Skip to main content
NCBI home page
Wiley Open Access Collection logoLink to Wiley Open Access Collection
. 2025 Feb 24;55(5):714–721. doi: 10.1111/imj.16647

A new era in myeloma: the advent of chimeric antigen receptor‐T (CAR‐T) cells and bispecific antibodies

P Joy Ho 1,2,✉, Eric W Li 1,2
PMCID: PMC12077589  PMID: 39989341

Abstract

T‐cell re‐directional therapies, including chimeric antigen receptor (CAR)‐T cell and bispecific antibodies (BsA), have transformed the treatment landscape to benefit patients with multiple myeloma. A number of these novel therapies has been approved internationally, with CAR‐T therapy recently approved in Australia. In this clinical perspective, we describe the development of CAR‐T and BsA therapies, highlighting the clinical benefits and risks, together with the significant costs and infrastructure support required for the provision of these therapies to myeloma patients.

Keywords: multiple myeloma, chimeric antigen receptor‐T therapy, cellular therapy, bispecific antibody, immunotherapy

Introduction

Multiple myeloma (MM) is a plasma cell neoplasm with a marked improvement in prognosis in recent years. Once considered a disease with a median overall survival (OS) of 3 years, recent Australasian data demonstrated an increase to 6.4 years (76.8 months) 1 while US data indicate an OS of 61% at 5 years. 2 Progress was achieved by the development of multiple therapeutic groups and regimens, including autologous transplantation, proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), monoclonal antibodies (MoAb) and antibody‐drug conjugates. As derivatives of IMiDs, more recent developments of cereblon E3 ubiquitin ligase modulators (CELMoDs) have promising efficacy through increased immunomodulatory and tumouricidal effects. A paradigm shift in response rates and survival has occurred in recent years due to advances in T‐cell re‐directional immunotherapy, with chimeric antigen receptor (CAR)‐T cells and bispecific antibodies (‘bispecifics’). We describe the developments in CAR‐T cell and bispecific therapy from an Australian perspective, emphasising that optimism from improved outcomes must be considered within a full understanding of potential toxicities, high treatment costs and substantial infrastructure requirements, presenting hurdles to equitable access that all stakeholders must try to overcome.

The last two decades – before CAR‐T and bispecifics

Following many years of ‘traditional’ cytotoxic chemotherapy including cyclophosphamide and platinum‐based agents, ‘novel therapy’ commenced with two major therapeutic groups, the IMiDs of thalidomide, lenalidomide and pomalidomide and the PIs of bortezomib, carfilzomib and ixazomib. Multiple combinations improved therapeutic outcomes in newly diagnosed (NDMM) and relapsed (RMM) patients. Autologous stem cell transplant (ASCT) was firmly established as the standard of care (SOC) in younger and fit patients, as part of multiple‐agent induction, consolidation and maintenance regimes. 3 MoAb are the third therapeutic group that has played a crucial role. 4 Daratumumab (D) and isatuximab (Isa) targeting CD38, a transmembrane glycoprotein highly expressed in myeloma, have been the most prominent. Both MoAb have shown efficacy in NDMM and RMM patients. 4 Elotuzumab, a MoAb targeting SLAMF7, highly expressed on MM plasma cells and natural killer (NK) cells, mediates NK cytotoxicity and is efficacious in combination with iMiDs in RMM. 4 B‐cell maturation antigen (BCMA), expressed almost exclusively on plasma cells, is targeted by an antibody‐drug conjugate belantamab, recently shown to be efficacious in conjunction with pomalidomide or bortezomib in RMM patients. 5 , 6

Advancements have also been made in the assessment of treatment response, crucial in the development of myeloma therapy. Responses specified by the International Myeloma Working Group (IMWG) and measured by quantitation of paraproteins and serum‐free light chains have been shown to correlate with progression‐free survival (PFS), which, in turn, is a surrogate for OS. Minimal residual disease (MRD) evaluation is increasingly important, enabling the assessment of highly potent therapies that achieve a depth of response not previously attained. 7 This is performed by either ‘next‐generation’ flow cytometry to a level of 10−5 (sensitivity being increased by further technological advances) or massive parallel sequencing at 10−6; while mass spectrometry for paraprotein detection at very high sensitivity and positron emission tomography imaging continue to be refined. Achievement of MRD negativity corresponds positively to clinical outcomes. In 2024, the US Food and Drug Administration (FDA) approved MRD as an endpoint for accelerated approval of myeloma therapeutics, including immunotherapy.

