Терапевтические варианты внематочного участия в миеломе.

Introduction

Multiple myeloma is the second most common hematologic malignancy, characterized by clonal proliferation of malignant plasma cells in the bone marrow [ 1 ]. In a minority of patients, myeloma subclones infiltrate extramedullary tissues or organs, forming soft tissue masses or diffuse infiltrations—a condition defined as extramedullary involvement (extramedullary disease, EMD) [ 2 ]. The current definition of EMD remains non-uniform, with two primary manifestations: (a) myeloma cells breaching the cortical bone to form adjacent soft tissue masses, typically presenting as osteolytic lesions with contiguous soft tissue involvement—designated as EM-B (bone-associated type); and (b) hematogenous dissemination of soft tissues or organs without bony contact, termed extramedullary extraosseous (EM-E) [ 2 – 4 ]. This distinction is clinically critical, as retrospective analyses demonstrate significantly worse prognosis in EM-E patients compared with EM-B cases [ 3 , 5 ]. Consequently, current consensus guidelines tend to exclude paraosseous lesions from the formal EMD definition [ 6 , 7 ]. Notably, solitary plasmacytoma (defined as a single extramedullary plasma cell lesion with < 10% clonal plasma cells in bone marrow) falls outside the EMD classification [ 8 ]. EMD may involve virtually any anatomical site, with a predilection for the skin, liver, lymph nodes, pleura, soft tissues, kidneys, and central nervous system [ 9 , 10 ]. When circulating myeloma cells exceed 5% of the peripheral blood, the diagnosis shifts to plasma cell leukemia (PCL), which is typically excluded from contemporary definitions of EMD [ 9 , 11 ].

EMD may occur either at initial diagnosis (primary) or during disease relapse (secondary), demonstrating highly aggressive clinical progression [ 3 , 12 ]. Recent advances in modern imaging techniques (e.g., CT, MRI, and PET/CT) and prolonged patient survival have revealed higher EMD incidence rates than historically reported [ 13 , 14 ]. Current data indicate EMD frequencies of 7%–17% at diagnosis and 6%–20% at relapse, with paraskeletal involvement predominating (85% of cases) [ 15 – 17 ]. The formation of EMD originates from the "bone marrow escape" of plasma cell subclones, which detach from the dependency on the bone marrow microenvironment and infiltrate into soft tissues [ 18 , 19 ]. The molecular mechanisms underlying its development are not yet fully understood. Studies have demonstrated that multiple genetic abnormalities, impaired homing capacity, enhanced invasiveness, and immune evasion are all involved in the pathogenesis of EMD [ 18 , 20 , 21 ].

EMD is inherently a high-risk disease stage, with EMD patients exhibiting significantly shorter overall survival (OS) and progression-free survival (PFS) compared with non-EMD patients [ 22 , 23 ]. The treatment landscape of MM has undergone remarkable changes with the frontline use of proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and anti-CD38 monoclonal antibody-based immunotherapies, leading to improved patient outcomes and an extension of median survival from approximately 3 years to 8–10 years [ 24 ]. The advent of immunotherapy and other novel mechanism-based agents has further brought hope for the treatment of relapsed/refractory multiple myeloma (RRMM) [ 13 ]. However, evidence-based guidance on optimal treatment strategies for EMD patients in the current era remains scarce, representing an unmet clinical need. This review systematically evaluates the efficacy of current therapeutic regimens for MM patients with EMD, providing evidence-based references to guide clinical decision-making.

Pathogenesis

A comprehensive understanding of the pathogenesis of EMD is crucial for elucidating drug resistance and facilitating the development of novel therapeutic agents. The extramedullary infiltration of MM involves complex molecular mechanisms. Currently, widely recognized mechanisms include genetic abnormalities, the roles of adhesion molecules and chemokines, immune evasion, and other factors.

Recent studies have clarified the genetic abnormalities driving extramedullary infiltration in MM. Nakamoto-Matsubara et al. [ 25 ] analyzed 528 MM patients and confirmed that RAS / BRAF mutations are likely essential for EMD, with additional poor prognostic factors like 1q duplication and del(17p) strongly linked to EMD progression. TP53 gain-of-function mutations are more prevalent in EMD patients compared to non-EMD cohorts, suggesting their potential role in extramedullary progression. Bingham et al. [ 26 ] identified clonal MAPK pathway-activating mutations in 80% of EMD patients, alongside frequent MYC oncogene activation, with these mutations consistently present across sequential biopsies from various anatomical sites, underscoring the critical role of MAPK signaling in EMD pathogenesis. These findings highlight distinct molecular abnormalities in EMD and provide a foundation for targeted therapeutic strategies.

Spatial heterogeneity in MM underscores the genetic divergence between medullary and extramedullary lesions, offering insights into clonal evolution and its genetic underpinnings. EMD lesions exhibit distinct molecular profiles, including recurrent RAS / BRAF mutations, downregulation of CXCR4, and reduced expression of therapeutic targets such as CD38 and signaling lymphocytic activation molecule family member 7 (SLAMF7) [ 27 ]. A study combining spatial transcriptomics and single-cell RNA sequencing of 14 EMD biopsies revealed marked copy number variation and localized emergence of novel subclones, reflecting genomic instability. Spatially heterogeneous expression of bispecific antibody targets further supports the rationale for dual-targeted therapies [ 21 ]. These findings suggest that EMD originates from genetically distinct subclones capable of surviving outside the bone marrow, which may underlie their resistance to standard therapies effective in medullary disease.

The roles of adhesion molecules and chemokines involve multiple mechanisms, including the disruption of CXCR4/CXCL12 signaling, the loss of CD56 expression, and the upregulation of CD44 and VLA-4 (very late antigen-4)/VCAM-1 (vascular cell adhesion molecule-1, CD106) interactions. These collective changes enable myeloma cells to detach from the bone marrow microenvironment and invade extramedullary sites [ 28 – 31 ]. Angiogenesis-related cytokines (e.g., VEGF and FGF) are upregulated during extramedullary infiltration, promoting tumor invasiveness [ 18 ]. Immune escape is driven by an immunosuppressive microenvironment, in which functionally exhausted TIM3 + /PD-1 + T cells spatially colocalize with myeloma cells, leading to impaired immune surveillance [ 21 ]. Epigenetic, the regulatory roles of non-coding RNAs, and treatment pressure also play a role, but these factors have not been extensively studied.

Treatment strategies

The treatment goals for patients with EMD are to achieve optimal hematologic response and EMD lesion disappearance, ameliorate end-organ dysfunction, and ultimately achieve long-term survival. Currently, available therapeutic agents for EMD include PIs, IMiDs, immunotherapies (such as monoclonal antibodies, bispecific antibodies, and chimeric antigen receptor T (CAR-T) cells), and other small-molecule targeted drugs (Fig. 1 ). Fig. 1 Drugs approved in multiple myeloma as per year of first approval by the FDA

Proteasome inhibitors

PIs induce apoptosis in plasma cells by inhibiting the 26S proteasome, leading to toxic protein accumulation and endoplasmic reticulum stress.

Bortezomib, the first proteasome inhibitor to be studied, is a first-line recommended treatment for newly diagnosed multiple myeloma (NDMM). An early study involving 23 RRMM patients, including four with EMD, showed that three of the four achieved complete EMD regression after bortezomib treatment [ 32 ]. The Mayo Clinic’s 2017 guidelines also recommend bortezomib-based regimens for EMD [ 33 ], highlighting its significant efficacy against extramedullary MM.

Ixazomib, a second-generation proteasome inhibitor, has limited clinical data regarding its efficacy in EMD patients. The study by Minarik et al. [ 34 ] demonstrated that EMD patients derived limited therapeutic benefit from an ixazomib-based regimen.

In the study by Muchtar et al. [ 35 ], the efficacy of carfilzomib was evaluated as salvage therapy for RRMM (Table 1 ). The results showed that the overall response rate (ORR) was 40% in patients with EMD and 49% in those without EMD, with no significant difference between the two groups. However, compared with non-EMD patients, EMD patients demonstrated a shorter duration of response (DOR) (9.3 months vs 3.9 months; p = 0.06). Another multicenter retrospective study evaluated 364 RRMM patients treated with the KRd regimen (Carfilzomib, lenalidomide, and dexamethasone), including 88 cases (24%) with EMD. The results demonstrated that although EMD remained a poor prognostic factor, this subgroup still achieved an 83% ORR, with median PFS and OS reaching 14 months and 36 months, respectively [ 36 ]. The ORR with the KRd regimen was comparable to that observed with bispecific antibody therapy in EMD patients [ 37 ]. These findings suggest that the KRd regimen demonstrates relatively favorable efficacy with a manageable safety profile in treating RRMM patients with EMD. Table 1 Carfilzomib, Pomalidomide, and anti-CD38 antibody for extramedullary disease in multiple myeloma Patient group Patient (n)/ EMD (n) Line of previous treatment Treatment Efficacy Survival Ref RRMM 135(32) median 3 Carfilzomib-based therapy EMD vs. non-EMD: ORR: 40%, 49% EMD vs. non-EMD: DOR: 3.9 months, 9.3 months [ 35 ] RRMM 364(88) median 1 KRD EMD vs. all patients: ORR: 83%, 90% EMD vs. all patients: mPFS: 14 months, 23.4 months; mOS: 36 months, 69.5 months [ 36 ] RRMM 45(45) (EM-B: 20; EM-E: 25) median 4 Carfilzomib-based therapy EMD: ORR: 59% Extramedullary lesions: ORR:27% EMD: mPFS: 5 months; mOS: 10 months [ 38 ] RRMM 174(13) median 6 Pom + low-dose dex EMD: ORR: 31% EMD vs. non-EMD: mOS: 16 months, NR [ 12 ] RRMM 6(6) (EM-B: 4; EM-E: 2) median 4 PAD/DP-PACE/VPD EMD: ORR: 83% EMD: mPFS: 5 months; mOS: 8 months [ 39 ] RRMM 36(5) (EM-B: 4; EM-E: 1) median 6.5 Pom + low-dose dex EMD vs. all patients: ORR: 0%, 42% ND [ 40 ] RRMM 148(18) median 5 Dara EMD vs. non-EMD: ORR: 16.7%, 33.1% EMD: ND; All patients: mPFS: 4 months; mOS: 20.1 months [ 41 ] RRMM 106(14) median 5 Dara EMD vs. non-EMD: ORR: 21.4%, 30.4% EMD: ND; All patients: mPFS: 3.7 months; mOS: 17.5 months [ 42 ] RRMM 186(41) (EM-B: 31; EM-E: 10) median 5 Dara-Rd EMD vs. non-EMD: ORR: 57.7%, 85.4% EMD vs. non-EMD: mPFS: 7.8 months, 27.3 months [ 43 ] RRMM 32(32) median 3 Dara-DCEP EMD: ORR: 67.7%; CR: 35.5% EMD: mPFS: 5 months; mOS: 10 months [ 44 ] Abbreviations: EMD, extramedullary disease; RRMM, relapsed/refractory multiple myeloma; EM-B, EMD, bone-associated; EM-E, extramedullary extraosseous; ORR, overall response rate; CR, complete response; mOS, median overall survival; mPFS, median progression-free survival; ND, no data; NR, not reached; KRD: carfilzomib-lenalidomide-dexamethasone; Pom, Pomalidomide; dex, dexamethasone; PAD, pomalidomide-doxorubicin-dexamethasone; DP-PACE, dexamethasone-pomalidomide-cisplatin-doxorubicin-cyclophosphamide-etoposide; VPD, bortezomib-pomalidomide-dexamethasone; Dara, daratumumab; Dara-Rd, daratumumab-lenalidomide-dexamethasone; DCEP, dexamethasone-cyclophosphamide-etoposide-cisplatin

Immunomodulatory drugs

IMiDs exert their effects through multiple mechanisms, including immune system modulation, suppression of the tumor microenvironment, and direct induction of tumor cell apoptosis, significantly improving outcomes for MM patients. Evolving from the first-generation thalidomide to second- and third-generation agents—lenalidomide and pomalidomide—these small molecules have become cornerstones of modern treatment regimens. Existing research indicates that thalidomide has limited efficacy against EMD and in patients with high-risk genetic features [ 2 , 45 , 46 ]. Although thalidomide significantly improves bone marrow/serologic parameters, the ORR for extramedullary lesions is markedly lower than in standard MM patients. Moreover, extramedullary lesions may continue progressing despite treatment [ 47 , 48 ]. This phenomenon is associated with the drug’s interference with the CXCR4/SDF-1α bone marrow homing pathway and downregulation of CD56 adhesion molecules, leading to tumor cell escape and the formation of "sanctuary" lesions [ 49 , 50 ].

Lenalidomide has become a standard first-line treatment option for NDMM. In a study involving 18 RRMM patients with EMD who received lenalidomide plus dexamethasone treatment, the results showed an ORR of 61.1% (11 patients), including 44.4% (eight patients) achieving complete EMD disappearance and 16.6% (three patients) showing reduced EMD volume. The median PFS and OS were 9.8 months and 14.6 months, respectively, with a 12-month survival rate of 55.6% [ 51 ]. Subsequent studies in this series confirmed that lenalidomide-based combinations yield significantly higher EMD response rates than thalidomide [ 46 , 47 ].

Pomalidomide is a third-generation IMiD with enhanced anti-myeloma activity and a comparable safety profile (Table 1 ). A retrospective analysis by Li et al. [ 39 ] evaluated the efficacy of pomalidomide-based regimens in six EMD patients. The results showed extramedullary ORR was 83% (five patients), including three patients (50%) with complete disappearance of lesions, achieving complete response (CR), and two patients (33%) with ≥ 50% reduction in lesion size, achieving partial response (PR). The median PFS and OS from the diagnosis of EMD were 5 months and 8 months, respectively. Another phase II clinical trial enrolled 174 patients with RRMM, among whom 7.5% (13/174) presented with EMD. These patients were treated with pomalidomide plus low-dose dexamethasone. In the EMD subgroup (n = 13), the ORR for EMD was 31%, comprising two CR and two PR. The EMD patients had a significantly shorter median OS of 16 months compared with the non-EMD patients (not reached, NR) [ 12 ]. This suggests that pomalidomide-containing combination regimens may be a viable treatment option for EMD patients.

