Avoid burning bridges before CAR-T therapy in myeloma Open Access

In this issue of Blood Advances, Frenking et al¹ reported the results of an analysis of bridging therapy (BT) regimens among 158 recipients of chimeric antigen receptor T-cell (CAR-T) therapy for multiple myeloma (MM) in 2 countries. The authors classified patients into 3 categories based on the extent of alkylating chemotherapy (CTX) exposure during BT. Non-CTX patients either received no BT or received alkylator-free BT regimens, for example, daratumumab, carfilzomib, and dexamethasone. Intermediate-CTX patients received 1 to 2 alkylating drugs as part of BT, for example, carfilzomib, cyclophosphamide, and dexamethasone. Finally, intensive-CTX patients received >2 alkylating drugs, for example, BT using cisplatin, doxorubicin, cyclophosphamide, and etoposide.

In line with similar retrospective studies (see table),^2,3 the progression-free survival (PFS) and overall survival were worse among intensive-CTX recipients than among patients who received intermediate-CTX or non-CTX regimens. However, Frenking et al focused their analysis not on BT’s efficacy but rather on its toxicities. Not only did post–CAR-T neutropenia and thrombocytopenia take longer to resolve in recipients who received intensive CTX, but the cumulative density of peri–CAR-T severe infections was almost 50% higher in the intensive-CTX group than in the non-CTX group.¹ 

There will be confounders with any nonrandomized analysis of BT focused on efficacy. Patients with more aggressive disease biology were more likely to have worse PFS with any line of therapy (LOT), both before and after CAR-T therapy. When aggressive disease biology is identified, oncologists may understandably recommend more intensive BT regimens with the metaphorical hope of fighting fire with fire during CAR-T product manufacturing. However, these patients may have poor postinfusion outcomes even if CAR-T products are immediately available. In contrast, the link between alkylating chemotherapy and cytopenias is much clearer. There is no doubt that alkylating chemotherapy causes bone marrow damage that may exacerbate immune effector cell-associated hematotoxicity syndrome (ICAHT).⁴ Unlike other acute post–CAR-T toxicities, such as cytokine release syndrome, ICAHT can sometimes persist for weeks to months after CAR-T therapy. Even with low-grade ICAHT, lingering cytopenias can cause substantial time toxicity for patients with MM because of frequent bloodwork, transfusions, and growth factor injections.⁵ Given that Frenking et al reported a median time to neutrophil recovery of 63 days in the intensive-CTX group, these logistical burdens may persist well after CAR-T recipients return to the care of their referring oncologists. More concerningly, serious infections happened sooner and more frequently in the intensive-CTX group than in the other 2 BT groups. Although one can reliably invoke the “correlation does not equal causation” mantra for any nonrandomized analysis of BT intensity and efficacy, the causative association between BT intensity and hematologic toxicities demonstrated by Frenking et al cannot be discounted so easily.

There are, of course, limitations to their analysis given the many complexities around BT in MM. First, physician decision-making is difficult to capture or predict in this setting. For example, intensive-CTX recipients had comparable distributions of high-risk cytogenetics and triple-class refractoriness when compared with recipients in the other BT groups.¹ Other potential confounders, such as bone marrow plasma cell burden, were not uniformly assessed before CAR-T therapy in this or previous real-world analyses. Particularly with intensive CTX, patients with aggressive disease biology may have commenced BT without successful CAR-T receipt because of manufacturing failures, worsening functional status, or nonrelapse mortality during the bridging period. Had a true intent-to-treat analysis been possible, it is conceivable that intensive-CTX recipients would have had even worse outcomes than reported. The authors’ decision to classify BT by numbers of CTX agents, although elegant in terms of its simplicity, would misclassify bridging regimens like TurboCy (with a total daily cyclophosphamide dose of 3000 mg/m² but no other CTX agents)⁶ as intermediate intensity rather than as high intensity. That being said, a previous study that focused on total cyclophosphamide dose during BT in MM reached similar conclusions regarding efficacy and safety.² Finally, patients in this analysis had received a median of 5 previous LOTs, and only 14% (n = 22) of patients had received ciltacabtagene autoleucel (cilta-cel). Both idecabtagene vicleucel (ide-cel) and cilta-cel obtained approval as earlier LOTs in the United States and Europe in 2024. We suspect that ICAHT may become less common as CAR-T is increasingly used in patients with less pretreated bone marrow parenchyma. Similarly, it is possible that cilta-cel has improved PFS but longer manufacturing periods than ide-cel.⁷ However, lengthier vein-to-vein intervals may predispose patients to require more aggressive BT regimens. Consequently, future analyses may reach different results as the CAR-T landscape in MM continues to evolve.

Nevertheless, Frenking et al have now established, beyond reasonable doubt, that intensive chemotherapy-based BT may potentially harm patients more than benefit them. This conclusion is echoed in the recent International Myeloma Working Group guidance in which high-dose alkylators are generally discouraged both as preleukapheresis holding therapy and as postleukapheresis BT.⁸ For patients with aggressive disease biology in the modern era, the use of bispecific antibodies that target a different antigen (eg, talquetamab) as BT may possibly be a superior option in terms of ICAHT and infection risk.^9,10 In common parlance, “burning bridges” refers to the deliberate act of ending relationships or preventing alternative pathways to a destination. However, with regard to CAR-T therapy in MM, perhaps intensive-CTX BT is a burning bridge itself: in other words, a bridge on fire that can technically be crossed but that may lead to lasting injuries well after the destination is reached. Given the increasing number of studies that demonstrated that bigger is not better when it comes to BT in MM,^1-3 perhaps the time has come for the marrow burning bridge that is high-intensity chemotherapy to ideally be avoided entirely.

Conflict-of-interest disclosure: R.B. reports serving as a consultant for Adaptive Biotechnologies, Bristol Myers Squibb, Caribou Biosciences, Genentech, Gilead/Kite, Janssen, Karyopharm, Legend Biotech, Pfizer, Poseida Therapeutics, Sanofi, and SparkCures, and conducting research for AbbVie, Bristol Myers Squibb, Janssen, Novartis, Pack Health, Prothena, and Sanofi. S.R. declares no competing financial interests.