Cellular immunotherapy

Cellular immunotherapy in MM has so far concentrated on CAR‐T ahead of CAR‐NK or other immune cells. In CAR‐T therapy, CARs are transduced into autologous T cells by technologies such as lentiviral gene transfer, to direct the specificity of the immune effector T cell against a tumour antigen. The receptor is based on a single‐chain variable‐region construct for antigen specificity, connected via hinge and transmembrane domains to T‐cell signalling and activation domains. Upon infusion, the CAR‐T cells proliferate and engage in myeloma cell destruction and tumour surveillance if persistent. Patients undergo leukapheresis by which autologous T cells are harvested and sent to a manufacturing laboratory for CAR transduction. During manufacture, which typically takes 21–28 days, bridging therapy may be required for tumour control. Before CAR‐T reinfusion, the patient undergoes lymphodepletion chemotherapy most commonly with fludarabine and cyclophosphamide, which enhances the expansion and persistence of CAR‐T cells by promoting a more favourable microenvironment, such as by modulating cytokines and decreasing inhibitory regulatory T cells.

Tumour antigen selection is crucial in both CAR‐T‐cell therapy and bispecifics (see below), for which the most established target in MM is BCMA. All except one of the current FDA‐approved myeloma CAR‐T and bispecific therapies are directed against the BCMA antigen. BCMA is an attractive target as the majority (60%–100%) of myeloma patients have MM plasma cells with detectable BCMA expression. 8 Demonstration of BCMA expression is not required before treatment with CAR‐T or bispecific therapies as numerous studies suggest that the efficacy of BCMA CAR‐T and bispecifics is not dependent on detectable expression, and the technique of detection may yield variable results. 8 Other targets such as GPRC5D and CD38 (in conjunction with BCMA), SLAMF‐7 and FcRH5 have been applied in early clinical trials or are in preclinical development. 9 , 10 , 11 , 12

CAR‐T therapy in myeloma: pivotal clinical trials

Two CAR‐T cellular therapies for MM, both targeting BCMA, are currently approved by the US FDA and EMA: ciltacabtagene autoleucel (cilta‐cel) and idecabtagene vicleucel (ide‐cel); the former was recently approved for funding in Australia. The FDA/EMA approval was based on two phase 2 studies, CARTITUDE‐1 (cilta‐cel) and KarMMa‐1 (ide‐cel) (Table 1); both included heavily pretreated patients with a median of six prior lines of therapy and a high level (80%–90%) of refractoriness to all three major classes of myeloma drugs (IMiD, PI and anti‐CD38 – termed ‘triple‐class refractory’). Triple‐class‐exposed patients experience a poor outcome – with PFS of 4.6 months from the following line of therapy and OS of 12.4 months in a real‐world population study without CAR‐T or bispecific therapy. 13 In CARTITUDE‐1, the overall response (OR) of cilta‐cel was 97.9%, of whom 82.5% achieved a CR. At the latest update at 33.4 months, median PFS was 34.9 months and OS was not reached, with 62.9% alive at 36 months 14 ; MRD negativity was 91.8%, with 55% sustained for ≥12 months. These results are unprecedented in myeloma therapy. The results of the KarMMa‐1 trial demonstrated numerically lower response rates, PFS and OS, which may reflect a higher proportion of patients with poor prognostic factors such as extramedullary disease (39%) and high‐risk cytogenetics (35%) (Table 1). 15

Table 1.

Clinical efficacy data for CAR‐T therapies cilta‐cel and ide‐cel from pivotal studies

Drug (pivotal trial) Patients (n) Median prior lines of treatment, n (range) Triple‐class refractory Overall response Complete response MRD negativity, n (%) PFS (months) (95% CI) OS (months) (95% CI)
Cilta‐cel (CARTITUDE‐1) 14 , 19 97 (CAR‐T infused) 6 (4–8) 85 (87.6%) 95 (97.9%) 80 (82.5%) 56 (91.8%, of 61 evaluable patients) 34.9 (25.2–NR) Not reached
Cilta‐cel (CARTITUDE‐4) 16 208 (enrolled) 2 (1–3) 30 (14.4%) 176 (84.6%) 152 (73.1%) 126 (60.6%) Not reached versus SOC 11.8 (9.7–13.8); HR 0.26 (0.18–0.39, P < 0.001) Not reported
Ide‐cel (KarMMa‐1) 15 128 (CAR‐T infused) 6 (3–16) 108 (84.4%) 94 (73.4%) 42 (32.8%) 33 (25.7%) 8.8 (5.6–11.6) 19.4 (18.2–NE)
Ide‐cel (KarMMa‐3) 18 254 (enrolled) 3 (2–4) 164 (64.6%) 181 (71.3%) 98 (38.6%) 51 (20.1%) 13.3 (11.8–16.1) versus SOC 4.4 (3.4–5.9); HR 0.49 (0.38–0.65, P < 0.001) 41.4 (30.9–NR) adjusted for cross‐over versus 23.4 (SOC)
Open in a new tab