Monoclonal antibody

CD38, a key adhesion molecule abundantly expressed in normal and malignant plasma cells (PCs), represents both a diagnostic hallmark of MM cells and a therapeutic target for anti-CD38 antibody (Daratumumab and Isatuximab) therapy (Fig. 2 ). Fig. 2 Novel therapies in multiple myeloma and their mechanisms of action. Abbreviations: CAR-T, chimeric antigen receptor T cells; BCMA, B-cell maturation antigen; GPRC5D, G protein-coupled receptor class C group 5 member D; SLAMF7, signaling lymphocytic activation molecule family member 7; FcRH5, Fc receptor homolog 5; XPO1, exportin 1; Created with BioRender.com

Daratumumab is currently approved for the treatment of NDMM and RRMM. However, daratumumab monotherapy shows limited efficacy in EMD (Table 1 ). A study by Usmani et al. [ 41 ] demonstrated that in heavily pretreated relapsed MM patients, the ORR was 16.7% (n = 18) in those with EMD compared with 33.1% (n = 130) in those without EMD. Combination regimens with daratumumab outperform monotherapy. A retrospective study by Jelinek et al. [ 43 ] involving 186 RRMM patients (41 cases with EMD) treated with daratumumab plus lenalidomide and dexamethasone (Dara-Rd) showed that EMD patients had a lower ORR and shorter median PFS compared with non-EMD patients. Additionally, soft tissue EMD (n = 10, EM-E) had worse median PFS than bone-related EMD (n = 31, EM-B). Another clinical trial evaluated DARA-DCEP (daratumumab with dexamethasone, cyclophosphamide, etoposide, and cisplatin) in 32 RRMM patients with EMD. The results demonstrated CR and ORR rates of 35.5% and 67.7%, with median PFS and OS of 5 months and 10 months, respectively [ 44 ]. Studies suggest that the limited efficacy of CD38-targeted therapy in EMD patients may be partly due to downregulation of CD38 expression in extramedullary plasma cells [ 52 ].

Elotuzumab is a humanized monoclonal antibody targeting SLAMF7. The ELOQUENT-2 study demonstrated that the combination of elotuzumab with lenalidomide and dexamethasone (ERd) significantly improved PFS and OS compared with Rd alone in patients with RRMM [ 53 ]. However, its therapeutic efficacy in patients with EMD remains insufficiently studied. A retrospective analysis by Danhof et al. evaluated elotuzumab-based combination therapy in 15 RRMM patients with EMD. The results showed an ORR of 40%, with median PFS and OS of 3.8 months and 12.9 months, respectively [ 54 ]. These findings indicate that elotuzumab has limited efficacy in EMD, underscoring the need to develop more effective therapeutic strategies.

Selinexor

Selinexor is a selective oral inhibitor of exportin 1 (XPO1) (Fig. 2 ). Myeloma cells rely on XPO1-mediated nucleocytoplasmic transport, and inhibition of this protein can block the nuclear export of key oncoprotein mRNAs. In NDMM patients with EMD, XVRd (Selinexor + Bortezomib + Lenalidomide + Dexamethasone) induction therapy achieved a 100% ORR with a median time to response of just one cycle, suggesting a promising approach for this high-risk population [ 55 ]. The STORM trial enrolled a total of 122 patients with RRMM, all of whom received treatment with the selinexor plus low-dose dexamethasone (Sel-dex) regimen. Among them, 27 had EMD at baseline (22 with EM-E and five with EM-B). Follow-up assessments of plasmacytomas were performed in 16 patients, demonstrating an ORR of only 18.5% (5/27) [ 56 ]. These results confirm that the Sel-dex regimen shows some therapeutic value in patients with EMD, although the clinical benefits remain unsatisfactory.

Chimeric antigen receptor (CAR) T cell therapy

CAR-T cells are engineered cells designed to express synthetic receptors capable of specifically recognizing tumor targets. B-cell maturation antigen (BCMA) is the earliest studied and currently the most clinically validated CAR-T cell therapy target in MM (Fig. 2 ). Currently, the U.S. Food and Drug Administration (FDA) has approved two autologous BCMA-targeted CAR-T cell therapies for RRMM: Idecabtagene vicleucel (ide-cel) and Ciltacabtagene autoleucel (cilta-cel).

BCMA CAR-T therapy has demonstrated excellent efficacy in the treatment of patients with RRMM. However, significant disparities exist in survival outcomes between patients with EMD and those without EMD. We have synthesized clinical data from multiple studies investigating BCMA CAR-T therapy in RRMM patients, with particular focus on evaluating therapeutic efficacy and prognostic outcomes in those with concomitant EMD (Table 2 ). In the Dima et al. cohort [ 57 ], the EMD subgroup (EM-E only, n = 47, 31%) exhibited significantly poorer efficacy metrics compared with non-EMD patients (n = 105, 69%), including reduced ORR (58% vs 96%, p < 0.00001), shorter median PFS (5.1 months vs 12.4 months, p < 0.0001), and inferior median OS (12.2 months vs 27.5 months, p = 0.00058). Further statistical analysis by the authors revealed no significant differences in median PFS and OS between patients with paramedullary plasmacytoma (EM-B) and those with BM-confined disease (BM-only). A retrospective analysis across multiple centers assessed 351 RRMM patients treated with ide-cel, comprising 84 (24%) with EMD (EM-E only) and 267 (76%) without EMD manifestations. A multicenter retrospective analysis evaluated 351 patients with RRMM treated with ide-cel, among whom 84 patients (24%) had extramedullary disease. The results showed that, compared with non-EMD patients, the EMD group had a lower ORR at day 90, as well as shorter median PFS and OS [ 58 ]. Pooled analyses of ide-cel and cilta-cel demonstrated similar ORR regardless of EMD status, but consistently inferior PFS and OS in EMD patients [ 59 ]. Beyond standalone CAR-T immunotherapy, combination strategies with small-molecule drugs may improve therapeutic outcomes. The combination of CAR-T cell therapy and pomalidomide demonstrated excellent tolerability and promising clinical efficacy. The underlying mechanism involves upregulation of IFN-γ and TNF-α secretion [ 60 ]. Two RRMM patients treated with selinexor plus BCMA CAR-T cells achieved stringent CR (sCR) following CAR-T cell infusion and maintained sCR status at data cutoff, with survival durations exceeding 13 months and 10 months, respectively. The study demonstrated that low-dose selinexor upregulates BCMA expression in plasma cell lines and enhances CAR-T cell function in vitro [ 61 ]. These findings provide critical evidence supporting further investigation of this combination therapy in EMD patients. Table 2 CAR-T cell therapies for extramedullary disease in multiple myeloma CAR target Patient group Patient (n)/ EMD (n) Agent Name Line of previous treatment Efficacy Survival Adverse events Ref BCMA RRMM 152 (47) (EM-E: 47) Ide-cel, cilta-cel median 6 EMD vs. non-EMD: ORR: 58% vs. 96%; CR: 28% vs 56% EMD vs. non-EMD: mPFS: 5.1 months, 12.4 months; mOS: 12.2 months, 27.5 months EMD vs. non-EMD: CRS: 81%, 78%; ≥ grade 3 CRS: 11%, 3%; ICANS: 36%, 25%; ≥ grade 3 ICANS: 6%, 7% [ 57 ] BCMA RRMM 269 (112) Ide-cel, Cilta-cel median 6 EMD predicts early relapse/progression post-CAR-T (HR: 1.92) ND ND [ 62 ] BCMA RRMM 20 (5) Cilta-cel median 8 Extramedullary lesions disappeared: 80% ND ND [ 63 ] BCMA RRMM 97 (13) Cilta-cel median 6 ND EMD vs. all patients: mDOR: 12.9 months, 23.3 months ND [ 64 ] BCMA RRMM 128 (50) Ide-cel median 6 ORR of EMD worse than no EMM (no specifics) ND ND [ 65 ] BCMA RRMM 69 (15) Anti-BCMA and anti-CD19 CAR-T cells median 4 EMD: ORR: 80%; EMD vs. non-EMD: mPFS: 8.3 months, 21.4 months mOS: 12.3 months, NR; ND [ 66 ] BCMA RRMM 351 (84) Ide-cel median 6 EMD vs. non-EMD: 90d-ORR: 52%, 82% EMD vs. non-EMD: mPFS: 5.3 months, 11.1 months; mOS: 14.8 months, 26.9 months; EMD vs. non-EMD: ≥ grade 3 CRS: 2%, 1.5%; ≥ grade 3 ICANS: 1%, 5% [ 58 ] BCMA RRMM 61 (27) (EM-B:10, EM-E:7, Both: 10) Anti‐BCMA CAR‐T cells median 3 EMD vs. non-EMD: CR: 59%, 81% EMD vs. non-EMD: 1-year PFS rate: 34.4% vs. 60.2% ND [ 67 ] BCMA RRMM 61 (25) Anti‐BCMA CAR‐T cells median 4 EMD vs. non-EMD: ORR: 84.00%, 94.44% ≥ CR: 36.00%, 61.11% EMD vs. non-EMD: mPFS: 121 days, 361 days; mOS: 248 days, 1024 days EMD vs. non-EMD: CRS: 84%, 100%; ≥ grade 3 CRS:12%, 27.8%; ICANS: 0, 2.8% [ 68 ] BCMA RRMM 33 (9) Ide-cel median 7 EMD vs. non-EMD: ORR: 89%, 83% ND ND [ 69 ] BCMA RRMM 17 (5) LCAR-B38M ≥ 3 EMD vs. non-EMD: ORR: 80%, 92% EMD: 1-year PFS rate: 20% EMD vs. non-EMD: ≥ Grade 3 CRS: 60%, 33% [ 70 ] BCMA RRMM 25 (7) Humanized anti‐BCMA CAR‐T cells median 7 EMD: ORR: 57% ND ND [ 71 ] BCMA RRMM 18 (5) CT103A median 4 EMD vs. non-EMD: ORR: 100%, 100% EMD vs. non-EMD: 1-year PFS rate: 20% vs. 79.1%; 1-year OS rate: 60% vs. 79.1% EMD vs. non-EMD: ≥ Grade 3 CRS: 0, 38.5% [ 72 ] BCMA RRMM 30 (18) (EM-E: 18) Anti‐BCMA CAR‐T cells median 4 EMD vs. non-EMD: ORR: 77.78%, 90% EM-E: median OS: 243 days ND [ 73 ] BCMA RRMM 21 (12) (EM-B:6, EM-E:6) Humanized anti‐BCMA CAR‐T cells ≥ 5 EM-E vs. EM-B vs. non-EMD: ORR: 83.33%, 83.33%, 88.89% EM-E vs. EM-B vs. non-EMD: 180 days-PFS rate: 50%, 83.33%, 88.89%; 180 days-OS rate: 83.33%, 100%, 88.89%; 360 days-PFS rate: 16.67%, 66.67%, 66.67%; 360 days-OS rate: 33.33%, 83.33%, 88.89% EM-E vs. EM-B vs. non-EMD: CRS: 100%, 100%, 100%; ≥ grade 3 CRS: 50%, 33.3%, 0; ICANS: 50%, 16.7%, 11.1%; ≥ grade 3 ICANS: 0, 0, 0 [ 74 ] BCMA RRMM 49 (11) HDS269B ≥ 3 EMD vs. non-EMD: ORR: 64%, 82% EMD vs. non-EMD: mOS: 5.0 months, 24.0 months; mPFS: 3.0 months, 10.5 months ND [ 75 ] BCMA RRMM 211 (95) Ide-cel median 6 EMD vs. non-EMD: Progressed ≤ 3 Months: 27.3%, 14.6% EMD is associated with worse PFS ([HR] = 1.71, 95% CI: 1.16–2.51) and OS (HR = 1.69, 95% CI: 1.00–2.86) ND [ 76 ] BCMA RRMM 2 (2) CT103A 3 Both achieved sCR Survival over 13 and 10 months, respectively EMD: Grade 2 CRS: 1 patient; No ICANS [ 61 ] BCMA RRMM 20 (7) Humanized anti-BCMA CAR-T cells ≥ 5 EMD vs. non-EMD: ORR: 71.43%, 84.61%; Extramedullary lesions: sCR/CR: 85.71% EMD vs. non-EMD: 180 days-PFS rate: 42.9%, 84.6%; 360 days-PFS rate: 28.6%, 72.5%; 180 days-OS rate:71.5%, 92.3%; 180 days-OS rate: 28.6%, 81.0% EMD vs. non-EMD: ≥ grade 3 CRS: 42.9%, 0 ICANS: 28.6%, 7.7%; ≥ grade 3 ICANS: 0, 0 [ 77 ] BCMA RRMM 134 (59) (EM-B: 25; EM-E: 34) Ide-cel, cilta-cel and other median ≥ 4 EM-E vs. EM-B vs. non-EMD: ORR: 76.5%, 92%, 88% EM-E vs. EM-B vs. non-EMD: mPFS: 9 months, 21.4 months, 24.2 months; mOS: 24 months, NR, NR ND [ 78 ] GPRC5D RRMM 33 (11) Anti-GPRC5D CAR-T cells median 4 EMD vs. non-EMD: ORR: 91%, 91% ND ND [ 79 ] GPRC5D RRMM 10 (4) OriCAR-017 median 5.5 EMD vs. non-EMD: ORR: 100%, 100% ND ≥ grade 3 CRS and ICANS: 0 [ 80 ] BCMA-CS1 RRMM 16 (6) CS1-BCMA CAR-T cells median 4 Extramedullary lesions disappeared: 66.7% ND ND [ 81 ] BCMA-CD38 RRMM 23 (9) BM38 CAR-T cells median 4 EMD: sCR: 44.4%; Extramedullary lesions disappeared: 55.6% ND ND [ 82 ] BCMA-CD19 NDMM 22 (12) (EM-B:9, EM-E:3) GC012F none EMD: sCR: 100%; MRD-: 100% ND ND [ 83 ] BCMA-CD38 RRMM 16 (8) BCMA-CD38 CAR-T cells ≥ 2 EMD: sCR: 75%; PD: 25%, Extramedullary lesions disappeared: 62.5% ND ND [ 84 ] BCMA-CD19 RRMM 31 (31) (EM-E:31) Anti-BCMA and anti-CD19 CAR-T cells median 4 EMD: ORR: 64.5%; ≥ CR: 25.8% EMD: mPFS: 5.0 months; mOS: 9.7 months EMD: CRS: 83.9%; ≥ grade 3 CRS: 25.8%; ICANS: 9.7%; ≥ grade 3 ICANS: 6.5% [ 85 ] BCMA- GPRC5D RRMM 21 (4) BCMA-GPRC5D CAR-T cells median 3 EMD: ORR: 75% ND ND [ 86 ] Abbreviations: EMD, extramedullary disease; RRMM, relapsed/refractory multiple myeloma; NDMM, newly diagnosed multiple myeloma; EM-B, EMD, bone-associated; EM-E, extramedullary extraosseous; ORR, overall response rate; CR, complete response; sCR, stringent complete response; VGPR, very good partial response rate; PD, progressive disease; PFS, progression-free survival; mOS, median overall survival; mPFS, median progression-free survival; ND, no data; NR, not reached; CRS, cytokine release syndrome; ICANS, immune effector cell-associated neurotoxicity syndrome; MRD, minimal residual disease; Ide-cel, Idecabtagene vicleucel; Cilta-cel, Ciltacabtagene autoleucel; CAR-T, chimeric antigen receptor T; BCMA, B-cell maturation antigen; GPRC5D, G protein-coupled receptor class C group 5 member D; CS1, also named SLAMF7, Signaling Lymphocytic Activation Molecule Family Member 7; mDOR, median duration of response; HR, hazard ratio

