{"entity":{"id":"myeloma-relapsed-refractory","kind":"cancer","name":"Relapsed or refractory multiple myeloma","aka":["RRMM","Relapsed myeloma","Triple-class refractory myeloma","Penta-refractory myeloma"],"tldr":"Myeloma almost always returns, and each return is harder to treat. Two kinds of immune therapy aimed at the BCMA protein on myeloma cells, CAR-T cells (KarMMa-3, CARTITUDE-4) and off-the-shelf bispecific antibodies (MajesTEC), now give deep remissions after other drugs fail, and a second target, GPRC5D, gives another option.","summary":"Relapse is defined by a rising M-protein or light chains, and refractory disease by progression on or within 60 days of a treatment. Choice at each relapse depends on which classes the disease has already resisted: proteasome inhibitors, immunomodulatory drugs and CD38 antibodies define triple-class exposure, and their five main members define penta-exposure. Early relapse after a lenalidomide-based first line is usually treated with a carfilzomib or pomalidomide triplet with a CD38 antibody, or with belantamab mafodotin combinations after DREAMM-7 (belantamab-bortezomib-dexamethasone versus daratumumab-bortezomib-dexamethasone, median progression-free survival 36.6 versus 13.4 months, hazard ratio 0.41, with a survival gain) and DREAMM-8 returned the antibody-drug conjugate to the market in 2025.\n\nBCMA-directed T-cell therapies changed the outlook for later lines. Idecabtagene vicleucel was the first CAR-T approved (2021); KarMMa-3 then showed it beat standard regimens after two to four prior lines, median progression-free survival 13.3 versus 4.4 months (hazard ratio 0.49). Ciltacabtagene autoleucel produced responses in 98 percent of heavily pretreated patients in CARTITUDE-1, with a third still progression-free at five years without further treatment, and CARTITUDE-4 showed it after one to three prior lines cut progression or death by about three quarters (hazard ratio 0.26) and lengthened life (hazard ratio 0.55), moving CAR-T to second line in 2024. Bispecific antibodies give an off-the-shelf alternative: teclistamab (MajesTEC-1, response rate 63 percent, approved 2022), elranatamab (MagnetisMM-3, 61 percent) and linvoseltamab (LINKER-MM1, 70 percent, approved 2025) against BCMA, and talquetamab (MonumenTAL-1, about 73 percent, approved 2023) against GPRC5D, which works after BCMA therapy fails. MajesTEC-3 (2025) showed teclistamab with daratumumab beating standard combinations in early relapse.\n\nThe price is toxicity and logistics: cytokine release syndrome and neurotoxicity with both approaches, delayed neurological and Parkinsonian events with cilta-cel, profound infections and hypogammaglobulinaemia with continuous BCMA bispecifics requiring immunoglobulin replacement, taste and skin toxicity with talquetamab, and manufacturing slots and hospital capacity for CAR-T. Sequencing (CAR-T before or after bispecific, BCMA then GPRC5D), fixed-duration bispecific dosing, CELMoDs such as iberdomide and mezigdomide, and trispecific antibodies are the current frontier.","asOf":"2026-09-17","wikipedia":"https://en.wikipedia.org/wiki/Multiple_myeloma","links":[{"label":"Wikipedia","url":"https://en.wikipedia.org/wiki/Multiple_myeloma"},{"label":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}],"tags":["subtype-page"],"related":["myeloma-transplant-eligible","myeloma-transplant-ineligible","plasma-cell-leukaemia","smouldering-myeloma"],"cancers":[],"sections":[],"technologies":["car-t","t-cell-engager","bispecific-antibody","celmods","car-t-manufacturing-process"],"targets":["bcma","gprc5d","cd38","xpo1","cereblon"],"drugs":[],"companies":[],"institutions":[],"pathways":[],"terms":["step-up-dosing","crs","icans","proteasome-inhibitor","imid","mrd-negativity-myeloma"],"trials":["majestec-1"],"people":[],"bottlenecks":[],"keyPapers":["paper-cartitude-4-cilta-cel-nejm-2023","paper-karmma-3-ide-cel-nejm-2023","paper-majestec-1-teclistamab-nejm-2022","paper-monumental-1-talquetamab-nejm-2022"],"journals":[],"dependsOn":[],"notes":[],"group":"haematologic","burden":"Almost