CAR‐T, chimeric antigen receptor T cell; HR, hazard ratio; MRD, minimal residual disease, as determined sensitivity threshold of 10−5; NE, not estimable; OS, overall survival; PFS, progression‐free survival; SOC, standard of care.

These encouraging results were followed by the demonstration of efficacy in earlier lines of treatment (Table 1). Patients who had received one to three prior lines were enrolled in CARTITUDE‐4, which compared cilta‐cel with international SOC of anti‐CD38 antibody, PI/IMiD combinations (pomalidomide, bortezomib, dexamethasone (PVd), or daratumamab, pomalidomide, dexamethasone (DPd)). The median PFS was superior for cilta‐cel compared to control (not‐reached vs 11.8 months; HR 0.26, P < 0.001). 16 A recent analysis of patients in CARTITUDE‐4 with functional high risk, defined as disease progression within 18 months after ASCT or start of frontline treatment, also found an improved PFS for cilta‐cel versus SOC (not reached vs 12 months, HR 0.27, P = 0.006), suggesting that cilta‐cel can mitigate or overcome high‐risk disease. 17 Ide‐cel was also compared with SOC in the KarMMa‐3 study in patients with two to four prior lines. Median PFS was 13.3 months for ide‐cel, versus 4.4 months for SOC (HR = 0.49; P < 0.001). While OS was not significantly different, a predetermined adjustment for cross‐over showed an OS benefit of ide‐cel (Table 1). 18 Both CAR T‐cell products delivered higher response and MRD rates than SOC. A notable criticism was the use of daratumumab in patients previously refractory to anti‐CD38 antibodies.

The risk–benefit balance: challenges in CAR‐T therapy

The unique challenges in managing significant toxicities of CAR‐T therapy have led to new protocols in patient care. Cytokine release syndrome (CRS) is a systemic inflammatory reaction varying in severity, from fever to hypotension and hypoxaemia, escalating to multi‐organ deterioration. It occurs in the majority of patients with myeloma (88%–95% in pivotal trials), but only 5% were severe (≥grade 3). Management protocols are well established, utilising agents such as steroids, tocilizumab and anakinra.

Neurotoxicity is another important toxicity, usually of early onset (1–2 weeks after infusion) – termed immune effector cell‐associated neurotoxicity syndrome (ICANS). This can also vary in severity with a range of presentations, such as word‐finding difficulties, dysgraphia and confusion, to severe cases with cerebral oedema and coma. The incidence of severe ICANS in KarMMa‐1 and CARTITUDE‐1 were 3% and 9% respectively. 15 , 19 Therapeutic protocols are also well established including steroids, tocilizumab, anakinra and anti‐epileptic medications. However, in severe and resistant cases, other strategies such as intrathecal and systemic chemotherapy have also been used with varying efficacy. 20 Neurotoxicity of subacute and late‐onset has been more prominent in myeloma than other diseases, including Guillain–Barré syndrome, cranial nerve palsies and Parkinsonism, the latter also termed movement and neurocognitive treatment‐emergent events (MNTs,) with a median onset of 27 (14–108) days after infusion in CARTITUDE‐1. Ongoing investigations into its pathogenesis are crucial to elucidate preventive and therapeutic strategies. So far, predisposing factors include high tumour burden, higher‐grade CRS or any grade ICANS, and high CAR T‐cell expansion/persistence. There is also evidence of a correlation with an early rise of absolute lymphocyte count (ALC). Strategies implemented to prevent and manage MNTs include enhanced bridging therapy to reduce tumour burden, early aggressive treatment of CRS and ICANS, use of steroids in high elevations of ALC after infusion and early symptom detection (e.g. with handwriting assessment).