Although BCMA CAR-T has demonstrated remarkable efficacy in RRMM, nearly half of the patients relapse within 1 year. Switching therapeutic targets may offer a new treatment strategy for these RRMM patients. Research on alternative targets for MM is actively advancing, including G protein-coupled receptor class C group 5 member D (GPRC5D), SLAMF7, CD38, CD138 (Syndecan-1), CD19, etc., among which GPRC5D is the most extensively studied target. GPRC5D is an orphan G protein-coupled receptor, and its ligand and signaling mechanisms remain unclear. This receptor is expressed on MM cells, while in normal tissues, its expression is largely confined to plasma cells, with only low-level expression in some cells of skin hair follicles and hard keratinized tissues. Currently, no GPRC5D-targeted CAR-T therapy has been approved, but multiple clinical trials in this field are actively progressing.

In addition to single-target CAR-T cell therapy, dual-target CAR-T cell therapies have also been reported for treating both NDMM and RRMM (Table 2 ). In the study by Qiang et al. [ 83 ], a total of 22 patients were enrolled, including 12 with EMD (nine EM-B and three EM-E cases). The results demonstrated that all 12 EMD patients achieved both a 100% sCR rate and a minimal residual disease (MRD) negative status. These clinical findings indicate that BCMA-CD19 dual-target CAR-T therapy shows remarkable efficacy in NDMM patients with EMD, though larger sample sizes and longer-term follow-up are still required. In another clinical trial of BCMA-CD38 dual-target CAR-T cell therapy, 16 RRMM patients were enrolled, including eight with EMD. The results demonstrated complete resolution of extramedullary lesions in five patients (62.5%). In RRMM patients, even with dual-target CAR-T therapy, the poor prognosis associated with EMD remains unresolved [ 82 , 84 , 85 ].

CAR-T cell therapy has demonstrated efficacy in RRMM patients. However, those with EMD exhibit inferior treatment responses and survival outcomes compared with non-EMD patients. EMD is an independent predictor of poorer PFS and OS. Prospective studies are warranted to develop optimized CAR-T regimens addressing EMD-specific challenges for survival improvement. Compared with RRMM, CAR-T cell therapy demonstrates superior efficacy in NDMM patients with EMD. Therefore, moving CAR-T cell therapy to the first-line setting may provide greater clinical benefit for this high-risk population.

Bispecific antibodies

Bispecific antibodies (BsAbs) are capable of simultaneously targeting tumor-associated antigens and CD3 molecules on T cells. This dual targeting redirects T cells to tumor sites, activates their cytotoxic function, and ultimately induces tumor cell death. Currently, the bispecific antibodies teclistamab and elranatamab (targeting BCMA), along with talquetamab (targeting GPRC5D), have been approved for the treatment of RRMM.

We summarize the efficacy profiles of currently approved BsAbs in MM patients with EMD in Table 3 . In the MajesTEC-1 Phase I/II clinical study, a total of 165 patients with RRMM were treated with teclistamab, including 28 patients with EMD (all classified as the EM-E subtype). Results demonstrated an ORR of 35.7% in the EM-E subgroup compared with 63% in the overall population. Teclistamab failed to overcome poor prognostic factors, including EMD, Stage III disease, or ≥ 60% bone marrow plasma cell infiltration, but still showed efficacy against high-risk cytogenetic abnormalities and penta-refractory disease [ 87 , 88 ]. In a retrospective study including 123 RRMM patients (43 with EMD), the results showed that the ORR in the EMD group was significantly lower than that in the non-EMD group, and the median PFS in the EMD group was significantly shorter [ 89 ]. In the MonumenTAL-1 clinical trial, a total of 232 patients received talquetamab treatment and were divided into cohorts based on dosing frequency: weekly (QW, n = 143) and biweekly (Q2W, n = 145), including 51 patients who had previously undergone T cell redirection therapy. The results showed an ORR of 74% (QW cohort) and 73% (Q2W cohort). Among patients with baseline plasmacytoma, the ORR was comparable between both cohorts, reaching approximately 50% [ 87 ]. Neither teclistamab nor talquetamab monotherapy demonstrated significant clinical benefit in RRMM patients with EMD. In the RedirecTT-1 study, which combined teclistamab and talquetamab for the treatment of RRMM, results showed that the EMD subgroup achieved an ORR of 61%, with an 18-month PFS rate of 80% among responders. However, it is noteworthy that the incidence of grade 3/4 infections in the combination therapy group was higher than that observed with either monotherapy [ 37 ]. Relapse following BCMA CAR-T cell therapy remains a significant clinical challenge, with limited therapeutic options. In a retrospective study analyzing outcomes of salvage therapies in patients who relapsed after ide-cel or cilta-cel treatment, 53% (73 cases) had EMD at relapse. Results revealed marked differences in efficacy: the ORR and CR rates were 79% and 39% for talquetamab and 64% and 32% for teclistamab, respectively, significantly higher than those observed in other treatment groups. Bispecific antibodies appeared to overcome the poor prognosis associated with EMD, suggesting their potential as a standard salvage regimen for patients relapsing after CAR-T cell therapy [ 90 ]. Elranatamab, another BCMA-targeting bispecific antibody, demonstrated encouraging results in the phase 2 MagnetisMM-3 clinical trial. The study enrolled 123 RRMM patients (including 39 with EMD), demonstrating an ORR of 38.5% in the EMD subgroup versus 71.4% in non-EMD patients. Notably, at the 15-month follow-up, 77.9% of patients maintained long-term responses to elranatamab despite having poor prognosis EMD features. These efficacy outcomes represent particularly outstanding results among currently approved bispecific antibodies for RRMM while maintaining a manageable safety profile [ 91 ]. Table 3 Bispecific antibodies for Extramedullary Disease in Multiple Myeloma Target Antigen Patient group Patient (n)/ EMD (n) Study Type Agent Name Line of previous treatment Efficacy Survival Ref BCMA × CD3 RRMM 165 (28) Multi-center phase 1/2 clinical trial (MajesTEC-1; Cohort A) Teclistamab median 5 EMD vs. non-EMD: ORR: 35.7%, 68.6% ND [ 88 ] BCMA × CD3 RRMM 26 (9) (EM-E: 9) Multi-center phase 2 clinical trial (MajesTEC-1) Teclistamab median 5 EMD: ORR:66.7% ND [ 92 ] BCMA × CD3 RRMM 40 (12) Multi-center phase 1/2 clinical trial (MajesTEC-1; Cohort C) Teclistamab median: 6 EMD vs. all patients: ORR: 58.3%, 52.5% ND [ 93 ] BCMA × CD3 RRMM 123 (43) Multi-center retrospective analysis (Germany) Teclistamab median 6 EMD vs. non-EMD: ORR: 37.2%, 72.6% EMD vs. non-EMD: mPFS: 2.1 months, NR [ 89 ] BCMA × CD3 RRMM 110 (48) Multi-center retrospective analysis (USA) Teclistamab median 6 EMD vs. non-EMD: ORR: 43%, 58% ND [ 90 ] BCMA × CD3 RRMM 123 (39) Multi-center phase 2 clinical trial (MagnetisMM-3) Elranatamab median 5 EMD vs. non-EMD: ORR: 38.5%, 71.4% EMD vs. non-EMD: 15 months PFS rate: 77.9%, 70.6% [ 91 ] GPRC5D × CD3 RRMM 232 (57) Multi-center phase 1 clinical trial (MonumenTAL-1) Talquetamab median 6 EMD: ORR: 40–45.5% ND [ 87 ] GPRC5D × CD3 RRMM 138 (60) (EM-E: 46) Multi-center retrospective study (Germany) Talquetamab median 6 EM-E: ≥ PR: [OR] = 0.30 EM-E: PFS: [HR] = 3.71; EM-E: OS: [HR] = 2.37 [ 94 ] GPRC5D × CD3 RRMM 375 (99) Multi-center phase 1 clinical trial (MonumenTAL-1) Talquetamab median 5 EM-E vs. non-EM-E: ORR: 0.4 mg/kg, QW: 48%, 82%; 0.8 mg/kg Q2W: 41%, 80% ND [ 95 ] BCMA × CD3, GPRC5D × CD3 RRMM 94 (34) Multi-center phase 1b/2 clinical trial (RedirecTT-1 trial) Teclistamab + Talquetamab median 4 EMD vs. all patients: ORR: 61%, 80% EMD vs. all patients: 18 months PFS rate: 82%, 86% [ 37 ] Abbreviations: EMD, extramedullary disease; RRMM, relapsed/refractory multiple myeloma; EM-E, extramedullary extraosseous; ORR, overall response rate; PR, partial response; PFS, progression-free survival; mPFS, median progression-free survival; ND, no data; NR, not reached; BCMA, B-cell maturation antigen; GPRC5D, class C G protein-coupled receptor member 5D; QW, weekly; Q2W, biweekly; HR, hazard ratio; OR, odds ratio

Cevostamab is a bispecific antibody that simultaneously targets Fc receptor homolog 5 (FcRH5) on tumor cells and CD3 on T cells. In heavily pretreated RRMM patients, cevostamab has consistently demonstrated clinically meaningful efficacy. However, its effectiveness against extramedullary disease remains unknown, and the final study results are highly anticipated [ 96 ].

BCMA-targeting antibody–drug conjugate

Belantamab Mafodotin (belamaf) is a novel BCMA-targeting antibody–drug conjugate (ADC). Dileo et al. [ 97 ] reported real-world clinical outcomes of belantamab mafodotin in 81 patients with RRMM, among whom 37% had EMD. The results showed a best ORR of 40.0%, with patients harboring EMD exhibiting a significantly lower ORR of 23%. The median PFS was 2 months in the EMD subgroup versus 5 months in the overall cohort, while median OS was 5 months and 12 months, respectively. Multivariate analysis identified EMD as the sole prognostic factor significantly impacting both PFS and OS. Compared with other emerging therapies, single-agent belantamab demonstrated activity comparable to BsAbs but lower than CAR-T cell therapy in patients with EMD [ 88 , 91 ]. However, in the DREAMM-3 trial, belantamab mafodotin failed to meet its primary endpoint of superior PFS compared with pomalidomide plus dexamethasone. This outcome had significant clinical implications for patients with limited treatment options, ultimately leading to the drug’s withdrawal from the U.S. and European markets.

The lower ORR observed with belantamab mafodotin in MM patients with EMD reflects its limitations as a monotherapy. However, compelling evidence from combination regimens, particularly those involving immunomodulatory agents or T cell engagers, supports its continued exploration and clinical utility in high-risk RRMM [ 98 ].

Autologous stem cell transplantation

Even in the era of novel mechanism-based agents and immunotherapies, autologous stem cell transplantation (ASCT) remains irreplaceable in the treatment of MM. A retrospective study of 275 NDMM patients (54 cases with EMD) demonstrated significantly inferior PFS and OS in EMD versus those without. Notably, among transplant-eligible patients, the presence of EMD did not significantly affect PFS or OS, whereas in transplant-ineligible patients, EMD served as an independent adverse prognostic factor for both PFS and OS, suggesting that ASCT may overcome the adverse prognosis associated with EMD [ 22 ]. In another multicenter retrospective study involving 226 MM patients with EMD (130 detected at initial diagnosis and 96 identified at disease relapse) [ 17 ]. The results demonstrated that ASCT recipients achieved significantly higher CR rates compared with non-ASCT patients, both in NDMM (29% vs 19%) and relapsed patients (41.7% vs 9.5%). Among NDMM, ASCT recipients showed significantly longer median PFS compared with non-ASCT patients (49 months vs. 28.1 months, P < 0.001). Furthermore, in the entire cohort (including both newly diagnosed and relapsed cases), the ASCT group demonstrated a markedly superior median OS versus the non-transplant group (79.5 months vs 34.7 months). ASCT demonstrated significant improvements in both CR rates and PFS among patients with EMD, with particularly enhanced efficacy observed in cases exhibiting paraskeletal involvement. These findings position ASCT as an independent prognostic factor in the EMD patient population. The data also demonstrated that patients receiving tandem ASCT had a lower mortality risk than those undergoing single ASCT [ 17 ].

The choice between single ASCT and tandem ASCT remains controversial, particularly for high-risk patients (such as those with EMD or high-risk cytogenetic abnormalities), where tandem ASCT may offer superior clinical benefits [ 99 ]. Autologous-allogeneic transplantation has demonstrated potential survival benefits in high-risk patients, though further clinical studies are required to validate its therapeutic efficacy [ 22 ].

