# Relapsed or refractory multiple myeloma

Source: https://onco.cc/cancers/myeloma-relapsed-refractory/  
OnCo record `myeloma-relapsed-refractory` (Cancer). Data CC BY-NC 4.0, attribute "Data from OnCo (onco.cc)"; commercial use needs a licence.

## TL;DR

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.

BCMA-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.

The 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.

## Fields

- Kind: Cancer
- Last checked: 2026-09-17
- Also known as: RRMM; Relapsed myeloma; Triple-class refractory myeloma; Penta-refractory myeloma
- Tags: subtype-page
- 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

## Standard of care

- First relapse, lenalidomide-refractory: 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). ([Daratumumab](https://onco.cc/drugs/daratumumab/), [Isatuximab](https://onco.cc/drugs/isatuximab/), [Carfilzomib](https://onco.cc/drugs/carfilzomib/), [Pomalidomide](https://onco.cc/drugs/pomalidomide/), [Dexamethasone](https://onco.cc/drugs/dexamethasone/), [Belantamab mafodotin](https://onco.cc/drugs/belantamab-mafodotin/), [DREAMM-7](https://onco.cc/trials/dreamm-7/), [DREAMM-8](https://onco.cc/trials/dreamm-8/), [Ciltacabtagene autoleucel](https://onco.cc/drugs/ciltacabtagene-autoleucel/), [CARTITUDE-4](https://onco.cc/trials/cartitude-4/))
- Triple-class exposed, two or more prior lines: 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). ([Ciltacabtagene autoleucel](https://onco.cc/drugs/ciltacabtagene-autoleucel/), [Idecabtagene vicleucel](https://onco.cc/drugs/idecabtagene-vicleucel/), [KarMMa-3](https://onco.cc/trials/karmma-3/), [CARTITUDE-1](https://onco.cc/trials/cartitude-1/), [Teclistamab](https://onco.cc/drugs/teclistamab/), [Elranatamab](https://onco.cc/drugs/elranatamab/), [Linvoseltamab](https://onco.cc/drugs/linvoseltamab/), [MajesTEC-1](https://onco.cc/trials/majestec-1/), [MajesTEC-3](https://onco.cc/trials/majestec-3/), [LINKER-MM1](https://onco.cc/trials/linker-mm1/), [MagnetisMM-3](https://onco.cc/trials/magnetismm-3/))
- After BCMA-directed therapy: Talquetamab against GPRC5D (MonumenTAL-1); selinexor combinations; CELMoDs and trispecifics in trials. ([Talquetamab](https://onco.cc/drugs/talquetamab/), [MonumenTAL-1](https://onco.cc/trials/monumental-1/), [Selinexor](https://onco.cc/drugs/selinexor/), [Iberdomide](https://onco.cc/drugs/iberdomide/), [Mezigdomide](https://onco.cc/drugs/mezigdomide/), [BCMA-directed therapy → GPRC5D-directed therapy](https://onco.cc/pairings/bcma-then-gprc5d/))
- Toxicity management: 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. ([Step-up dosing (T-cell engagers)](https://onco.cc/terms/step-up-dosing/), [Cytokine release syndrome (CRS)](https://onco.cc/terms/crs/), [ICANS (neurotoxicity)](https://onco.cc/terms/icans/), [Caution: T-cell redirectors and infections](https://onco.cc/pairings/bispecific-infection-prophylaxis/))

## State of the art

- 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.

## Open problems

- 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.

## Sources

- Wikipedia: https://en.wikipedia.org/wiki/Multiple_myeloma
- Wikipedia: https://en.wikipedia.org/wiki/Multiple_myeloma
- NCCN Guidelines: Multiple Myeloma: https://www.nccn.org/guidelines/guidelines-detail?category=1&id=1445