Other toxicities include cytopenia, usually of early onset but can be prolonged up to 6–12 months and hypogammaglobulinaemia with infection risk. Management follows standard haematological protocols, for example, colony‐stimulating factors, usually avoiding early use to prevent CRS exacerbation. In refractory cytopenia, stem cell re‐infusions have been applied with variable efficacy. Haemophagocytic lymphohistiocytosis (HLH) features can overlap with CRS, described as a specific immune effector cell‐associated HLH syndrome (IEC‐HS). Management includes steroids, IL6‐blockade, anakinra, ruxolitinib (a JAK‐2 inhibitor) and emapalumab (a gamma‐interferon antibody).

There is also an increased risk of secondary malignancies from CAR‐T therapies, added to the risk from myeloma‐associated immunosuppression and prior treatments (especially alkylating agents and iMiDs). For cilta‐cel, myeloid neoplasms (myelodysplastic syndrome and acute myeloid leukaemia) were observed in 10 out of 97 patients in CARTITUDE‐1. 14 , 19 As these patients were heavily pretreated (a median of six prior lines), evaluating secondary malignancy risk in less extensively treated patients receiving CAR‐T would be more informative. In CARTITUDE‐4, patients received cilta‐cel following a median of two prior lines, the incidence was 4% 16 and 6% in the KarMMa‐3 trial with a median of three prior lines. 18 , 20 One study revealed that myeloid gene mutations present before CAR‐T were expanded following treatment, raising the possibility that CAR‐T may promote the expansion of pre‐existing clones. 21 Secondary T‐cell malignancies were highlighted by the FDA in late 2023 after 22 cases were notified from five of the six registered CAR‐T products covering lymphoma, acute lymphoblastic leukaemia and myeloma, out of 27 000 CAR‐T doses. Genetic analysis in some, but not all, cases demonstrated the CAR transgene in the malignant clone, indicating that the CAR‐T product was involved in the pathogenesis. Overall, T‐cell malignancies and other secondary cancers occurring after CAR‐T cells are relatively rare, and the risk:benefit balance would likely favour CAR‐T at least in RMM. Whether this applies to frontline treatment will require more data and prolonged follow‐up from current trials.

Current and ongoing developments in CAR‐T for myeloma in Australia

Clinical trials are in progress in Australia using cilta‐cel in NDMM for TE and NTE patients. Other new developments include novel manufacturing platforms aiming to preserve T‐cell stemness, achieve robust in vivo expansion and prolong CAR‐T cell persistence; shorter manufacturing times would benefit patients with rapidly progressive disease. Another CAR‐T therapy anticipated in trials in Australia targets the non‐BCMA target GPRC5D which has shown efficacy. 9

Due to the significant risks of CAR‐T therapy which require specialised knowledge and multidisciplinary care, it is acknowledged by professional organisations such as the American (ASTCT) and Australia and New Zealand Society of Transplantation and Cellular Therapy (ANZTCT) that haematology units with appropriate experience, training and infrastructure should be designated CAR‐T units with specific accreditation. In the United States and Europe, this is undertaken by the Foundation of the Accreditation of Cellular Therapy (FACT) and the Joint Accreditation Committee of International Society of Cell and Gene Therapy‐Europe and EBMT (JACIE) respectively. Australian units have undergone or are attaining such accreditation according to international standards.

T‐cell‐engaging bispecific antibodies

T‐cell‐engaging bispecific antibodies (bispecifics) induce T‐cell cytotoxicity by engaging effector T cells with the tumour cell. The current bispecifics mostly have IgG‐like structures, simultaneously targeting CD3 on T cells and a myeloma antigen such as BCMA to enable HLA‐independent T‐cell killing. Bispecifics are available ‘off‐the‐shelf’, a particular advantage for patients with rapidly progressive disease. However, most protocols still recommend initial inpatient therapy for management of side‐effects such as CRS before transition to an outpatient setting and are mostly administered until disease progression.

Pivotal studies of bispecifics in myeloma

There are three bispecifics currently approved by the FDA for myeloma: teclistamab and elranatamab which target BCMA, and talquetamab which targets GPRC5D, an antigen primarily expressed in plasma cells but also in other tissues (Table 2). Linvoseltamab, also directed against BCMA, is currently undergoing review. Australian centres are involved in clinical studies in all these agents, but availability for general use is to be determined.

Table 2.