Central nervous system involvement in multiple myeloma

Central nervous system involvement in multiple myeloma (CNS-MM) is a rare complication with particularly poor prognosis, demonstrating a median OS of less than 6 months from diagnosis of CNS involvement based on available clinical data [ 100 ]. The management of CNS-involved patients presents unique therapeutic challenges, primarily due to (1) limited blood–brain barrier (BBB) penetration of novel agents and (2) systematic exclusion of CNS involvement in eligibility criteria for CAR-T cell therapies and most next-generation drug clinical trials, which collectively contribute to the current lack of evidence-based consensus guidelines for optimal treatment strategies.

The optimal treatment approach for MM with CNS involvement remains unclear. Current main therapeutic strategies include systemic therapies combined with intrathecal chemotherapy and/or radiotherapy, as well as high-dose chemotherapy followed by ASCT, none of which have significantly improved prognosis [ 101 , 102 ]. IMiDs have demonstrated the ability to cross the BBB, though thalidomide and lenalidomide exhibit limited therapeutic efficacy [ 100 , 102 ]. In contrast, pomalidomide shows superior CNS penetration and demonstrates effectiveness against extramedullary lesions. Clinical reports have confirmed that pomalidomide achieves favorable treatment outcomes in CNS-MM [ 103 , 104 ]. While proteasome inhibitors (bortezomib, carfilzomib, and ixazomib) exhibit poor CNS penetration, marizomib demonstrates effective BBB crossing capability and has shown potential therapeutic efficacy in CNS-MM [ 105 ]. Selinexor demonstrates excellent CNS penetration in animal models, with a brain-to-plasma concentration ratio of 0.61–0.72 [ 106 ]. The drug has shown significant efficacy as monotherapy in CNS lymphoma [ 107 ]. Notably, the combination of selinexor with daratumumab and dexamethasone (Dara-Sd) has achieved complete remission in patients with recurrent CNS-MM [ 103 ]. A recent large-scale real-world study demonstrated that the survival outcomes of CNS-MM patients remain poor; however, anti-myeloma therapies introduced after 2016 have shown a positive impact on survival, with median OS extended to 12 months [ 108 ]. The presence of soft tissue plasmacytomas significantly increases both the risk of MM patients developing CNS-MM and post-CNS-MM mortality. Previous studies have reported clinical benefits of ASCT for MM patients with CNS involvement, primarily attributed to the BBB penetration capability of high-dose melphalan (200 mg/m 2 ) used in the conditioning regimen [ 109 , 110 ].

Venetoclax, a selective BCL-2 inhibitor, has demonstrated efficacy in MM patients with t (11;14) translocation, but reports on its use in PCL remain extremely limited. A multicenter retrospective analysis of six PCL patients (two primary PCL, four secondary PCL) showed promising results with venetoclax treatment, achieving an ORR of 100%. However, both median PFS and OS were relatively short at 10 months and 12.2 months, respectively. Notably, secondary PCL exhibited worse outcomes compared to primary PCL [ 111 ]. The relatively low incidence of PCL significantly limits the conduct of large-scale clinical trials, making it challenging to obtain more robust evidence.

Currently, the application of T cell redirection therapy is limited in terms of patient numbers, but this approach has demonstrated potential therapeutic activity in CNS-MM patients. A retrospective study conducted by Wang et al. [ 112 ] demonstrated that in four CNS-MM patients who received BCMA CAR-T cell therapy, 75% achieved ORR without any occurrence of immune effector cell-associated neurotoxicity syndrome (ICANS), highlighting the significant clinical efficacy of this treatment approach.

However, relapse occurred in 2 patients (50%), underscoring that disease recurrence remains a major therapeutic challenge. A study of 10 RRMM patients with CNS involvement demonstrated remarkable efficacy, showing an optimal ORR of 80% and an exceptional CNS response rate of 100%. Additionally, the treatment exhibited a favorable safety profile, with no grade ≥ 3 CRS reported and only one case of grade ≥ 3 ICANS observed [ 113 ]. While current evidence supports the safety and feasibility of CAR-T therapy for MM patients with CNS involvement, the observed early relapses suggest that post-CAR-T maintenance strategies and novel targeting approaches may be critical for outcome improvement. These preliminary findings await validation through larger scale prospective clinical trials.

Radiotherapy plays a critical role in palliative care and local disease control in selected cases of CNS involvement [ 114 ]. Indications include isolated CNS lesions, emergent neurological conditions such as spinal cord compression, and cases where intrathecal or systemic therapies are ineffective or poorly tolerated. Radiotherapy should be individualized based on the patient’s clinical status and is commonly integrated into a multimodal approach alongside systemic therapies [ 115 ]. However, caution is warranted when used concurrently with bispecific antibodies, due to the theoretical risk of increased immunogenicity and potential for overlapping adverse effects.

Management approach

Primary EMD

The treatment approach for NDMM with EMD should be tailored based on the patient’s age, fitness, and extramedullary disease features. Since patients with EM-B demonstrate similar survival outcomes to those with BM-only and exhibit significantly better prognosis compared to patients with EM-E, their treatment approach should be differentiated accordingly [ 57 ]. For transplant-eligible EM-B patients, the clinical recommendation is to use a proteasome inhibitor-based triple or quadruple drug combination regimen for induction therapy, followed sequentially by auto-HSCT and maintenance therapy. Commonly used induction regimens include PAD (bortezomib/doxorubicin/dexamethasone), RVD (lenalidomide/bortezomib/dexamethasone), KAD (carfilzomib/doxorubicin/dexamethasone), or KRD (carfilzomib/lenalidomide/dexamethasone). Given that daratumumab may improve therapeutic efficacy, it can be incorporated into the induction treatment regimen. In high tumor burden or those failing to achieve at least PR after two cycles of initial induction therapy patients, intensive cytotoxic-containing regimens such as V(K)DR-PACE (bortezomib(carfilzomib)/dexamethasone/lenalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide) may be considered for rapid tumor debulking. For transplant-eligible EM-E patients, intensive anti-myeloma regimens are recommended, such as daratumumab combined with V(K)DR-PACE induction therapy to reduce disease burden rapidly, followed sequentially by auto-HSCT and maintenance therapy. If suitable clinical trials are available, trial participation is recommended as the preferred option. A two-drug combination regimen (e.g., PIs + IMiDs) is the preferred maintenance therapy approach. For transplant-ineligible patients, both EM-B and EM-E subtypes require multi-cycle induction therapy. Given this population's poorer overall prognosis, triplet or quadruplet regimens incorporating PIs and/or CD38 monoclonal antibodies are recommended. In patients who respond to treatment, the effective regimen can be continued until maximum efficacy is achieved, followed by transition to maintenance therapy. Currently, CAR-T cell therapy or the combination regimen selinexor with RVD has shown significant efficacy in primary EMD, offering a promising new treatment option for this refractory subgroup of patients [ 55 , 83 ].

Secondary EMD

MM patients with extramedullary relapse have limited treatment options and extremely poor prognosis. Clinical trial participation should be considered when available. CAR-T and bispecific antibodies represent important emerging therapeutic options. Vegiventi et al. [ 116 ] conducted a systematic review of 21 studies and six ASCO abstracts for meta-analysis, revealing that the CAR-T group demonstrated significantly higher EMD response rates compared to the bispecific antibody group, though pooled data could not be directly compared due to study heterogeneity. A retrospective study from Mayo Clinic compared the efficacy of three BCMA-directed therapies – CAR-T, BsAbs, and ADCs. The results demonstrated superior overall efficacy with CAR-T therapy, supporting its use as the preferred option. However, alternative treatment strategies should be considered for patients with prior BCMA exposure or rapidly progressive disease [ 117 ]. Given that most patients have previously received bortezomib- and lenalidomide-containing frontline therapies at relapse, newer regimens incorporating carfilzomib or pomalidomide represent viable alternatives. Notably, the addition of bendamustine to these regimens has demonstrated promising response rates in RRMM patients with EMD. While the selinexor-dexamethasone regimen demonstrates definitive clinical activity in secondary EMD, its therapeutic efficacy remains suboptimal. The exploration of novel selinexor-based combinations (e.g., with PIs or monoclonal antibodies) holds significant clinical value.Lymphoma-like intensive chemotherapy regimens, such as PACE, DECP (dexamethasone/etoposide/cyclophosphamide/cisplatin), and DT-PACE (dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide), should be considered. Our management approach for EMD patients is shown in Fig. 3 . Fig. 3 Management approach for MM with EMD. Abbreviations: MM, multiple myeloma; EMD, extramedullary disease; EM-B, EMD, bone-associated; EM-E, extramedullary extraosseous; RVD, lenalidomide-bortezomib-dexamethasone; KRD, carfilzomib-lenalidomide-dexamethasone; PAD, bortezomib-doxorubicin-dexamethasone; KAD, carfilzomib-doxorubicin-dexamethasone; Dara, daratumumab; V(K)DR, bortezomib(carfilzomib)-dexamethasone-lenalidomide; PACE, cisplatin-doxorubicin-cyclophosphamide-etoposide; auto-HSCT, autologous stem cell transplantation; PIs, proteasome inhibitors; IMiDs, immunomodulatory drugs; DT, dexamethasone-thalidomide; DCEP, dexamethasone-cyclophosphamide-etoposide-cisplatin; CAR-T, chimeric antigen receptor T cell therapy; KPD, carfilzomib-pomalidomide-dexamethasone; PVD, pomalidomide-bortezomib-dexamethasone; KCyD, carfilzomib-cyclophosphamide-dexamethasone

Conclusion

The advent of novel therapies has significantly improved survival outcomes in patients with MM. However, EMD remains a major therapeutic challenge. Although emerging T cell-based therapies such as CAR-T cells and bispecific antibodies demonstrate high response rates, EMD patients experience shorter remission durations and poorer prognosis compared with their non-EMD counterparts. This therapeutic disparity may stem from the complex pathophysiological mechanisms underlying EMD. Through a systematic review of published literature, this article synthesizes the efficacy and safety profiles of various treatment strategies for EMD in the novel therapeutic era, thereby providing evidence-based guidance for optimal treatment selection in EMD patients. Future research should focus on optimizing the rational application of existing therapies while developing novel targeted agents and mechanistically distinct drugs. Based on genetic and other individualized features, achieving more accurate risk stratification and personalized treatment strategies, ultimately offering new therapeutic hope for this high-risk patient population.

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Acknowledgements

We would like to acknowledge the hard and dedicated work of all the staff that implemented the intervention and evaluation components of the study.

Author contributions

Conception and design: BJ.F; manuscript writing: all authors; final approval of manuscript: all authors.

Funding

This work was supported by grants from the National Natural Science Foundation of China (Grant No. 82370143 and 82000109) and the Natural Science Foundation of Henan (Grant No. 242300421509).

Data availability

No datasets were generated or analysed during the current study.

Declarations

Conflict of interest

The authors declare no competing interests.

Informed consent

This study is a literature review and does not require the informed consent of patients.

References

1. Kazandjian D Multiple myeloma epidemiology and survival: a unique malignancy Semin Oncol 2016 43 6 676 681 28061985 10.1053/j.seminoncol.2016.11.004 PMC5283695 Kazandjian D. Multiple myeloma epidemiology and survival: a unique malignancy. Semin Oncol. 2016;43(6):676–81. 28061985 10.1053/j.seminoncol.2016.11.004 PMC5283695

2. Bladé J Fernández De Larrea C Rosiñol L Cibeira MT Jiménez R Powles R Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach J Clin Oncol 2011 29 28 3805 3812 21900099 10.1200/JCO.2011.34.9290 Bladé J, Fernández De Larrea C, Rosiñol L, Cibeira MT, Jiménez R, Powles R. Soft-tissue plasmacytomas in multiple myeloma: incidence, mechanisms of extramedullary spread, and treatment approach. J Clin Oncol. 2011;29(28):3805–12. 21900099 10.1200/JCO.2011.34.9290

3. Pour L Sevcikova S Greslikova H Kupska R Majkova P Zahradova L Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse Haematologica 2014 99 2 360 364 24038024 10.3324/haematol.2013.094409 PMC3912968 Pour L, Sevcikova S, Greslikova H, Kupska R, Majkova P, Zahradova L, et al. Soft-tissue extramedullary multiple myeloma prognosis is significantly worse in comparison to bone-related extramedullary relapse. Haematologica. 2014;99(2):360–4. 24038024 10.3324/haematol.2013.094409 PMC3912968

4. Bladé J Beksac M Caers J Jurczyszyn A von Lilienfeld-Toal M Moreau P Extramedullary disease in multiple myeloma: a systematic literature review Blood Cancer J 2022 12 3 45 35314675 10.1038/s41408-022-00643-3 PMC8938478 Bladé J, Beksac M, Caers J, Jurczyszyn A, von Lilienfeld-Toal M, Moreau P, et al. Extramedullary disease in multiple myeloma: a systematic literature review. Blood Cancer J. 2022;12(3):45. 35314675 10.1038/s41408-022-00643-3 PMC8938478

5. Xu K Agbuduwe C Kanellias N Wilson W McMillan A Papanikolaou X Bone-independent extramedullary disease is associated with inferior overall survival in multiple myeloma patients: a single-center, real-world experience Haematologica 2025 110 5 1182 1186 39633554 10.3324/haematol.2024.286409 PMC12050924 Xu K, Agbuduwe C, Kanellias N, Wilson W, McMillan A, Papanikolaou X, et al. Bone-independent extramedullary disease is associated with inferior overall survival in multiple myeloma patients: a single-center, real-world experience. Haematologica. 2025;110(5):1182–6. 39633554 10.3324/haematol.2024.286409 PMC12050924

6. Rosiñol L Beksac M Zamagni E Van de Donk N Anderson KC Badros A Expert review on soft-tissue plasmacytomas in multiple myeloma: definition, disease assessment and treatment considerations Br J Haematol 2021 194 3 496 507 33724461 10.1111/bjh.17338 Rosiñol L, Beksac M, Zamagni E, Van de Donk N, Anderson KC, Badros A, et al. Expert review on soft-tissue plasmacytomas in multiple myeloma: definition, disease assessment and treatment considerations. Br J Haematol. 2021;194(3):496–507. 33724461 10.1111/bjh.17338

7. Weinstock M Ghobrial IM Extramedullary multiple myeloma Leuk Lymphoma 2013 54 6 1135 1141 23210572 10.3109/10428194.2012.740562 Weinstock M, Ghobrial IM. Extramedullary multiple myeloma. Leuk Lymphoma. 2013;54(6):1135–41. 23210572 10.3109/10428194.2012.740562