## Connected records

- technologies: [Autologous CAR-T manufacturing, batch by batch](https://onco.cc/technologies/car-t-manufacturing-process/), [Bispecific antibodies](https://onco.cc/technologies/bispecific-antibody/), [CAR-T cell therapy](https://onco.cc/technologies/car-t/), [Cereblon E3 ligase modulators (CELMoDs)](https://onco.cc/technologies/celmods/), [T-cell engagers (bispecific)](https://onco.cc/technologies/t-cell-engager/)
- targets: [BCMA](https://onco.cc/targets/bcma/), [CD38](https://onco.cc/targets/cd38/), [Cereblon (CRBN)](https://onco.cc/targets/cereblon/), [Exportin-1 (XPO1)](https://onco.cc/targets/xpo1/), [GPRC5D](https://onco.cc/targets/gprc5d/)
- terms: [Cytokine release syndrome (CRS)](https://onco.cc/terms/crs/), [ICANS (neurotoxicity)](https://onco.cc/terms/icans/), [Immunomodulatory drugs (IMiDs) and CELMoDs](https://onco.cc/terms/imid/), [MRD negativity (myeloma, 10⁻⁵ / 10⁻⁶)](https://onco.cc/terms/mrd-negativity-myeloma/), [Proteasome inhibitor (bortezomib, carfilzomib, ixazomib)](https://onco.cc/terms/proteasome-inhibitor/), [Step-up dosing (T-cell engagers)](https://onco.cc/terms/step-up-dosing/)
- drugs: [Arlocabtagene Autoleucel](https://onco.cc/drugs/arlocabtagene-autoleucel/), [Belantamab mafodotin](https://onco.cc/drugs/belantamab-mafodotin/), [Bortezomib](https://onco.cc/drugs/bortezomib/), [Carfilzomib](https://onco.cc/drugs/carfilzomib/), [Ciltacabtagene autoleucel](https://onco.cc/drugs/ciltacabtagene-autoleucel/), [Daratumumab](https://onco.cc/drugs/daratumumab/), [Dexamethasone](https://onco.cc/drugs/dexamethasone/), [Elranatamab](https://onco.cc/drugs/elranatamab/), [Iberdomide](https://onco.cc/drugs/iberdomide/), [Idecabtagene vicleucel](https://onco.cc/drugs/idecabtagene-vicleucel/), [Isatuximab](https://onco.cc/drugs/isatuximab/), [Linvoseltamab](https://onco.cc/drugs/linvoseltamab/), [Mezigdomide](https://onco.cc/drugs/mezigdomide/), [Pomalidomide](https://onco.cc/drugs/pomalidomide/), [Selinexor](https://onco.cc/drugs/selinexor/), [Talquetamab](https://onco.cc/drugs/talquetamab/), [Teclistamab](https://onco.cc/drugs/teclistamab/)
- trials: [A Study to Compare the Efficacy and Safety of BMS-986393 Versus Standard Regimens in Adult Participants With Relapsed or Refractory and Lenalidomide-exposed Multiple Myeloma (QUINTESSENTIAL-2)](https://onco.cc/trials/quintessential-2/), [CARTITUDE-1](https://onco.cc/trials/cartitude-1/), [CARTITUDE-4](https://onco.cc/trials/cartitude-4/), [DREAMM-7](https://onco.cc/trials/dreamm-7/), [DREAMM-8](https://onco.cc/trials/dreamm-8/), [iMMagine-1](https://onco.cc/trials/immagine-1/), [KarMMa-3](https://onco.cc/trials/karmma-3/), [LINKER-MM1](https://onco.cc/trials/linker-mm1/), [MagnetisMM-3](https://onco.cc/trials/magnetismm-3/), [MajesTEC-1](https://onco.cc/trials/majestec-1/), [MajesTEC-3](https://onco.cc/trials/majestec-3/), [MonumenTAL-1](https://onco.cc/trials/monumental-1/)
- ideas: [Plan the second CAR-T target before the first one is lost](https://onco.cc/ideas/idea-bio1-adaptive-car-antigen-switch/)
- pairings: [BCMA-directed therapy → GPRC5D-directed therapy](https://onco.cc/pairings/bcma-then-gprc5d/), [Caution: T-cell redirectors and infections](https://onco.cc/pairings/bispecific-infection-prophylaxis/)
- cancers: [Multiple myeloma](https://onco.cc/cancers/multiple-myeloma/)

---
JSON: https://onco.cc/api/v1/entities/myeloma-relapsed-refractory.json