Clinical efficacy data for bispecific antibody therapies elranatamab, talquetamab and teclistamab from pivotal studies

Drug (pivotal trial) Patients (n) Median prior lines of treatment, n (range) Triple‐class refractory Overall response Complete response MRD negativity PFS months (95% CI) OS months (95% CI)
Elranatamab (MagnetisMM‐3) 24 123 5 (2–12) 119 (96.7%) 75 (61.0%) 46 (37.4%) 27 (89.7%, of 30 evaluable patients) 17.2 (9.8–NE) Not reached
Talquetamab 0.8 mg/kg second weekly (MonumenTAL‐1) 25 , 26 145 5 (2–17) 100 (69.0%) 106 (73.1%) 47 (32.4%) 69% (of 16 evaluable patients with CR or sCR) 11.2 (8.4–14.6) Not reported
Teclistamab (MajesTEC‐1) 22 165 5 (2–14) 128 (77.6%) 104 (63.0%) 65 (39.4%) 44 (26.7%) 11.3 (8.8–17.1) 18.3 (15.1–NE)
Open in a new tab

MRD, minimal residual disease, as determined sensitivity threshold of 10−5; NE, not estimable; OS, overall survival; PFS, progression‐free survival.

The first FDA‐approved bispecific therapy was teclistamab, directed against CD3xBCMA, first demonstrated to be efficacious in patients with a median of five prior lines and 77.6% triple‐class refractory. The results were encouraging with PFS 11.3 months, OS 18.3 months and 26.7% MRD negativity. 22 Elranatamab, another CD3xBCMA‐targeting bispecific yielded favourable results in the MagnetisMM‐3 study of patients with median five prior lines and 96.7% triple class refractory, showing PFS 17·2 months and median OS not reached. 23 , 24 For talquetamab targeting GPRC5D, another myeloma antigen with unique and wider expression, the pivotal trial in a similar population (median six prior lines) showed a PFS of up to 11.2 months in the latest update. 25 , 26 As talquetamab is directed against a non‐BCMA antigen, its effectiveness in patients previously exposed to BCMA‐directed therapies such as CAR‐T or bispecifics is of particular interest – OR was favourable at 67%–84%, comparable with BCMA‐naïve patients of 70%–74%. Several bispecifics such as ones directed against both BCMA and GPRC5D, as well as non‐BCMA targets such as FcRH5 continue in development. 10 , 12

Toxicities of bispecifics – another consideration of risk versus benefit

Infections and CRS are two major side effects of bispecifics. The prevalence of infections may be attributed to mechanisms such as T‐cell exhaustion or depletion of specific T‐cell subsets, as well as neutropenia and hypogammaglobinaemia. In the registrational studies of teclistamab and elranatamab, total infection rates were 76% and 67%, respectively, with high rates of severe (≥grade 3) infections at 45% and 35%. 22 , 23 Given these concerns, the IMWG guidelines suggest prophylactic antibiotics during periods of highest risk in the first few cycles or if prolonged steroids are required, while emphasising the importance of viral and pneumocystis prophylaxis. 27 Intravenous immunoglobulin has been recommended for all patients with IgG levels of less than 4 g/L. The non‐BCMA targeting bispecific talquetamab appears to be associated with a lower severe infection rate. 26 Overall, CRS occurred in 58%–72%, mostly mild, with step‐up dosing as mitigation; prophylactic tocilizumab has been shown to reduce the incidence and severity of CRS. 22 , 23 , 26 , 28 Management is similar to CAR‐Ts which include tocilizumab, steroids and supportive care as the key elements. ICANS has been reported in 3%–4% in the pivotal teclistamab and elranatamab trials, but more frequently for talquetamab of approximately 10%, mostly mild. So far, no delayed neurotoxicity/Parkinsonian syndromes have been observed. Cytopenias are common with severe neutropenia occurring in up to two‐thirds of patients and severe thrombocytopenia in up to 26%. Unique on‐target, off‐tumour side effects can also occur for talquetamab as GPRC5D is expressed in keratinised tissues of the skin and oral mucosa and neural tissue such as the inferior olivary nucleus important in cerebellar function, resulting in toxicities such as dysgeusia, nail and skin disorders, with no cerebellar disorders to date. 26

