most recent IgG level). Comparative analyses of the 2 strategies are limited by confounders inherent to retrospective data, including temporal trends in deaths owing to coronavirus disease 2019 over the past 5 years. Nevertheless, 1 study demonstrated that grade ≥3 infections were 90% less likely during months that primary IgRT prophylaxis was administered than during the months that it was not.²⁸ In another study of >200 patients, primary IVIG prophylaxis was associated with improved infection-free survival, both for all-grade infections (median survival, 7.7 vs 3.0 months; P = .021) and for high-grade infections (median, 14.0 vs 7.5 months; P = .022). In this study, the only independent predictors of overall survival in multivariate analyses were extramedullary disease, high-risk cytogenetics, and the use of primary IVIG prophylaxis (hazard ratio, 0.37; 95% confidence interval, 0.16-0.86; P = .021).³⁷ The benefits of IgRT in this setting to reduce infections are thus clearly present. Conversely, IVIG has very few risks in MM apart from a minimally elevated risk of thrombosis.^21,39 

As a third rationale specifically in favor of primary IgRT prophylaxis with bsAb therapy as opposed to preemptive IgG-guided treatment, a single IgG level cannot fully quantify humoral immunity. An IgG threshold of 400 mg/dL in the setting of immune effector cell therapies does not necessarily ensure seroprotection against circulating viruses (eg, influenza and severe acute respiratory syndrome coronavirus 2) for which IgRT can confer meaningful immunity.^40-42 Furthermore, approximately half of the patients who receive bsAbs for MM have IgG paraproteins that are produced by malignant plasma cells.^29-31 For these patients, serum IgG levels may remain elevated for months following bsAb therapy despite profound immunoparesis. Although the manual subtraction of paraprotein concentrations from serum IgG levels has been proposed,^28,29,43 this approach has not been validated and does not account for the inherent imprecision of serum protein electrophoresis measurements as opposed to immunoturbidimetric IgG assays. Given that hypogammaglobulinemia may develop as soon as 1 week following bsAb initiation,⁴⁴ relying on once-monthly bloodwork to decide on the appropriateness of IgRT may also leave patients vulnerable to infections in the interim.

With these points in mind, an RCT of primary prophylaxis vs preemptive treatment in the setting of bsAb therapy for MM, despite being the gold standard for clinical research, would be challenging if not impossible to complete. Even with the limitations inherent to retrospective data, improved infection-free survival and potentially improved overall survival (with the caveats discussed previously)³⁷ following primary prophylaxis may dissuade physicians and patients from participating in a trial in which immunoglobulin RT is withheld. The same equipoise-related principle may apply to patients with other obvious markers of ongoing plasma cell aplasia, for example, uninvolved serum free light chains becoming undetectable.⁴⁵ Even if such an RCT was completed, the generalizability of the preemptive treatment arm would undoubtedly be called into question given the lack of consensus with defining this approach. What IgG threshold was used to define hypogammaglobulinemia? How frequently were serum IgG levels checked? How, if at all, was the concurrent presence of an IgG paraprotein (present in approximately half of patients with MM who are receiving bsAb therapy)^29-31 accounted for? Indeed, one of the strengths of primary IgRT prophylaxis is its simplicity without the risk for undertreating patients who are almost universally at high risk of infections.

This reality of course does not preclude future RCT-based research into the optimization of IgG replacement following bsAb therapy in MM. As shown in Figure 1, several unanswered questions warrant further prospective analyses within the framework of primary prophylaxis. For example, given that IVIG is often dosed at 0.4 g/kg every 4 weeks, future investigations should study alternative dosing strategies, including flat-dose regimens.⁴⁶ Strategies to adapt IgRT regimens based on risk profiles, for example, lower dose intensities for GPRC5D-targeted bsAbs (which likely have a lower risk of infections than BCMA-targeted bsAbs)^11,47-49 or higher dose intensities for bsAb-containing combinations (which, particularly for BCMA-targeted bsAbs, likely carry a higher risk of infections),⁵⁰ warrant further study as well. In responding patients, bsAb dose intensity is generally de-escalated over time, regardless of the target.^51,52 Identifying thresholds at which point IgRT can be discontinued, either based on bsAb dosing frequency itself or by measuring serum IgG troughs as bsAb therapy is de-escalated, would be excellent research questions as well. Finally, although this viewpoint has generally focused on IVIG given its widespread commercial availability across the world, SC (SCIG) has also been shown to reduce infections in MM.¹⁷ When compared with IVIG, SCIG may cause fewer administration-related reactions, lead to more stable IgG troughs, and reduce the time toxicity by facilitating shorter clinic visits and even home-based administration.^21,53-55 As such, we encourage future adoption of SCIG in both real-world practice and prospective trials.

These types of investigations will also be critical to improve the cost-effectiveness of IgRT in this setting, which has remained a barrier to its routine use in patients with hematologic malignancies.^19,22 Exact IVIG costs will vary widely based on patient weights, dosing details, and country-specific acquisition pricing; however, estimates of US $20 000 to US $40 000 per patient per year are reasonable to assume in both high-income countries and low- and middle-income countries.^22,56-59 These price estimates do not include infusion-related expenses, which can range from $140 to $730 per hour depending on the setting.^60,61 In many countries, these costs are not reimbursed by payers and thus are largely paid out of pocket by patients.^58,62 Fixed flat-dose IVIG may be 1 approach to lower these costs, with 1 study demonstrating comparable efficacy and only a third of the total costs required for flat dosing when compared with traditional weight-based dosing after CAR-T therapy in lymphoma.⁶³ In many countries, SCIG is more cost-effective than IVIG given the high costs of infusions and/or hospitalizations required for the latter.^64-66 Regardless of the route of administration, steps to improve the country-specific production of plasma-based protein therapies (which have been discussed at length elsewhere)^67-70 are of paramount importance to reduce the costs and increase IgRT availability around the world as bsAb recipients spend increasing lengths of time in remission on continued therapy.

As these advancements continue, primary IgRT prophylaxis (regardless of IgG levels) should clearly be considered an SOC intervention for patients with MM who are receiving bsAb therapy. We acknowledge the limitations of this recommendation, most notably a lack of randomized evidence. However, there are many components of the care of bsAb recipients for which important safety-related provisions have been implemented widely without RCT data to confirm their benefit; for example, acyclovir for varicella prophylaxis or dexamethasone as a premedication to prevent cytokine release syndrome.^24,39 IgRT prophylaxis falls into the same category as an essential strategy to ensure patient safety. Immunoglobulin levels can certainly be considered alongside other factors to guide individual decision-making; for example, lymphopenia, comorbidities, or histories of infections. Nevertheless, based on currently available data, restricting access to IgRT based on a single IgG threshold is neither scientifically sound nor clinically appropriate for patients with MM who are receiving bsAb therapy.