8. Caers J Paiva B Zamagni E Leleu X Bladé J Kristinsson SY Diagnosis, treatment, and response assessment in solitary plasmacytoma: updated recommendations from a European Expert Panel J Hematol Oncol 2018 11 1 10 29338789 10.1186/s13045-017-0549-1 PMC5771205 Caers J, Paiva B, Zamagni E, Leleu X, Bladé J, Kristinsson SY, et al. Diagnosis, treatment, and response assessment in solitary plasmacytoma: updated recommendations from a European Expert Panel. J Hematol Oncol. 2018;11(1):10. 29338789 10.1186/s13045-017-0549-1 PMC5771205

9. Bhutani M Foureau DM Atrash S Voorhees PM Usmani SZ Extramedullary multiple myeloma Leukemia 2020 34 1 1 20 31776467 10.1038/s41375-019-0660-0 Bhutani M, Foureau DM, Atrash S, Voorhees PM, Usmani SZ. Extramedullary multiple myeloma. Leukemia. 2020;34(1):1–20. 31776467 10.1038/s41375-019-0660-0

10. Zolnowski D Karp S Warncke P Zinn J Pannach M Herbst R Challenges in the treatment of soft-tissue plasmacytoma: a retrospective analysis of 120 patients with extramedullary multiple myeloma J Cancer Res Clin Oncol 2024 150 10 482 39470843 10.1007/s00432-024-05993-y PMC11522042 Zolnowski D, Karp S, Warncke P, Zinn J, Pannach M, Herbst R, et al. Challenges in the treatment of soft-tissue plasmacytoma: a retrospective analysis of 120 patients with extramedullary multiple myeloma. J Cancer Res Clin Oncol. 2024;150(10): 482. 39470843 10.1007/s00432-024-05993-y PMC11522042

11. Fernández De Larrea C Kyle R Rosiñol L Paiva B Engelhardt M Usmani S Primary plasma cell leukemia: consensus definition by the International Myeloma Working Group according to peripheral blood plasma cell percentage Blood Cancer J 2021 11 12 192 34857730 10.1038/s41408-021-00587-0 PMC8640034 Fernández De Larrea C, Kyle R, Rosiñol L, Paiva B, Engelhardt M, Usmani S, et al. Primary plasma cell leukemia: consensus definition by the International Myeloma Working Group according to peripheral blood plasma cell percentage. Blood Cancer J. 2021;11(12):192. 34857730 10.1038/s41408-021-00587-0 PMC8640034

12. Short KD Rajkumar SV Larson D Buadi F Hayman S Dispenzieri A Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary myeloma Leukemia 2011 25 6 906 908 21350560 10.1038/leu.2011.29 PMC3736849 Short KD, Rajkumar SV, Larson D, Buadi F, Hayman S, Dispenzieri A, et al. Incidence of extramedullary disease in patients with multiple myeloma in the era of novel therapy, and the activity of pomalidomide on extramedullary myeloma. Leukemia. 2011;25(6):906–8. 21350560 10.1038/leu.2011.29 PMC3736849

13. Rajkumar SV Multiple myeloma: 2024 update on diagnosis, risk-stratification, and management Am J Hematol 2024 99 9 1802 1824 38943315 10.1002/ajh.27422 PMC11404783 Rajkumar SV. Multiple myeloma: 2024 update on diagnosis, risk-stratification, and management. Am J Hematol. 2024;99(9):1802–24. 38943315 10.1002/ajh.27422 PMC11404783

14. Dimopoulos MA Hillengass J Usmani S Zamagni E Lentzsch S Davies FE Role of magnetic resonance imaging in the management of patients with multiple myeloma: a consensus statement J Clin Oncol 2015 33 6 657 664 25605835 10.1200/JCO.2014.57.9961 Dimopoulos MA, Hillengass J, Usmani S, Zamagni E, Lentzsch S, Davies FE, et al. Role of magnetic resonance imaging in the management of patients with multiple myeloma: a consensus statement. J Clin Oncol. 2015;33(6):657–64. 25605835 10.1200/JCO.2014.57.9961

15. Bansal R Rakshit S Kumar S Extramedullary disease in multiple myeloma Blood Cancer J 2021 11 9 161 34588423 10.1038/s41408-021-00527-y PMC8481260 Bansal R, Rakshit S, Kumar S. Extramedullary disease in multiple myeloma. Blood Cancer J. 2021;11(9):161. 34588423 10.1038/s41408-021-00527-y PMC8481260

16. Varga C Xie W Laubach J Ghobrial IM O'Donnell EK Weinstock M Development of extramedullary myeloma in the era of novel agents: no evidence of increased risk with lenalidomide-bortezomib combinations Br J Haematol 2015 169 6 843 850 26032514 10.1111/bjh.13382 Varga C, Xie W, Laubach J, Ghobrial IM, O’Donnell EK, Weinstock M, et al. Development of extramedullary myeloma in the era of novel agents: no evidence of increased risk with lenalidomide-bortezomib combinations. Br J Haematol. 2015;169(6):843–50. 26032514 10.1111/bjh.13382

17. Beksac M Seval GC Kanellias N Coriu D Rosiñol L Ozet G A real world multicenter retrospective study on extramedullary disease from Balkan Myeloma Study Group and Barcelona University: analysis of parameters that improve outcome Haematologica 2020 105 1 201 208 31278209 10.3324/haematol.2019.219295 PMC6939516 Beksac M, Seval GC, Kanellias N, Coriu D, Rosiñol L, Ozet G, et al. A real world multicenter retrospective study on extramedullary disease from Balkan Myeloma Study Group and Barcelona University: analysis of parameters that improve outcome. Haematologica. 2020;105(1):201–8. 31278209 10.3324/haematol.2019.219295 PMC6939516

18. Vande Broek I Vanderkerken K Van Camp B Van Riet I Extravasation and homing mechanisms in multiple myeloma Clin Exp Metas 2008 25 4 325 334 10.1007/s10585-007-9108-4 17952614 Vande Broek I, Vanderkerken K, Van Camp B, Van Riet I. Extravasation and homing mechanisms in multiple myeloma. Clin Exp Metas. 2008;25(4):325–34. 10.1007/s10585-007-9108-4 17952614

19. Garcés JJ San-Miguel J Paiva B Biological characterization and clinical relevance of circulating tumor cells: opening the Pandora's box of multiple myeloma Cancers (Basel) 2022 10.3390/cancers14061430 35326579 PMC8946760 Garcés JJ, San-Miguel J, Paiva B. Biological characterization and clinical relevance of circulating tumor cells: opening the Pandora’s box of multiple myeloma. Cancers (Basel). 2022. 10.3390/cancers14061430. 35326579 10.3390/cancers14061430 PMC8946760

20. McAvera R Quinn J Murphy P Glavey S Genetic abnormalities in extramedullary multiple myeloma Int J Mol Sci 2023 10.3390/ijms241411259 37511018 PMC10379577 McAvera R, Quinn J, Murphy P, Glavey S. Genetic abnormalities in extramedullary multiple myeloma. Int J Mol Sci. 2023. 10.3390/ijms241411259. 37511018 10.3390/ijms241411259 PMC10379577

21. John M Helal M Duell J Mattavelli G Stanojkovska E Afrin N Spatial transcriptomics reveals profound subclonal heterogeneity and T-cell dysfunction in extramedullary myeloma Blood 2024 144 20 2121 2135 39172759 10.1182/blood.2024024590 John M, Helal M, Duell J, Mattavelli G, Stanojkovska E, Afrin N, et al. Spatial transcriptomics reveals profound subclonal heterogeneity and T-cell dysfunction in extramedullary myeloma. Blood. 2024;144(20):2121–35. 39172759 10.1182/blood.2024024590

22. Lee SE Kim JH Jeon YW Yoon JH Shin SH Eom KS Impact of extramedullary plasmacytomas on outcomes according to treatment approach in newly diagnosed symptomatic multiple myeloma Ann Hematol 2015 94 3 445 452 25257340 10.1007/s00277-014-2216-8 Lee SE, Kim JH, Jeon YW, Yoon JH, Shin SH, Eom KS, et al. Impact of extramedullary plasmacytomas on outcomes according to treatment approach in newly diagnosed symptomatic multiple myeloma. Ann Hematol. 2015;94(3):445–52. 25257340 10.1007/s00277-014-2216-8

23. Ho M; Paruzzo L; Minehart J; Nabar N; Noll JH; Luo T, et al. Extramedullary Multiple Myeloma: Challenges and Opportunities. Current oncology Toronto Ont. 2025;32(3). 10.3390/curroncol32030182 PMC11940950 40136386

24. Gulla A Anderson KC Multiple myeloma: the (r)evolution of current therapy and a glance into future Haematologica 2020 105 10 2358 2367 33054076 10.3324/haematol.2020.247015 PMC7556665 Gulla A, Anderson KC. Multiple myeloma: the (r)evolution of current therapy and a glance into future. Haematologica. 2020;105(10):2358–67. 33054076 10.3324/haematol.2020.247015 PMC7556665

25. Nakamoto-Matsubara R Nardi V Horick N Fukushima T Han RS Shome R Integration of clinical outcomes and molecular features in extramedullary disease in multiple myeloma Blood Cancer J 2024 14 1 224 39715752 10.1038/s41408-024-01190-9 PMC11666541 Nakamoto-Matsubara R, Nardi V, Horick N, Fukushima T, Han RS, Shome R, et al. Integration of clinical outcomes and molecular features in extramedullary disease in multiple myeloma. Blood Cancer J. 2024;14(1):224. 39715752 10.1038/s41408-024-01190-9 PMC11666541

26. Bingham N Shah J Wong D Lim SL Bergin K Kalff A Whole genome sequencing and the genetics of extramedullary disease in multiple myeloma Blood Cancer J 2025 15 1 5 39799110 10.1038/s41408-024-01208-2 PMC11724953 Bingham N, Shah J, Wong D, Lim SL, Bergin K, Kalff A, et al. Whole genome sequencing and the genetics of extramedullary disease in multiple myeloma. Blood Cancer J. 2025;15(1):5. 39799110 10.1038/s41408-024-01208-2 PMC11724953

27. Jelinek T Zihala D Sevcikova T Anilkumar Sithara A Kapustova V Sahinbegovic H Beyond the marrow: insights from comprehensive next-generation sequencing of extramedullary multiple myeloma tumors Leukemia 2024 38 6 1323 1333 38493239 10.1038/s41375-024-02206-w PMC11147761 Jelinek T, Zihala D, Sevcikova T, Anilkumar Sithara A, Kapustova V, Sahinbegovic H, et al. Beyond the marrow: insights from comprehensive next-generation sequencing of extramedullary multiple myeloma tumors. Leukemia. 2024;38(6):1323–33. 38493239 10.1038/s41375-024-02206-w PMC11147761

28. Alsayed Y Ngo H Runnels J Leleu X Singha UK Pitsillides CM Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma Blood 2007 109 7 2708 2717 17119115 10.1182/blood-2006-07-035857 PMC1852222 Alsayed Y, Ngo H, Runnels J, Leleu X, Singha UK, Pitsillides CM, et al. Mechanisms of regulation of CXCR4/SDF-1 (CXCL12)-dependent migration and homing in multiple myeloma. Blood. 2007;109(7):2708–17. 17119115 10.1182/blood-2006-07-035857 PMC1852222

29. Roccaro AM Mishima Y Sacco A Moschetta M Tai YT Shi J CXCR4 regulates extra-medullary myeloma through epithelial-mesenchymal-transition-like transcriptional activation Cell Rep 2015 12 4 622 635 26190113 10.1016/j.celrep.2015.06.059 PMC4961259 Roccaro AM, Mishima Y, Sacco A, Moschetta M, Tai YT, Shi J, et al. CXCR4 regulates extra-medullary myeloma through epithelial-mesenchymal-transition-like transcriptional activation. Cell Rep. 2015;12(4):622–35. 26190113 10.1016/j.celrep.2015.06.059 PMC4961259

30. Dahl IM Rasmussen T Kauric G Husebekk A Differential expression of CD56 and CD44 in the evolution of extramedullary myeloma Br J Haematol 2002 116 2 273 277 11841427 10.1046/j.1365-2141.2002.03258.x Dahl IM, Rasmussen T, Kauric G, Husebekk A. Differential expression of CD56 and CD44 in the evolution of extramedullary myeloma. Br J Haematol. 2002;116(2):273–7. 11841427 10.1046/j.1365-2141.2002.03258.x

31. Hathi D Chanswangphuwana C Cho N Fontana F Maji D Ritchey J Ablation of VLA4 in multiple myeloma cells redirects tumor spread and prolongs survival Sci Rep 2022 12 1 30 34996933 10.1038/s41598-021-03748-0 PMC8741970 Hathi D, Chanswangphuwana C, Cho N, Fontana F, Maji D, Ritchey J, et al. Ablation of VLA4 in multiple myeloma cells redirects tumor spread and prolongs survival. Sci Rep. 2022;12(1): 30. 34996933 10.1038/s41598-021-03748-0 PMC8741970

32. Laura R Cibeira MT Uriburu C Yantorno S Salamero O Bladé J Bortezomib: an effective agent in extramedullary disease in multiple myeloma Eur J Haematol 2006 76 5 405 408 16529604 10.1111/j.0902-4441.2005.t01-1-EJH2462.x Laura R, Cibeira MT, Uriburu C, Yantorno S, Salamero O, Bladé J, et al. Bortezomib: an effective agent in extramedullary disease in multiple myeloma. Eur J Haematol. 2006;76(5):405–8. 16529604 10.1111/j.0902-4441.2005.t01-1-EJH2462.x

33. Dingli D Ailawadhi S Bergsagel PL Buadi FK Dispenzieri A Fonseca R Therapy for relapsed multiple myeloma: guidelines from the mayo stratification for myeloma and risk-adapted therapy Mayo Clin Proc 2017 92 4 578 598 28291589 10.1016/j.mayocp.2017.01.003 PMC5554888 Dingli D, Ailawadhi S, Bergsagel PL, Buadi FK, Dispenzieri A, Fonseca R, et al. Therapy for relapsed multiple myeloma: guidelines from the mayo stratification for myeloma and risk-adapted therapy. Mayo Clin Proc. 2017;92(4):578–98. 28291589 10.1016/j.mayocp.2017.01.003 PMC5554888