Ongoing bispecific developments and challenges in Australia

Efforts are directed at moving the approved agents towards the frontline and expanding the number of agents and potential targets, such as FcRH5 for which current trials are being conducted in Australia. 12 Studies evaluating the use of bispecifics in earlier lines of treatment are also in progress in many Australian centres. In both TE and NTE patients, the addition of bispecifics to induction and/or maintenance regimens, including the use in combination with other myeloma agents such as anti‐CD38 antibodies and immunomodulators, are currently trialled. Furthermore, combination studies of bispecifics with different targets, such as teclistamab and talqueltamab, are explored; in multiply relapsed patients (median five prior lines), early data demonstrated OR up to 92% and CR of 31%, approaching response rates of CAR‐T, although survival outcomes are awaited. 29

A major challenge in Australia is to adapt these protocols to outpatient settings, which would require significant support of ambulatory facilities such as personnel and early re‐admission systems to ensure patient safety, and increase accessibility. Fixed‐duration therapy to enable treatment‐free periods and improve quality of life is investigated, in the hope of demonstrating equal efficacy with current protocols of treatment until progression. 12 Prophylactic measures to reduce toxicities, such as the administration of tocilizumab to decrease the incidence and severity of CRS, may improve the feasibility of outpatient administration and warrant continued investigation.

Sequencing of CAR‐T cell therapy and bispecifics

The simultaneous development of these two immunotherapies which share many biologic targets has raised important questions on optimal sequencing. Limited data suggest a reduced CAR‐T‐cell therapy response rate in patients previously exposed to anti‐BCMA therapy, so a CAR‐T before bispecific strategy is probably advocated where both are available. 30 However, there are also data demonstrating that non‐BCMA targeting CAR‐T‐cell therapy and bispecific following BCMA‐targeting immunotherapy can still deliver high OR. A proportion of anti‐BCMA resistant cases may be explained by deletions or mutations in the genes encoding BCMA (TNFRSF17) that result in loss of expression or an epitope change in the extracellular domain. This can arise after CAR‐T but appears more common due to the selective pressure imposed by the continuous therapy of bispecifics. 31 , 32 These observations suggest that alternating biologic targets may be an important strategy to optimise outcomes, and it is possible to envisage for the future that personalised treatment could be based on molecular lesions unique to each patient at relapse.

Conclusion

The landscape of myeloma therapy has changed dramatically in recent years, with the development of T‐cell re‐directional therapies of CAR‐T therapy and bispecific antibodies. An unprecedented level of efficacy has been possible due to highly specialised clinical expertise within the setting of significant infrastructure requirements. To date, both modalities have been accessible through clinical trials in Australia. The approval of the first CAR‐T therapy for myeloma in Australia in 2024 is the first step to ensure that the scientific gains made, to which Australia has significantly contributed, will be realised for the benefit of our patients. This requires the concerted efforts of all stakeholders – government, biotechnological industry, physicians and academia, to ensure efficient and equitable access in the community. Despite the optimism, a ‘cure’ – the ultimate goal – remains on the horizon as relapses continue to occur. Highly innovative research in which Australia plays a major role, including the search for more targets and combinations, moving both modalities towards the frontline, and novel strategies in sequencing and mitigating toxicities, could bring us closer to the goal. CAR‐T therapy and bispecifics have heralded a new era of T‐cell immunotherapy in myeloma.

Acknowledgements

Sydney Blood Cancer Research Institute for ongoing support of research in MM. Open access publishing facilitated by The University of Sydney, as part of the Wiley ‐ The University of Sydney agreement via the Council of Australian University Librarians.

Funding: None.

Conflict of interest: P. J. Ho: Advisory board (no honorarium accepted): Antengene, Gilead, GSK, Janssen, Pfizer; Research support: Novartis, Janssen. E. W. Li: None to declare.