everyone with myeloma relapses eventually; with each line of treatment remissions shorten, and until 2021 patients whose disease resisted the three main drug classes survived about a year.","subtypes":["First relapse after lenalidomide-based therapy (lenalidomide-refractory)","Early relapse, one to three prior lines (cilta-cel, CARTITUDE-4; belantamab combinations)","Triple-class exposed or refractory myeloma (CAR-T, bispecifics)","Penta-refractory myeloma","Relapse after BCMA-directed therapy (GPRC5D-directed talquetamab)","Extramedullary relapse","Functional high-risk myeloma (relapse within 18 months of diagnosis)"],"biomarkers":["Classes and agents the disease is refractory to","Time from last therapy and depth of prior response","BCMA and GPRC5D expression and BCMA loss after prior BCMA therapy","Soluble BCMA","Extramedullary disease on PET-CT","Cytogenetics at relapse (del(17p), 1q gain)","Lymphocyte count and fitness for apheresis"],"standardOfCare":[{"setting":"First relapse, lenalidomide-refractory","approach":"Daratumumab or isatuximab with carfilzomib or pomalidomide and dexamethasone; belantamab mafodotin with bortezomib- or pomalidomide-dexamethasone (DREAMM-7, DREAMM-8); cilta-cel after one to three lines (CARTITUDE-4).","refs":["daratumumab","isatuximab","carfilzomib","pomalidomide","dexamethasone","belantamab-mafodotin","dreamm-7","dreamm-8","ciltacabtagene-autoleucel","cartitude-4"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Triple-class exposed, two or more prior lines","approach":"BCMA CAR-T (cilta-cel or ide-cel, KarMMa-3) where slots and fitness allow; BCMA bispecific (teclistamab, elranatamab, linvoseltamab) otherwise; teclistamab-daratumumab (MajesTEC-3).","refs":["ciltacabtagene-autoleucel","idecabtagene-vicleucel","karmma-3","cartitude-1","teclistamab","elranatamab","linvoseltamab","majestec-1","majestec-3","linker-mm1","magnetismm-3"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"After BCMA-directed therapy","approach":"Talquetamab against GPRC5D (MonumenTAL-1); selinexor combinations; CELMoDs and trispecifics in trials.","refs":["talquetamab","monumental-1","selinexor","iberdomide","mezigdomide","bcma-then-gprc5d"],"guideline":{"version":"NCCN Guidelines: Multiple Myeloma","url":"https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445"}},{"setting":"Toxicity management","approach":"Step-up dosing and tocilizumab for cytokine release syndrome, immunoglobulin replacement and antimicrobial prophylaxis on bispecifics, neurological monitoring after cilta-cel, ocular examinations on belantamab.","refs":["step-up-dosing","crs","icans","bispecific-infection-prophylaxis"]}],"stateOfArt":["BCMA CAR-T now belongs in second line after CARTITUDE-4 lengthened life; a third of CARTITUDE-1 patients remain progression-free at five years after a single infusion.","Four approved bispecific antibodies, three against BCMA and one against GPRC5D, give off-the-shelf immune therapy with response rates of 60 to 70 percent in heavily pretreated patients.","Belantamab mafodotin returned in 2025 for early relapse with a survival gain in DREAMM-7."],"history":[{"year":2003,"title":"Bortezomib approved for relapsed myeloma: the first proteasome inhibitor","refs":["bortezomib"]},{"year":2012,"title":"Carfilzomib approved; pomalidomide follows in 2013","refs":["carfilzomib","pomalidomide"]},{"year":2015,"title":"Daratumumab, the first CD38 antibody, approved for heavily pretreated myeloma","refs":["daratumumab"]},{"year":2021,"title":"Ide-cel: first BCMA CAR-T approved","refs":["idecabtagene-vicleucel"]},{"year":2022,"title":"Teclistamab: first BCMA bispecific approved (MajesTEC-1)","refs":["teclistamab","majestec-1"]},{"year":2023,"title":"KarMMa-3 and CARTITUDE-4: CAR-T beats standard regimens in randomised trials; talquetamab and