34. Minarik J Pika T Radocha J Jungova A Straub J Jelinek T Survival benefit of ixazomib, lenalidomide and dexamethasone (IRD) over lenalidomide and dexamethasone (Rd) in relapsed and refractory multiple myeloma patients in routine clinical practice BMC Cancer 2021 21 1 73 33451293 10.1186/s12885-020-07732-1 PMC7810195 Minarik J, Pika T, Radocha J, Jungova A, Straub J, Jelinek T, et al. Survival benefit of ixazomib, lenalidomide and dexamethasone (IRD) over lenalidomide and dexamethasone (Rd) in relapsed and refractory multiple myeloma patients in routine clinical practice. BMC Cancer. 2021;21(1): 73. 33451293 10.1186/s12885-020-07732-1 PMC7810195

35. Muchtar E Gatt ME Rouvio O Ganzel C Chubar E Suriu C Efficacy and safety of salvage therapy using Carfilzomib for relapsed or refractory multiple myeloma patients: a multicentre retrospective observational study Br J Haematol 2016 172 1 89 96 26567759 10.1111/bjh.13799 Muchtar E, Gatt ME, Rouvio O, Ganzel C, Chubar E, Suriu C, et al. Efficacy and safety of salvage therapy using Carfilzomib for relapsed or refractory multiple myeloma patients: a multicentre retrospective observational study. Br J Haematol. 2016;172(1):89–96. 26567759 10.1111/bjh.13799

36. Lee JH Choi J Min CK Park SS Jo JC Lee YJ Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: results of the multicenter KMMWP2201 study Haematologica 2024 109 11 3681 3692 38841794 10.3324/haematol.2024.285534 PMC11532698 Lee JH, Choi J, Min CK, Park SS, Jo JC, Lee YJ, et al. Superior outcomes and high-risk features with carfilzomib, lenalidomide, and dexamethasone combination therapy for patients with relapsed and refractory multiple myeloma: results of the multicenter KMMWP2201 study. Haematologica. 2024;109(11):3681–92. 38841794 10.3324/haematol.2024.285534 PMC11532698

37. Cohen YC Magen H Gatt M Sebag M Kim K Min CK Talquetamab plus teclistamab in relapsed or refractory multiple myeloma N Engl J Med 2025 392 2 138 149 39778168 10.1056/NEJMoa2406536 Cohen YC, Magen H, Gatt M, Sebag M, Kim K, Min CK, et al. Talquetamab plus teclistamab in relapsed or refractory multiple myeloma. N Engl J Med. 2025;392(2):138–49. 39778168 10.1056/NEJMoa2406536

38. Zhou X Flüchter P Nickel K Meckel K Messerschmidt J Böckle D Carfilzomib based treatment strategies in the management of relapsed/refractory multiple myeloma with extramedullary disease Cancers (Basel) 2020 10.3390/cancers12041035 32340174 PMC7225914 Zhou X, Flüchter P, Nickel K, Meckel K, Messerschmidt J, Böckle D, et al. Carfilzomib based treatment strategies in the management of relapsed/refractory multiple myeloma with extramedullary disease. Cancers (Basel). 2020. 10.3390/cancers12041035. 32340174 10.3390/cancers12041035 PMC7225914

39. Li Y Ji J Lu H Li J Qu X Pomalidomide-based therapy for extramedullary multiple myeloma Hematology (Amsterdam, Netherlands) 2022 27 1 88 94 35068387 10.1080/16078454.2021.2019364 Li Y, Ji J, Lu H, Li J, Qu X. Pomalidomide-based therapy for extramedullary multiple myeloma. Hematology (Amsterdam, Netherlands). 2022;27(1):88–94. 35068387 10.1080/16078454.2021.2019364

40. Ichinohe T Kuroda Y Okamoto S Matsue K Iida S Sunami K A multicenter phase 2 study of pomalidomide plus dexamethasone in patients with relapsed and refractory multiple myeloma: the Japanese MM-011 trial Exp Hematol Oncol 2015 5 11 27096106 10.1186/s40164-016-0040-7 PMC4835896 Ichinohe T, Kuroda Y, Okamoto S, Matsue K, Iida S, Sunami K, et al. A multicenter phase 2 study of pomalidomide plus dexamethasone in patients with relapsed and refractory multiple myeloma: the Japanese MM-011 trial. Exp Hematol Oncol. 2015;5:11. 27096106 10.1186/s40164-016-0040-7 PMC4835896

41. Usmani SZ Weiss BM Plesner T Bahlis NJ Belch A Lonial S Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma Blood 2016 128 1 37 44 27216216 10.1182/blood-2016-03-705210 PMC4937359 Usmani SZ, Weiss BM, Plesner T, Bahlis NJ, Belch A, Lonial S, et al. Clinical efficacy of daratumumab monotherapy in patients with heavily pretreated relapsed or refractory multiple myeloma. Blood. 2016;128(1):37–44. 27216216 10.1182/blood-2016-03-705210 PMC4937359

42. Lonial S Weiss BM Usmani SZ Singhal S Chari A Bahlis NJ Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial Lancet (London, England) 2016 387 10027 1551 1560 26778538 10.1016/S0140-6736(15)01120-4 Lonial S, Weiss BM, Usmani SZ, Singhal S, Chari A, Bahlis NJ, et al. Daratumumab monotherapy in patients with treatment-refractory multiple myeloma (SIRIUS): an open-label, randomised, phase 2 trial. Lancet (London, England). 2016;387(10027):1551–60. 26778538 10.1016/S0140-6736(15)01120-4

43. Jelinek T Sevcikova T Zihala D Popkova T Kapustova V Broskevicova L Limited efficacy of daratumumab in multiple myeloma with extramedullary disease Leukemia 2022 36 1 288 291 34247197 10.1038/s41375-021-01343-w Jelinek T, Sevcikova T, Zihala D, Popkova T, Kapustova V, Broskevicova L, et al. Limited efficacy of daratumumab in multiple myeloma with extramedullary disease. Leukemia. 2022;36(1):288–91. 34247197 10.1038/s41375-021-01343-w

44. Byun JM Min CK Kim K Bang SM Lee JJ Kim JS Phase II trial of daratumumab with DCEP in relapsed/refractory multiple myeloma patients with extramedullary disease J Hematol Oncol 2022 15 1 150 36274163 10.1186/s13045-022-01374-5 PMC9590218 Byun JM, Min CK, Kim K, Bang SM, Lee JJ, Kim JS, et al. Phase II trial of daratumumab with DCEP in relapsed/refractory multiple myeloma patients with extramedullary disease. J Hematol Oncol. 2022;15(1): 150. 36274163 10.1186/s13045-022-01374-5 PMC9590218

45. Sonneveld P Avet-Loiseau H Lonial S Usmani S Siegel D Anderson KC Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group Blood 2016 127 24 2955 2962 27002115 10.1182/blood-2016-01-631200 PMC4920674 Sonneveld P, Avet-Loiseau H, Lonial S, Usmani S, Siegel D, Anderson KC, et al. Treatment of multiple myeloma with high-risk cytogenetics: a consensus of the International Myeloma Working Group. Blood. 2016;127(24):2955–62. 27002115 10.1182/blood-2016-01-631200 PMC4920674

46. Rosiñol L Cibeira MT Bladé J Esteve J Aymerich M Rozman M Extramedullary multiple myeloma escapes the effect of thalidomide Haematologica 2004 89 7 832 836 15257935 Rosiñol L, Cibeira MT, Bladé J, Esteve J, Aymerich M, Rozman M, et al. Extramedullary multiple myeloma escapes the effect of thalidomide. Haematologica. 2004;89(7):832–6. 15257935

47. Bladé J Perales M Rosiñol L Tuset M Montoto S Esteve J Thalidomide in multiple myeloma: lack of response of soft-tissue plasmacytomas Br J Haematol 2001 113 2 422 424 11380408 10.1046/j.1365-2141.2001.02765.x Bladé J, Perales M, Rosiñol L, Tuset M, Montoto S, Esteve J, et al. Thalidomide in multiple myeloma: lack of response of soft-tissue plasmacytomas. Br J Haematol. 2001;113(2):422–4. 11380408 10.1046/j.1365-2141.2001.02765.x

48. Anagnostopoulos A Gika D Hamilos G Zervas K Zomas A Pouli A Treatment of relapsed/refractory multiple myeloma with thalidomide-based regimens: identification of prognostic factors Leuk Lymphoma 2004 45 11 2275 2279 15512817 10.1080/10428190410001733772 Anagnostopoulos A, Gika D, Hamilos G, Zervas K, Zomas A, Pouli A, et al. Treatment of relapsed/refractory multiple myeloma with thalidomide-based regimens: identification of prognostic factors. Leuk Lymphoma. 2004;45(11):2275–9. 15512817 10.1080/10428190410001733772

49. Oliveira AM Maria DA Metzger M Linardi C Giorgi RR Moura F Thalidomide treatment down-regulates SDF-1alpha and CXCR4 expression in multiple myeloma patients Leuk Res 2009 33 7 970 973 18976811 10.1016/j.leukres.2008.09.018 Oliveira AM, Maria DA, Metzger M, Linardi C, Giorgi RR, Moura F, et al. Thalidomide treatment down-regulates SDF-1alpha and CXCR4 expression in multiple myeloma patients. Leuk Res. 2009;33(7):970–3. 18976811 10.1016/j.leukres.2008.09.018

50. Raanani P Shpilberg O Ben-Bassat I Extramedullary disease and targeted therapies for hematological malignancies–is the association real? Ann Oncol 2007 18 1 7 12 16790518 10.1093/annonc/mdl129 Raanani P, Shpilberg O, Ben-Bassat I. Extramedullary disease and targeted therapies for hematological malignancies–is the association real? Ann Oncol. 2007;18(1):7–12. 16790518 10.1093/annonc/mdl129

51. Calvo-Villas JM Alegre A Calle C Hernández MT García-Sánchez R Ramírez G Lenalidomide is effective for extramedullary disease in relapsed or refractory multiple myeloma Eur J Haematol 2011 87 3 281 284 21557775 10.1111/j.1600-0609.2011.01644.x Calvo-Villas JM, Alegre A, Calle C, Hernández MT, García-Sánchez R, Ramírez G. Lenalidomide is effective for extramedullary disease in relapsed or refractory multiple myeloma. Eur J Haematol. 2011;87(3):281–4. 21557775 10.1111/j.1600-0609.2011.01644.x

52. Notarfranchi L Accardi F Mancini C Martella E Bonomini S Segreto R CD38 expression by plasma cells in extramedullary multiple myeloma Haematologica 2024 109 4 1297 1300 37941401 10.3324/haematol.2023.284169 PMC10985432 Notarfranchi L, Accardi F, Mancini C, Martella E, Bonomini S, Segreto R, et al. CD38 expression by plasma cells in extramedullary multiple myeloma. Haematologica. 2024;109(4):1297–300. 37941401 10.3324/haematol.2023.284169 PMC10985432

53. Dimopoulos MA Lonial S White D Moreau P Weisel K San-Miguel J Elotuzumab, lenalidomide, and dexamethasone in RRMM: final overall survival results from the phase 3 randomized ELOQUENT-2 study Blood Cancer J 2020 10 9 91 32887873 10.1038/s41408-020-00357-4 PMC7474076 Dimopoulos MA, Lonial S, White D, Moreau P, Weisel K, San-Miguel J, et al. Elotuzumab, lenalidomide, and dexamethasone in RRMM: final overall survival results from the phase 3 randomized ELOQUENT-2 study. Blood Cancer J. 2020;10(9):91. 32887873 10.1038/s41408-020-00357-4 PMC7474076

54. Danhof S Rasche L Mottok A Steinmüller T Zhou X Schreder M Elotuzumab for the treatment of extramedullary myeloma: a retrospective analysis of clinical efficacy and SLAMF7 expression patterns Ann Hematol 2021 100 6 1537 1546 33575947 10.1007/s00277-021-04447-6 PMC8116297 Danhof S, Rasche L, Mottok A, Steinmüller T, Zhou X, Schreder M, et al. Elotuzumab for the treatment of extramedullary myeloma: a retrospective analysis of clinical efficacy and SLAMF7 expression patterns. Ann Hematol. 2021;100(6):1537–46. 33575947 10.1007/s00277-021-04447-6 PMC8116297

55. Yin J Zhou X Li X Yuan C Chu X Hao L Selinexor combined with bortezomib, lenalidomide, and dexamethasone for the treatment of newly diagnosed multiple myeloma with extramedullary disease Sci Rep 2024 14 1 28557 39558020 10.1038/s41598-024-79537-2 PMC11573974 Yin J, Zhou X, Li X, Yuan C, Chu X, Hao L, et al. Selinexor combined with bortezomib, lenalidomide, and dexamethasone for the treatment of newly diagnosed multiple myeloma with extramedullary disease. Sci Rep. 2024;14(1):28557. 39558020 10.1038/s41598-024-79537-2 PMC11573974

56. Chari A Vogl DT Gavriatopoulou M Nooka AK Yee AJ Huff CA Oral selinexor-dexamethasone for triple-class refractory multiple myeloma N Engl J Med 2019 381 8 727 738 31433920 10.1056/NEJMoa1903455 Chari A, Vogl DT, Gavriatopoulou M, Nooka AK, Yee AJ, Huff CA, et al. Oral selinexor-dexamethasone for triple-class refractory multiple myeloma. N Engl J Med. 2019;381(8):727–38. 31433920 10.1056/NEJMoa1903455

57. Dima D Abdallah AO Davis JA Awada H Goel U Rashid A Impact of extraosseous extramedullary disease on outcomes of patients with relapsed-refractory multiple myeloma receiving standard-of-care chimeric antigen receptor T-cell therapy Blood Cancer J 2024 14 1 90 38821914 10.1038/s41408-024-01068-w PMC11143360 Dima D, Abdallah AO, Davis JA, Awada H, Goel U, Rashid A, et al. Impact of extraosseous extramedullary disease on outcomes of patients with relapsed-refractory multiple myeloma receiving standard-of-care chimeric antigen receptor T-cell therapy. Blood Cancer J. 2024;14(1):90. 38821914 10.1038/s41408-024-01068-w PMC11143360

