For a patient who has progressed on daratumumab (Darzalex) and is being prepared for BCMA‑directed CAR‑T cell therapy, should daratumumab be discontinued or continued (e.g., with carfilzomib) as bridging therapy?

Discontinue Daratumumab Before BCMA CAR-T Cell Therapy

For a patient who has progressed on daratumumab and is being prepared for BCMA-directed CAR-T cell therapy, daratumumab should be discontinued rather than continued with carfilzomib as bridging therapy.

Rationale for Discontinuing Daratumumab

Mechanism-Based Concerns with Anti-CD38 Therapy

• Daratumumab targets CD38, which is expressed on both myeloma cells and normal immune cells, including T cells that are critical for CAR-T manufacturing and function 1.
• Continuing daratumumab through the bridging period may impair T-cell collection during leukapheresis and compromise the quality of the CAR-T product 1.
• Any systemic immunosuppressive treatment may impair the efficacy of CAR-T therapy, and daratumumab's immunomodulatory effects on T cells constitute a relative contraindication during the pre-CAR-T period 1.

Evidence from Clinical Trials

• Multiple ongoing trials evaluating CAR-T therapy in high-risk myeloma populations do not incorporate daratumumab as bridging therapy 1.
• The NCT05870917 trial uses VRD (bortezomib, lenalidomide, dexamethasone) as induction before BCMA CAR-T, specifically avoiding anti-CD38 agents 1.
• The GEM-PLASMACAR trial allows "induction therapy according to center's guidelines" before CAR-T but does not mandate daratumumab continuation 1.

Disease Progression Context

• The patient has already progressed on daratumumab, indicating daratumumab-refractory disease 2.
• Real-world evidence demonstrates that patients with daratumumab-refractory disease who receive carfilzomib after daratumumab (Da-Car sequence) have poor outcomes with median time to next treatment of only 4.3 months 2.
• Adding carfilzomib to daratumumab in this setting is unlikely to provide meaningful disease control given documented daratumumab resistance 2.

Recommended Bridging Strategy

Preferred Bridging Options

• Use carfilzomib-based combinations WITHOUT daratumumab as bridging therapy if disease burden requires treatment during the 4-6 week vein-to-vein time 1.
• Consider carfilzomib, lenalidomide, and dexamethasone (KRd) if the patient is lenalidomide-sensitive 1.
• Bridging therapy aims to reduce disease burden and increase CAR-T efficacy while minimizing immunotoxicity, and should be tailored based on response to prior therapy, tumor burden, and anatomical sites of disease 1.

Alternative Bridging Approaches

• Low-dose chemotherapy or radiation therapy may be appropriate alternatives, particularly for localized disease or if systemic therapy poses excessive risk 1, 3.
• Bridging radiation with BCMA CAR-T appears safe and feasible, with a median dose of 22 Gy and median time from radiation to CAR-T infusion of 25 days showing acceptable toxicity profiles 3.
• Bridging can be omitted entirely if the CAR-T vein-to-vein time is short and disease burden is low 1.

Timing Considerations

Washout Period

• Ensure adequate time between last daratumumab dose and leukapheresis to allow recovery of T-cell function and minimize manufacturing interference 1.
• While specific washout periods are not definitively established in guidelines, the half-life of daratumumab (approximately 18 days at steady state) suggests waiting at least 4-6 weeks when feasible 1.

Monitoring During Bridging

• Patient-specific bridging recommendations should be made by a multidisciplinary team following review of response to prior therapy, overall tumor burden, and anatomical sites of disease 1.
• Monitor for disease progression including lymphadenopathy, B symptoms, cytopenias, or rising markers that would necessitate more aggressive bridging intervention 1.

Common Pitfalls to Avoid

• Do not continue daratumumab simply because it was part of the prior regimen—progression on daratumumab indicates resistance and provides strong rationale for discontinuation 2.
• Do not assume that adding carfilzomib to daratumumab will overcome daratumumab resistance—sequential therapy data show poor outcomes with this approach 2.
• Do not delay CAR-T therapy to pursue additional lines of conventional therapy in patients with aggressive, daratumumab-refractory disease, as this may compromise eligibility for CAR-T 1.

Special Considerations for High-Risk Disease

• Patients progressing on daratumumab often have high-risk features including adverse cytogenetics, 1q amplification, or early relapse after transplant 2.
• These high-risk patients should be prioritized for CAR-T therapy rather than prolonged bridging with conventional agents that have already demonstrated inadequate disease control 1.
• The NCT06140966 trial specifically enrolls ultra-high-risk patients (including those with double-hit myeloma and extramedullary disease) and uses daratumumab-carfilzomib combinations in the post-CAR-T consolidation and maintenance phases, not as pre-CAR-T bridging 1.