elranatamab approved","refs":["karmma-3","cartitude-4","talquetamab","elranatamab"]},{"year":2025,"title":"Linvoseltamab approved; belantamab returns after DREAMM-7 and DREAMM-8; MajesTEC-3 reads out","refs":["linvoseltamab","belantamab-mafodotin","dreamm-7","majestec-3"]}],"pipeline":["ciltacabtagene-autoleucel","teclistamab","talquetamab","linvoseltamab","belantamab-mafodotin","iberdomide","mezigdomide","arlocabtagene-autoleucel","immagine-1","quintessential-2","idea-bio1-adaptive-car-antigen-switch"],"openProblems":["Sequencing CAR-T and bispecifics, and whether a second T-cell therapy works after the first.","Infections on continuous BCMA bispecifics, and whether fixed-duration dosing is safe.","CAR-T manufacturing capacity, slots and cost, and the patients who progress while waiting."],"parent":"multiple-myeloma"},"route":"/cancers/myeloma-relapsed-refractory/","neighbours":{"cancer":[{"id":"multiple-myeloma","kind":"cancer","name":"Multiple myeloma","route":"/cancers/multiple-myeloma/"},{"id":"myeloma-transplant-eligible","kind":"cancer","name":"Newly diagnosed multiple myeloma, transplant-eligible","route":"/cancers/myeloma-transplant-eligible/"},{"id":"myeloma-transplant-ineligible","kind":"cancer","name":"Newly diagnosed multiple myeloma, transplant-ineligible","route":"/cancers/myeloma-transplant-ineligible/"},{"id":"plasma-cell-leukaemia","kind":"cancer","name":"Plasma cell leukaemia","route":"/cancers/plasma-cell-leukaemia/"},{"id":"smouldering-myeloma","kind":"cancer","name":"Smouldering multiple myeloma","route":"/cancers/smouldering-myeloma/"}],"technology":[{"id":"car-t-manufacturing-process","kind":"technology","name":"Autologous CAR-T manufacturing, batch by batch","route":"/technologies/car-t-manufacturing-process/"},{"id":"bispecific-antibody","kind":"technology","name":"Bispecific antibodies","route":"/technologies/bispecific-antibody/"},{"id":"car-t","kind":"technology","name":"CAR-T cell therapy","route":"/technologies/car-t/"},{"id":"celmods","kind":"technology","name":"Cereblon E3 ligase modulators (CELMoDs)","route":"/technologies/celmods/"},{"id":"t-cell-engager","kind":"technology","name":"T-cell engagers (bispecific)","route":"/technologies/t-cell-engager/"}],"target":[{"id":"bcma","kind":"target","name":"BCMA","route":"/targets/bcma/"},{"id":"cd38","kind":"target","name":"CD38","route":"/targets/cd38/"},{"id":"cereblon","kind":"target","name":"Cereblon (CRBN)","route":"/targets/cereblon/"},{"id":"xpo1","kind":"target","name":"Exportin-1 (XPO1)","route":"/targets/xpo1/"},{"id":"fcrh5","kind":"target","name":"FcRH5 (FCRL5)","route":"/targets/fcrh5/"},{"id":"gprc5d","kind":"target","name":"GPRC5D","route":"/targets/gprc5d/"},{"id":"ikzf3","kind":"target","name":"IKZF3 (Aiolos)","route":"/targets/ikzf3/"}],"term":[{"id":"crs","kind":"term","name":"Cytokine release syndrome (CRS)","route":"/terms/crs/"},{"id":"icans","kind":"term","name":"ICANS (neurotoxicity)","route":"/terms/icans/"},{"id":"imid","kind":"term","name":"Immunomodulatory drugs (IMiDs) and CELMoDs","route":"/terms/imid/"},{"id":"m-protein-free-light-chains","kind":"term","name":"M-protein, immunofixation and serum free light chains","route":"/terms/m-protein-free-light-chains/"},{"id":"mrd-negativity-myeloma","kind":"term","name":"MRD negativity (myeloma, 10⁻⁵ / 10⁻⁶)","route":"/terms/mrd-negativity-myeloma/"},{"id":"proteasome-inhibitor","kind":"term","name":"Proteasome inhibitor (bortezomib, carfilzomib, ixazomib)","route":"/terms/proteasome-inhibitor/"},{"id":"step-up-dosing","kind":"term","name":"Step-up dosing (T-cell engagers)","route":"/terms/step-up-dosing/"},{"id":"cyclin-d1-t11-14","kind":"term","name":"t(11;14), cyclin D1 and SOX11","route":"/terms/cyclin-d1-t11-14/"}],"trial":[{"id":"nct04776330","kind":"trial","name":"a Clinical Research of BCMA-Targeted Prime CAR-T Cell Therapy in Relapsed/Refractory Multiple Myeloma and Plasma Cell 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