58. Zanwar S Sidana S Shune L Puglianini OC Pasvolsky O Gonzalez R Impact of extramedullary multiple myeloma on outcomes with idecabtagene vicleucel J Hematol Oncol 2024 17 1 42 38845015 10.1186/s13045-024-01555-4 PMC11157748 Zanwar S, Sidana S, Shune L, Puglianini OC, Pasvolsky O, Gonzalez R, et al. Impact of extramedullary multiple myeloma on outcomes with idecabtagene vicleucel. J Hematol Oncol. 2024;17(1): 42. 38845015 10.1186/s13045-024-01555-4 PMC11157748

59. Besliu C Tanase AD Rotaru I Espinoza J Vidal L Poelman M The evolving landscape in multiple myeloma: from risk stratification to T cell-directed advanced therapies Cancers (Basel) 2025 10.3390/cancers17030525 39941892 PMC11817212 Besliu C, Tanase AD, Rotaru I, Espinoza J, Vidal L, Poelman M, et al. The evolving landscape in multiple myeloma: from risk stratification to T cell-directed advanced therapies. Cancers (Basel). 2025. 10.3390/cancers17030525. 39941892 10.3390/cancers17030525 PMC11817212

60. Zhao J Yang H Ge J Li L Yao Q He S Pomalidomide improves the effectiveness of CAR-T treatment in the relapsed and refractory multiple myeloma or B-cell leukemia/lymphoma with extramedullary disease Blood Sci (Baltimore, Md) 2024 6 2 e00184 10.1097/BS9.0000000000000184 PMC10906647 38433987 Zhao J, Yang H, Ge J, Li L, Yao Q, He S, et al. Pomalidomide improves the effectiveness of CAR-T treatment in the relapsed and refractory multiple myeloma or B-cell leukemia/lymphoma with extramedullary disease. Blood Sci (Baltimore, Md). 2024;6(2): e00184. 10.1097/BS9.0000000000000184 PMC10906647 38433987

61. Wang D Fu H Que Y Ruan H Xu M Long X A novel two-step administration of XPO-1 inhibitor may enhance the effect of anti-BCMA CAR-T in relapsed/refractory extramedullary multiple myeloma J Transl Med 2023 21 1 812 37964302 10.1186/s12967-023-04655-w PMC10647128 Wang D, Fu H, Que Y, Ruan H, Xu M, Long X, et al. A novel two-step administration of XPO-1 inhibitor may enhance the effect of anti-BCMA CAR-T in relapsed/refractory extramedullary multiple myeloma. J Transl Med. 2023;21(1):812. 37964302 10.1186/s12967-023-04655-w PMC10647128

62. Gagelmann N Dima D Merz M Hashmi H Ahmed N Tovar N Development and validation of a prediction model of outcome after B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in relapsed/refractory multiple myeloma J Clin Oncol 2024 42 14 1665 1675 38358946 10.1200/JCO.23.02232 PMC11095856 Gagelmann N, Dima D, Merz M, Hashmi H, Ahmed N, Tovar N, et al. Development and validation of a prediction model of outcome after B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in relapsed/refractory multiple myeloma. J Clin Oncol. 2024;42(14):1665–75. 38358946 10.1200/JCO.23.02232 PMC11095856

63. Cohen AD Mateos MV Cohen YC Rodriguez-Otero P Paiva B van de Donk N Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents Blood 2023 141 3 219 230 36095849 10.1182/blood.2022015526 PMC10562529 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(3):219–30. 36095849 10.1182/blood.2022015526 PMC10562529

64. Berdeja JG Madduri D Usmani SZ Jakubowiak A Agha M Cohen AD Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study Lancet (London, England) 2021 398 10297 314 324 34175021 10.1016/S0140-6736(21)00933-8 Berdeja JG, Madduri D, Usmani SZ, Jakubowiak A, Agha M, Cohen AD, et al. Ciltacabtagene autoleucel, a B-cell maturation antigen-directed chimeric antigen receptor T-cell therapy in patients with relapsed or refractory multiple myeloma (CARTITUDE-1): a phase 1b/2 open-label study. Lancet (London, England). 2021;398(10297):314–24. 34175021 10.1016/S0140-6736(21)00933-8

65. Munshi NC Anderson LD Jr Shah N Madduri D Berdeja J Lonial S Idecabtagene vicleucel in relapsed and refractory multiple myeloma N Engl J Med 2021 384 8 705 716 33626253 10.1056/NEJMoa2024850 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(8):705–16. 33626253 10.1056/NEJMoa2024850

66. Wang Y Cao J Gu W Shi M Lan J Yan Z Long-term follow-up of combination of B-cell maturation antigen and CD19 chimeric antigen receptor T cells in multiple myeloma J Clin Oncol 2022 40 20 2246 2256 35333600 10.1200/JCO.21.01676 Wang Y, Cao J, Gu W, Shi M, Lan J, Yan Z, et al. Long-term follow-up of combination of B-cell maturation antigen and CD19 chimeric antigen receptor T cells in multiple myeloma. J Clin Oncol. 2022;40(20):2246–56. 35333600 10.1200/JCO.21.01676

67. Zhang M Zhou L Zhao H Zhang Y Wei G Hong R Risk factors associated with durable progression-free survival in patients with relapsed or refractory multiple myeloma treated with anti-BCMA CAR T-cell therapy Clin Cancer Res 2021 27 23 6384 6392 34548316 10.1158/1078-0432.CCR-21-2031 PMC9401500 Zhang M, Zhou L, Zhao H, Zhang Y, Wei G, Hong R, et al. Risk factors associated with durable progression-free survival in patients with relapsed or refractory multiple myeloma treated with anti-BCMA CAR T-cell therapy. Clin Cancer Res. 2021;27(23):6384–92. 34548316 10.1158/1078-0432.CCR-21-2031 PMC9401500

68. Que Y Xu M Xu Y Almeida VDF Zhu L Wang Z Anti-BCMA CAR-T cell therapy in relapsed/refractory multiple myeloma patients with extramedullary disease: a single center analysis of two clinical trials Front Immunol 2021 12 755866 34777368 10.3389/fimmu.2021.755866 PMC8589080 Que Y, Xu M, Xu Y, Almeida VDF, Zhu L, Wang Z, et al. Anti-BCMA CAR-T cell therapy in relapsed/refractory multiple myeloma patients with extramedullary disease: a single center analysis of two clinical trials. Front Immunol. 2021;12: 755866. 34777368 10.3389/fimmu.2021.755866 PMC8589080

69. Raje N Berdeja J Lin Y Siegel D Jagannath S Madduri D Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma N Engl J Med 2019 380 18 1726 1737 31042825 10.1056/NEJMoa1817226 PMC8202968 Raje N, Berdeja J, Lin Y, Siegel D, Jagannath S, Madduri D, et al. Anti-BCMA CAR T-cell therapy bb2121 in relapsed or refractory multiple myeloma. N Engl J Med. 2019;380(18):1726–37. 31042825 10.1056/NEJMoa1817226 PMC8202968

70. Xu J Chen LJ Yang SS Sun Y Wu W Liu YF Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma Proc Natl Acad Sci USA 2019 116 19 9543 9551 30988175 10.1073/pnas.1819745116 PMC6510991 Xu J, Chen LJ, Yang SS, Sun Y, Wu W, Liu YF, et al. Exploratory trial of a biepitopic CAR T-targeting B cell maturation antigen in relapsed/refractory multiple myeloma. Proc Natl Acad Sci USA. 2019;116(19):9543–51. 30988175 10.1073/pnas.1819745116 PMC6510991

71. Cohen AD Garfall AL Stadtmauer EA Melenhorst JJ Lacey SF Lancaster E B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma J Clin Invest 2019 129 6 2210 2221 30896447 10.1172/JCI126397 PMC6546468 Cohen AD, Garfall AL, Stadtmauer EA, Melenhorst JJ, Lacey SF, Lancaster E, et al. B cell maturation antigen-specific CAR T cells are clinically active in multiple myeloma. J Clin Invest. 2019;129(6):2210–21. 30896447 10.1172/JCI126397 PMC6546468

72. Wang D Wang J Hu G Wang W Xiao Y Cai H A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma Blood 2021 137 21 2890 2901 33512480 10.1182/blood.2020008936 Wang D, Wang J, Hu G, Wang W, Xiao Y, Cai H, et al. A phase 1 study of a novel fully human BCMA-targeting CAR (CT103A) in patients with relapsed/refractory multiple myeloma. Blood. 2021;137(21):2890–901. 33512480 10.1182/blood.2020008936

73. Li C Cao W Que Y Wang Q Xiao Y Gu C A phase I study of anti-BCMA CAR T cell therapy in relapsed/refractory multiple myeloma and plasma cell leukemia Clin Transl Med 2021 11 3 e346 33784005 10.1002/ctm2.346 PMC7943908 Li C, Cao W, Que Y, Wang Q, Xiao Y, Gu C, et al. A phase I study of anti-BCMA CAR T cell therapy in relapsed/refractory multiple myeloma and plasma cell leukemia. Clin Transl Med. 2021;11(3): e346. 33784005 10.1002/ctm2.346 PMC7943908

74. Li W Liu M Yuan T Yan L Cui R Deng Q Efficacy and follow-up of humanized anti-BCMA CAR-T cell therapy in relapsed/refractory multiple myeloma patients with extramedullary-extraosseous, extramedullary-bone related, and without extramedullary disease Hematol Oncol 2022 40 2 223 232 34942032 10.1002/hon.2958 PMC9305928 Li W, Liu M, Yuan T, Yan L, Cui R, Deng Q. Efficacy and follow-up of humanized anti-BCMA CAR-T cell therapy in relapsed/refractory multiple myeloma patients with extramedullary-extraosseous, extramedullary-bone related, and without extramedullary disease. Hematol Oncol. 2022;40(2):223–32. 34942032 10.1002/hon.2958 PMC9305928

75. Chen D Zhu Y Chen Z Jiang S He H Qiang W A 5-year follow-up clinical study of the b-cell maturation antigen chimeric antigen receptor t-cell therapy HDS269B in patients with relapsed or refractory multiple myeloma Clin Cancer Res 2024 30 17 3747 3756 38869658 10.1158/1078-0432.CCR-24-0414 PMC11369620 Chen D, Zhu Y, Chen Z, Jiang S, He H, Qiang W, et al. A 5-year follow-up clinical study of the b-cell maturation antigen chimeric antigen receptor t-cell therapy HDS269B in patients with relapsed or refractory multiple myeloma. Clin Cancer Res. 2024;30(17):3747–56. 38869658 10.1158/1078-0432.CCR-24-0414 PMC11369620

76. Hashmi H Hansen DK Peres LC Puglianini OC Freeman C De Avila G Factors associated with refractoriness or early progression after idecabtagene vicleucel in patients with relapsed/ refractory multiple myeloma: US Myeloma Immunotherapy Consortium real world experience Haematologica 2024 109 5 1514 1524 37855036 10.3324/haematol.2023.283888 PMC11063864 Hashmi H, Hansen DK, Peres LC, Puglianini OC, Freeman C, De Avila G, et al. Factors associated with refractoriness or early progression after idecabtagene vicleucel in patients with relapsed/ refractory multiple myeloma: US Myeloma Immunotherapy Consortium real world experience. Haematologica. 2024;109(5):1514–24. 37855036 10.3324/haematol.2023.283888 PMC11063864

77. Deng H Liu M Yuan T Zhang H Cui R Li J Efficacy of humanized Anti-BCMA CAR T cell therapy in relapsed/refractory multiple myeloma patients with and without extramedullary disease Front Immunol 2021 12 720571 34421924 10.3389/fimmu.2021.720571 PMC8374046 Deng H, Liu M, Yuan T, Zhang H, Cui R, Li J, et al. Efficacy of humanized Anti-BCMA CAR T cell therapy in relapsed/refractory multiple myeloma patients with and without extramedullary disease. Front Immunol. 2021;12: 720571. 34421924 10.3389/fimmu.2021.720571 PMC8374046

78. Pan D; Mouhieddine TH; Sheng T; Fu W; Moshier E; Richter J, et al. Extramedullary disease but not paraskeletal disease portends inferior outcomes after CAR T cell therapy in multiple myeloma. Bone marrow transplantation. 2025. 10.1038/s41409-025-02593-3 40319194

79. Xia J Li H Yan Z Zhou D Wang Y Qi Y Anti-G protein-coupled receptor, class C group 5 member D chimeric antigen receptor T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase II trial J Clin Oncol 2023 41 14 2583 2593 36881785 10.1200/JCO.22.01824 PMC10414745 Xia J, Li H, Yan Z, Zhou D, Wang Y, Qi Y, et al. Anti-G protein-coupled receptor, class C group 5 member D chimeric antigen receptor T cells in patients with relapsed or refractory multiple myeloma: a single-arm, phase II trial. J Clin Oncol. 2023;41(14):2583–93. 36881785 10.1200/JCO.22.01824 PMC10414745

80. Zhang M Wei G Zhou L Zhou J Chen S Zhang W GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial Lancet Haematol 2023 10 2 e107 e116 36725117 10.1016/S2352-3026(22)00372-6 Zhang M, Wei G, Zhou L, Zhou J, Chen S, Zhang W, et al. GPRC5D CAR T cells (OriCAR-017) in patients with relapsed or refractory multiple myeloma (POLARIS): a first-in-human, single-centre, single-arm, phase 1 trial. Lancet Haematol. 2023;10(2):e107–16. 36725117 10.1016/S2352-3026(22)00372-6

81. Li C Xu J Luo W Liao D Xie W Wei Q Bispecific CS1-BCMA CAR-T cells are clinically active in relapsed or refractory multiple myeloma Leukemia 2024 38 1 149 159 37848634 10.1038/s41375-023-02065-x PMC10776387 Li C, Xu J, Luo W, Liao D, Xie W, Wei Q, et al. Bispecific CS1-BCMA CAR-T cells are clinically active in relapsed or refractory multiple myeloma. Leukemia. 2024;38(1):149–59. 37848634 10.1038/s41375-023-02065-x PMC10776387