References

  • 1. Australia and New Zealand Myeloma and Related Diseases Registry (ANZMRDR) . Data provided by personal communication, A. Spencer, 2024. https://www.mrdr.net.au.
  • 2. Surveillance, Epidemiology and End Results (SEER) Program . Cancer Stat Facts: Multiple Myeloma (2014–2020) [cited 2024 Sept 5]. Available from URL: https://seer.cancer.gov/statfacts/html/mulmy.html
  • 3. Joshua DE, Bryant C, Dix C, Gibson J, Ho PJ. Biology and therapy of multiple myeloma. Med J Aust 2019; 210: 375–380. [DOI] [PubMed] [Google Scholar]
  • 4. van de Donk N, Zweegman S. Monoclonal antibodies in the treatment of multiple myeloma. Hematol Oncol Clin North Am 2024; 38: 337–360. [DOI] [PubMed] [Google Scholar]
  • 5. Dimopoulos MA, Beksac M, Pour L, Delimpasi S, Vorobyev V, Quach H et al. Belantamab mafodotin, pomalidomide, and dexamethasone in multiple myeloma. N Engl J Med 2024; 391: 408–421. [DOI] [PubMed] [Google Scholar]
  • 6. Hungria V, Robak P, Hus M, Zherebtsova V, Ward C, Ho PJ et al. Belantamab mafodotin, bortezomib, and dexamethasone for multiple myeloma. N Engl J Med 2024; 391: 393–407. [DOI] [PubMed] [Google Scholar]
  • 7. Bal S, Costa LJ. Best practices for the assessment of measurable residual disease (MRD) in multiple myeloma. Clin Adv Hematol Oncol 2020; 18(Suppl 1): 1–20. [PubMed] [Google Scholar]
  • 8. Shah N, Chari A, Scott E, Mezzi K, Usmani SZ. B‐cell maturation antigen (BCMA) in multiple myeloma: rationale for targeting and current therapeutic approaches. Leukemia 2020; 34: 985–1005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9. Mailankody S, Devlin SM, Landa J, Nath K, Diamonte C, Carstens EJ et al. GPRC5D‐targeted CAR T cells for myeloma. N Engl J Med 2022; 387: 1196–1206. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10. Mei H, Li C, Jiang H, Zhao X, Huang Z, Jin D et al. A bispecific CAR‐T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma. J Hematol Oncol 2021; 14: 161. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11. Prommersberger S, Reiser M, Beckmann J, Danhof S, Amberger M, Quade‐Lyssy P et al. CARAMBA: a first‐in‐human clinical trial with SLAMF7 CAR‐T cells prepared by virus‐free Sleeping Beauty gene transfer to treat multiple myeloma. Gene Ther 2021; 28: 560–571. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12. Lesokhin A, Richter J, Trudel S, Cohen AD, Spencer A, Forsberg PA et al. Enduring responses after 1‐year, fixed‐duration cevostamab therapy in patients with relapsed/refractory multiple myeloma: early experience from a phase I study. Blood 2022; 140: 4415–4417. [Google Scholar]
  • 13. Mateos MV, Weisel K, De Stefano V, Goldschmidt H, Delforge M, Mohty M et al. LocoMMotion: a prospective, non‐interventional, multinational study of real‐life current standards of care in patients with relapsed and/or refractory multiple myeloma. Leukemia 2022; 36: 1371–1376. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14. Lin Y, Martin T, Usmani SZ, Berdeja J, Jakubowiak A, Agha M et al. CARTITUDE‐1 final results: phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma. J Clin Oncol 2023; 41: 8009. [Google Scholar]
  • 15. Munshi NC, Anderson LD Jr, Shah N, Madduri D, Berdeja J, Lonial S et al. Idecabtagene vicleucel in relapsed and refractory multiple myeloma. N Engl J Med 2021; 384: 705–716. [DOI] [PubMed] [Google Scholar]
  • 16. San‐Miguel J, Dhakal B, Yong K, Spencer A, Anguille S, Mateos MV et al. Cilta‐cel or standard care in lenalidomide‐refractory multiple myeloma. N Engl J Med 2023; 389: 335–347. [DOI] [PubMed] [Google Scholar]
  • 17. Costa L, Weisel K, van de Donk N, Sidana S, Cohen YC, Purtill D et al. Ciltacabtagene autoleucel vs standard of care in patients with functional high‐risk multiple myeloma: CARTITUDE‐4 subgroup analysis. J Clin Oncol 2023; 42: 7504. [Google Scholar]
  • 18. Rodríguez‐Otero P, Ailawadhi S, Arnulf B, Patel KK, Cavo M, Nooka A et al. Idecabtagene vicleucel (ide‐cel) versus standard (std) regimens in patients (pts) with triple‐class‐exposed (TCE) relapsed and refractory multiple myeloma (RRMM): updated analysis from KarMMa‐3. Blood 2023; 142: 1028–1032.37707872 [Google Scholar]
