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Daratumumab-sensitive, lenalidomide-refractory
First relapse with disease that remains sensitive to daratumumab but is refractory to lenalidomide. Consider prior treatment exposure, duration of response, disease tempo, comorbidities, treatment access, and patient preference when selecting therapy.
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Preferred: teclistamab + daratumumab
Use teclistamab + daratumumab in an eligible patient with retained sensitivity to anti-CD38 therapy. Confirm prior treatment exposure, previous B-cell maturation antigen–directed therapy, infection risk, access, and treatment goals before initiation.
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Second Choice: Cilta-Cel Based On Patient Preference
Consider ciltacabtagene autoleucel in an eligible patient with lenalidomide-refractory disease when aligned with treatment goals and patient preference. Account for fitness, access, leukapheresis, manufacturing time, bridging requirements, and the logistics of cellular therapy.
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Lenalidomide- and daratumumab-sensitive
First relapse with retained sensitivity to both lenalidomide and daratumumab. Consider prior duration of benefit, cumulative toxicity, disease tempo, comorbidities, and patient preference when selecting the next regimen.
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Preferred: teclistamab + daratumumab
Use teclistamab + daratumumab in an eligible patient with retained sensitivity to anti-CD38 therapy. Consider prior treatment exposure, infection risk, previous B-cell maturation antigen–directed therapy, treatment access, and patient preference.
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Alternate: daratumumab + lenalidomide + dexamethasone
Consider daratumumab + lenalidomide + dexamethasone when both daratumumab and lenalidomide remain clinically active. Reassess prior duration of response, renal function, cytopenias, thrombotic risk, cumulative toxicity, and patient preference.
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Ciltacabtagene autoleucel not recommended in this branch
Favor the effective non–cellular therapy options above in this clinical setting. The current U.S. indication for ciltacabtagene autoleucel after one or more prior lines requires lenalidomide-refractory disease.
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Daratumumab- and lenalidomide-refractory
First relapse with disease refractory to both daratumumab and lenalidomide. Consider prior treatment exposure, previous B-cell maturation antigen–directed therapy, disease tempo, fitness, access, and patient preference when selecting therapy.
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Preferred: Teclistamab
Consider teclistamab according to prior treatment exposure, previous B-cell maturation antigen–directed therapy, local indication and access. Carefully assess infection risk and the feasibility of ongoing bispecific-antibody therapy.
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Second choice: ciltacabtagene autoleucel based on patient preference
Consider ciltacabtagene autoleucel in an eligible patient with lenalidomide-refractory disease based on treatment goals, patient preference, fitness, access, and the feasibility of cellular-therapy delivery.
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Stem Cells Collected Without Prior Transplant
Stem cells have previously been collected, but the patient has not undergone autologous stem cell transplantation. Reassess transplant fitness, disease trajectory, stored-cell availability, other relapse options, and patient preference.
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Biochemical-only relapse after prolonged remission, standard-risk disease
Slowly evolving biochemical relapse after a prolonged remission in standard-risk disease. Confirm the absence of myeloma-related symptoms or new end-organ effects and assess the rate of biomarker rise before deciding whether treatment is required.
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Continue Observation If Patient Is Amenable
Continue close observation while the relapse remains slow and asymptomatic. Individualize surveillance according to biomarker kinetics, disease-risk features, comorbidities, frailty, and patient preference.
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Initiate Treatment If Disease Trajectory Worsens
Initiate systemic therapy if biomarker kinetics accelerate, disease-related symptoms or end-organ effects develop, or other findings indicate clinically meaningful progression.
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Bridging required before ciltacabtagene autoleucel
Disease control is required while awaiting chimeric antigen receptor T-cell manufacturing. Select bridging therapy according to disease tempo, prior treatment exposure, cytopenias, infection risk, organ function, anticipated manufacturing time, and center practice.
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Use Talquetamab Alone Or In Combination
Consider talquetamab-based bridging when disease control is needed before ciltacabtagene autoleucel. Coordinate treatment timing and sequencing with the cellular-therapy center and individualize according to prior therapy, disease burden, toxicity risk, and access.
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Practice note: finite-duration bispecific antibody therapy
Bispecific antibody therapy may be given for a finite duration of approximately 6–12 months depending on clinical context.