Relapsed refractory multiple myeloma (RRMM) is a form of blood cancer that returns after treatment (relapsed) and continues to grow or worsen even while receiving therapy (refractory).
Relapsed: The cancer returns or signs of disease increase after a period of helpful response or remission.
Refractory: The disease fails to achieve at least a minimal response or progresses within 60 days of the last treatment.
Double/Triple-Refractory: Describes cancer resistant to specific major drug classes like proteasome inhibitors, immunomodulatory drugs, or anti-CD38 monoclonal antibodies.b
Modern Treatment Options
CAR T-Cell Therapy: Reprograms T-cells to target and destroy myeloma cells (such as idecabtagene vicleucel or ciltacabtagene autoleucel).
Bispecific Antibodies: Engages your immune system by binding to both T-cells and myeloma cells (such as teclistamab, talqueamab or elranatamab).
Novel Combinations: Re-treating or mixing different classes of proteasome inhibitors, immunomodulatory agents, and monoclonal antibodies with steroids.
The NCCN recommends treatment selection for relapsed/refractory multiple myeloma (RRMM) based on the number of prior lines of therapy and drug class refractoriness (anti-CD38, bortezomib, or lenalidomide refractory).
Key principles include using a new triplet regimen preferably containing drugs/drug classes the patient has not been exposed to, and reconsidering prior regimens if relapse occurs ≥6 months after stopping therapy.
After 1–3 Prior Therapies — Preferred Regimens
Anti-CD38 refractory: Carfilzomib/lenalidomide/dexamethasone (KRd, category 1), carfilzomib/pomalidomide/dexamethasone (KPd), pomalidomide/bortezomib/dexamethasone.
Bortezomib refractory: KRd, daratumumab/carfilzomib/dexamethason, daratumumab/lenalidomide/dexamethasone, isatuximab/carfilzomib/dexamethasone,KPd
Lenalidomide refractory: Daratumumab/bortezomib/dexamethasone
Additional preferred options after specific prior exposures include daratumumab/pomalidomide/dexamethasone, daratumumab/teclistamab isatuximab/pomalidomide/dexamethasone, and elotuzumab/pomalidomide/dexamethasone.
CAR T-Cell Therapy (1–3 Prior Therapies)
Ciltacabtagene autoleucel: after ≥1 prior line including an IMiD and PI, refractory to lenalidomide
Idecabtagene vicleucel: after ≥2 prior lines including an IMiD, anti-CD38 mAb, and PI
Other recommended regimens include elotuzumab/lenalidomide/dexamethasone, ixazomib/lenalidomide/dexamethasone, selinexor/bortezomib/dexamethasone, and belantamab mafodotin/bortezomib/dexamethasone, Venetoclax/dexamethasone ± daratumumab or PI is listed as useful in certain circumstances only for t(11;14) patients.
After ≥3 Prior Lines of Therapy — Preferred Regimens
CAR T-cell therapy: Ciltacabtagene autoleucel, idecabtagene vicleucel
Bispecific antibodies (after ≥4 prior therapies including anti-CD38 mAb, PI, and IMiD): elranatamab, linvoseltamab (added v2.2026), talquetamab, teclistamab
Other options include high-dose cyclophosphamide, selinexor/dexamethasone (for penta-refractory disease), belantamab mafodotin, and bendamustine-based regimens.
Talquetamab may be considered as a bridge to BCMA CAR-T therapy-GPRC5D targeted.
Autologous HCT should be considered in eligible patients who have not previously received HCT or had a prolonged response to initial HCT.
Alkylating agents can impact T-cell collection for CAR T-cell therapy.
Immunoglobulin replacement should be considered for IgG <400 mg/dL
Several landmark trials have shaped the current RRMM landscape.
The CARTITUDE-4 trial demonstrated significant PFS and OS benefits for cilta-cel versus standard of care with an ORR of 84.6% and sCR rate of 69%.
The DREAMM-7 trial showed belantamab mafodotin/bortezomib/dexamethasone significantly improved PFS and OS versus daratumumab/bortezomib/dexamethasone, with a 36-month OS rate of 74%.
The DREAMM-8 trial also met its PFS endpoint for belantamab mafodotin/pomalidomide/dexamethasone versus PVd (HR 0.52).
Teclistamab plus daratumumab demonstrated an 83% reduction in the risk of progression or death compared to DPd or DVd in RRMM, with significantly improved complete response rates, MRD negativity, and overall survival.
This combination was recently added to NCCN preferred regimens for bortezomib- or lenalidomide-refractory patients after one prior therapy including lenalidomide and a PI.
Referral to a CAR-T center is recommended for all patients at first relapse, given manufacturing timelines.
The International Myeloma Working Group notes that after BCMA-targeted therapy failure, CELMoDs (iberdomide, mezigdomide) and selinexor-based combinations show promising activity, though conventional regimens yield ORR no higher than ~30% with median PFS of ~4 months in this heavily pretreated setting.