  • 19. Martin T, Usmani SZ, Berdeja JG, Agha M, Cohen AD, Hari P et al. Ciltacabtagene autoleucel, an anti‐B‐cell maturation antigen chimeric antigen receptor T‐cell therapy, for relapsed/refractory multiple myeloma: CARTITUDE‐1 2‐year follow‐up. J Clin Oncol 2023; 41: 1265–1274. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 20. Lin Y, Qiu L, Usmani S, Joo CW, Costa L, Derman B et al. Consensus guidelines and recommendations for the management and response assessment of chimeric antigen receptor T‐cell therapy in clinical practice for relapsed and refractory multiple myeloma: a report from the International Myeloma Working Group Immunotherapy Committee. Lancet Oncol 2024; 25: e374–e387. [DOI] [PubMed] [Google Scholar]
  • 21. Vainstein V, Avni B, Grisariu S, Kfir‐Erenfeld S, Asherie N, Nachmias B et al. Clonal myeloid dysplasia following CAR T‐cell therapy: chicken or the egg? Cancer 2023; 15: 3471–3480. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 22. Moreau P, Garfall AL, van de Donk N, Nahi H, San‐Miguel JF, Oriol A et al. Teclistamab in relapsed or refractory multiple myeloma. N Engl J Med 2022; 387: 495–505. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23. Lesokhin AM, Tomasson MH, Arnulf B, Bahlis NJ, Miles Prince H, Niesvizky R et al. Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM‐3 trial results. Nat Med 2023; 29: 2259–2267. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24. Tomasson MH, Iida S, Niesvizky R, Mohty M, Bahlis N, Martinez‐Lopez J et al. Long‐term efficacy and safety of elranatamab monotherapy in the phase 2 MagnetisMM‐3 trial in relapsed or refractory multiple myeloma (RRMM). Blood 2023; 142: 3385–3386. [Google Scholar]
  • 25. Rasche L, Schinke C, Touzeau C, Minnema MC, van de Donk N, Rodriguez‐Otero P, et al. Long‐term efficacy and safety results from the phase 1/2 monumental‐1 study of talquetamab, a GPRC5D×CD3 bispecific antibody, in patients with relapsed/refractory multiple myeloma. EHA 2024 (Hemasphere); 2024; P915.
  • 26. Chari A, Minnema MC, Berdeja JG, Oriol A, van de Donk N, Rodríguez‐Otero P et al. Talquetamab, a T‐cell‐redirecting GPRC5D bispecific antibody for multiple myeloma. N Engl J Med 2022; 387: 2232–2244. [DOI] [PubMed] [Google Scholar]
  • 27. Rodriguez‐Otero P, Usmani S, Cohen AD, van de Donk N, Leleu X, Gállego Pérez‐Larraya J et al. International Myeloma Working Group immunotherapy committee consensus guidelines and recommendations for optimal use of T‐cell‐engaging bispecific antibodies in multiple myeloma. Lancet Oncol 2024; 25: e205–e216. [DOI] [PubMed] [Google Scholar]
  • 28. Scott SA, Marin EM, Maples KT, Joseph NS, Hofmeister CC, Gupta VA et al. Prophylactic tocilizumab to prevent cytokine release syndrome (CRS) with teclistamab: a single‐center experience. Blood Cancer J 2023; 13: 191. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 29. Cohen YC, Morillo D, Gatt ME, Sebag M, Kim K, Min CK et al. First results from the RedirecTT‐1 study with teclistamab (tec) + talquetamab (tal) simultaneously targeting BCMA and GPRC5D in patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol 2023; 41: 8002. [Google Scholar]
  • 30. Cohen AD, Mateos MV, Cohen YC, Rodriguez‐Otero P, Paiva B, van de Donk N et al. Efficacy and safety of cilta‐cel in patients with progressive multiple myeloma after exposure to other BCMA‐targeting agents. Blood 2023; 141: 219–230. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 31. Lee H, Ahn S, Maity R, Leblay N, Ziccheddu B, Truger M et al. Mechanisms of antigen escape from BCMA‐ or GPRC5D‐targeted immunotherapies in multiple myeloma. Nat Med 2023; 29: 2295–2306. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32. Zhou X, Rasche L, Kortüm KM, Mersi J, Einsele H. BCMA loss in the epoch of novel immunotherapy for multiple myeloma: from biology to clinical practice. Haematologica 2023; 108: 958–968. [DOI] [PMC free article] [PubMed] [Google Scholar]

Articles from Internal Medicine Journal are provided here courtesy of Wiley

RESOURCES