82. Mei H Li C Jiang H Zhao X Huang Z Jin D A bispecific CAR-T cell therapy targeting BCMA and CD38 in relapsed or refractory multiple myeloma J Hematol Oncol 2021 14 1 161 34627333 10.1186/s13045-021-01170-7 PMC8501733 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(1): 161. 34627333 10.1186/s13045-021-01170-7 PMC8501733

83. Qiang W Lu J Jia Y Liu J Liu J He H B-cell maturation antigen/CD19 dual-targeting immunotherapy in newly diagnosed multiple myeloma JAMA Oncol 2024 10 9 1259 1263 39052306 10.1001/jamaoncol.2024.2172 PMC11273281 Qiang W, Lu J, Jia Y, Liu J, Liu J, He H, et al. B-cell maturation antigen/CD19 dual-targeting immunotherapy in newly diagnosed multiple myeloma. JAMA Oncol. 2024;10(9):1259–63. 39052306 10.1001/jamaoncol.2024.2172 PMC11273281

84. Tang Y Yin H Zhao X Jin D Liang Y Xiong T High efficacy and safety of CD38 and BCMA bispecific CAR-T in relapsed or refractory multiple myeloma J Exper Clin Cancer Res : CR 2022 41 1 2 34980210 10.1186/s13046-021-02214-z PMC8722124 Tang Y, Yin H, Zhao X, Jin D, Liang Y, Xiong T, et al. High efficacy and safety of CD38 and BCMA bispecific CAR-T in relapsed or refractory multiple myeloma. J Exper Clin Cancer Res : CR. 2022;41(1):2. 34980210 10.1186/s13046-021-02214-z PMC8722124

85. Qi Y Li H Qi K Zhu F Cheng H Chen W Clinical outcomes and microenvironment profiling in relapsed/refractory multiple myeloma patients with extramedullary disease receiving anti-BCMA CAR T-cell-based therapy Am J Hematol 2024 99 12 2286 2295 39194355 10.1002/ajh.27469 Qi Y, Li H, Qi K, Zhu F, Cheng H, Chen W, et al. Clinical outcomes and microenvironment profiling in relapsed/refractory multiple myeloma patients with extramedullary disease receiving anti-BCMA CAR T-cell-based therapy. Am J Hematol. 2024;99(12):2286–95. 39194355 10.1002/ajh.27469

86. Zhou D Sun Q Xia J Gu W Qian J Zhuang W Anti-BCMA/GPRC5D bispecific CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, single-centre, phase 1 trial Lancet Haematol 2024 11 10 e751 e760 39059405 10.1016/S2352-3026(24)00176-5 Zhou D, Sun Q, Xia J, Gu W, Qian J, Zhuang W, et al. Anti-BCMA/GPRC5D bispecific CAR T cells in patients with relapsed or refractory multiple myeloma: a single-arm, single-centre, phase 1 trial. Lancet Haematol. 2024;11(10):e751–60. 39059405 10.1016/S2352-3026(24)00176-5

87. Chari A Minnema MC Berdeja JG Oriol A van de Donk N Rodríguez-Otero P Talquetamab, a T-cell-redirecting GPRC5D bispecific antibody for multiple myeloma N Engl J Med 2022 387 24 2232 2244 36507686 10.1056/NEJMoa2204591 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(24):2232–44. 36507686 10.1056/NEJMoa2204591

88. Moreau P Garfall AL van de Donk N Nahi H San-Miguel JF Oriol A Teclistamab in relapsed or refractory multiple myeloma N Engl J Med 2022 387 6 495 505 35661166 10.1056/NEJMoa2203478 PMC10587778 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(6):495–505. 35661166 10.1056/NEJMoa2203478 PMC10587778

89. Riedhammer C Bassermann F Besemer B Bewarder M Brunner F Carpinteiro A Real-world analysis of teclistamab in 123 RRMM patients from Germany Leukemia 2024 38 2 365 371 38245601 10.1038/s41375-024-02154-5 PMC10844072 Riedhammer C, Bassermann F, Besemer B, Bewarder M, Brunner F, Carpinteiro A, et al. Real-world analysis of teclistamab in 123 RRMM patients from Germany. Leukemia. 2024;38(2):365–71. 38245601 10.1038/s41375-024-02154-5 PMC10844072

90. Mohan M Monge J Shah N Luan D Forsberg M Bhatlapenumarthi V Teclistamab in relapsed refractory multiple myeloma: multi-institutional real-world study Blood Cancer J 2024 14 1 35 38443345 10.1038/s41408-024-01003-z PMC10914756 Mohan M, Monge J, Shah N, Luan D, Forsberg M, Bhatlapenumarthi V, et al. Teclistamab in relapsed refractory multiple myeloma: multi-institutional real-world study. Blood Cancer J. 2024;14(1):35. 38443345 10.1038/s41408-024-01003-z PMC10914756

91. Lesokhin AM Tomasson MH Arnulf B Bahlis NJ Miles Prince H Niesvizky R Elranatamab in relapsed or refractory multiple myeloma: phase 2 MagnetisMM-3 trial results Nat Med 2023 29 9 2259 2267 37582952 10.1038/s41591-023-02528-9 PMC10504075 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(9):2259–67. 37582952 10.1038/s41591-023-02528-9 PMC10504075

92. Cai Z Xia Z He AL Dong YJ Wang Y Liao A Efficacy, safety, and pharmacokinetics of teclistamab in Chinese patients with relapsed/refractory multiple myeloma from the China cohort of MajesTEC-1 Cancer 2025 131 1 e35665 39660861 10.1002/cncr.35665 PMC11694538 Cai Z, Xia Z, He AL, Dong YJ, Wang Y, Liao A, et al. Efficacy, safety, and pharmacokinetics of teclistamab in Chinese patients with relapsed/refractory multiple myeloma from the China cohort of MajesTEC-1. Cancer. 2025;131(1): e35665. 39660861 10.1002/cncr.35665 PMC11694538

93. Touzeau C Krishnan AY Moreau P Perrot A Usmani SZ Manier S Efficacy and safety of teclistamab in patients with relapsed/refractory multiple myeloma after BCMA-targeting therapies Blood 2024 144 23 2375 2388 39172760 10.1182/blood.2023023616 Touzeau C, Krishnan AY, Moreau P, Perrot A, Usmani SZ, Manier S, et al. Efficacy and safety of teclistamab in patients with relapsed/refractory multiple myeloma after BCMA-targeting therapies. Blood. 2024;144(23):2375–88. 39172760 10.1182/blood.2023023616

94. Frenking JH Riedhammer C Teipel R Bassermann F Besemer B Bewarder M A German multicenter real-world analysis of talquetamab in 138 patients with relapsed/refractory multiple myeloma HemaSphere 2025 9 4 e70114 40248128 10.1002/hem3.70114 PMC12005056 Frenking JH, Riedhammer C, Teipel R, Bassermann F, Besemer B, Bewarder M, et al. A German multicenter real-world analysis of talquetamab in 138 patients with relapsed/refractory multiple myeloma. HemaSphere. 2025;9(4): e70114. 40248128 10.1002/hem3.70114 PMC12005056

95. Chari A Touzeau C Schinke C Minnema MC Berdeja JG Oriol A Safety and activity of talquetamab in patients with relapsed or refractory multiple myeloma (MonumenTAL-1): a multicentre, open-label, phase 1–2 study Lancet Haematol 2025 12 4 e269 e281 40090350 10.1016/S2352-3026(24)00385-5 Chari A, Touzeau C, Schinke C, Minnema MC, Berdeja JG, Oriol A, et al. Safety and activity of talquetamab in patients with relapsed or refractory multiple myeloma (MonumenTAL-1): a multicentre, open-label, phase 1–2 study. Lancet Haematol. 2025;12(4):e269–81. 40090350 10.1016/S2352-3026(24)00385-5

96. Jiang D Huang H Qin H Tang K Shi X Zhu T Chimeric antigen receptor T cells targeting FcRH5 provide robust tumour-specific responses in murine xenograft models of multiple myeloma Nat Commun 2023 14 1 3642 37339964 10.1038/s41467-023-39395-4 PMC10282100 Jiang D, Huang H, Qin H, Tang K, Shi X, Zhu T, et al. Chimeric antigen receptor T cells targeting FcRH5 provide robust tumour-specific responses in murine xenograft models of multiple myeloma. Nat Commun. 2023;14(1): 3642. 37339964 10.1038/s41467-023-39395-4 PMC10282100

97. Dileo R Mewawalla P Babu K Yin Y Strouse C Chen E A real-world experience of efficacy and safety of belantamab mafodotin in relapsed refractory multiple myeloma Blood Cancer J 2025 15 1 34 40064854 10.1038/s41408-025-01226-8 PMC11893888 Dileo R, Mewawalla P, Babu K, Yin Y, Strouse C, Chen E, et al. A real-world experience of efficacy and safety of belantamab mafodotin in relapsed refractory multiple myeloma. Blood Cancer J. 2025;15(1): 34. 40064854 10.1038/s41408-025-01226-8 PMC11893888

98. Almodovar Diaz AA Alouch SS Chawla Y Gonsalves WI The antibody drug conjugate, belantamab-mafodotin, in the treatment of multiple myeloma: a comprehensive review Blood Lymphat Cancer Targets Ther 2024 14 71 87 10.2147/BLCTT.S490021 PMC11631777 39664714 Almodovar Diaz AA, Alouch SS, Chawla Y, Gonsalves WI. The antibody drug conjugate, belantamab-mafodotin, in the treatment of multiple myeloma: a comprehensive review. Blood Lymphat Cancer Targets Ther. 2024;14:71–87. 10.2147/BLCTT.S490021 PMC11631777 39664714

99. Gagelmann N Eikema DJ Koster L Caillot D Pioltelli P Lleonart JB Tandem autologous stem cell transplantation improves outcomes in newly diagnosed multiple myeloma with extramedullary disease and high-risk cytogenetics: a study from the chronic malignancies working party of the european society for blood and marrow transplantation Biol Blood Marrow trans 2019 25 11 2134 2142 10.1016/j.bbmt.2019.07.004 31288095 Gagelmann N, Eikema DJ, Koster L, Caillot D, Pioltelli P, Lleonart JB, et al. Tandem autologous stem cell transplantation improves outcomes in newly diagnosed multiple myeloma with extramedullary disease and high-risk cytogenetics: a study from the chronic malignancies working party of the european society for blood and marrow transplantation. Biol Blood Marrow trans. 2019;25(11):2134–42. 10.1016/j.bbmt.2019.07.004 31288095

100. Chen CI Masih-Khan E Jiang H Rabea A Cserti-Gazdewich C Jimenez-Zepeda VH Central nervous system involvement with multiple myeloma: long term survival can be achieved with radiation, intrathecal chemotherapy, and immunomodulatory agents Br J Haematol 2013 162 4 483 488 23772701 10.1111/bjh.12414 Chen CI, Masih-Khan E, Jiang H, Rabea A, Cserti-Gazdewich C, Jimenez-Zepeda VH, et al. Central nervous system involvement with multiple myeloma: long term survival can be achieved with radiation, intrathecal chemotherapy, and immunomodulatory agents. Br J Haematol. 2013;162(4):483–8. 23772701 10.1111/bjh.12414

101. Jurczyszyn A Grzasko N Gozzetti A Czepiel J Cerase A Hungria V Central nervous system involvement by multiple myeloma: A multi-institutional retrospective study of 172 patients in daily clinical practice Am J Hematol 2016 91 6 575 580 26955792 10.1002/ajh.24351 PMC5502095 Jurczyszyn A, Grzasko N, Gozzetti A, Czepiel J, Cerase A, Hungria V, et al. Central nervous system involvement by multiple myeloma: A multi-institutional retrospective study of 172 patients in daily clinical practice. Am J Hematol. 2016;91(6):575–80. 26955792 10.1002/ajh.24351 PMC5502095

102. Katodritou E Terpos E Kastritis E Delimpasis S Symeonidis AS Repousis P Lack of survival improvement with novel anti-myeloma agents for patients with multiple myeloma and central nervous system involvement: the Greek myeloma study group experience Ann Hematol 2015 94 12 2033 2042 26420061 10.1007/s00277-015-2484-y Katodritou E, Terpos E, Kastritis E, Delimpasis S, Symeonidis AS, Repousis P, et al. Lack of survival improvement with novel anti-myeloma agents for patients with multiple myeloma and central nervous system involvement: the Greek myeloma study group experience. Ann Hematol. 2015;94(12):2033–42. 26420061 10.1007/s00277-015-2484-y

103. Fernandez LG 3rd Oyon DE Gondi V Grimm S Khan OH Secondary CNS myeloma with remission after systemic CNS-penetrating agents Neuro-oncol Adv 2022 4 1 vdac106 10.1093/noajnl/vdac106 PMC9307102 35892045 Fernandez LG 3rd, Oyon DE, Gondi V, Grimm S, Khan OH. Secondary CNS myeloma with remission after systemic CNS-penetrating agents. Neuro-oncol Adv. 2022;4(1): vdac106. 10.1093/noajnl/vdac106 PMC9307102 35892045

104. Mussetti A Dalto S Montefusco V Effective treatment of pomalidomide in central nervous system myelomatosis Leuk Lymphoma 2013 54 4 864 866 22880953 10.3109/10428194.2012.718343 Mussetti A, Dalto S, Montefusco V. Effective treatment of pomalidomide in central nervous system myelomatosis. Leuk Lymphoma. 2013;54(4):864–6. 22880953 10.3109/10428194.2012.718343

105. Badros A Singh Z Dhakal B Kwok Y MacLaren A Richardson P Marizomib for central nervous system-multiple myeloma Br J Haematol 2017 177 2 221 225 28387460 10.1111/bjh.14498 Badros A, Singh Z, Dhakal B, Kwok Y, MacLaren A, Richardson P, et al. Marizomib for central nervous system-multiple myeloma. Br J Haematol. 2017;177(2):221–5. 28387460 10.1111/bjh.14498

106. Green AL Ramkissoon SH McCauley D Jones K Perry JA Hsu JH Preclinical antitumor efficacy of selective exportin 1 inhibitors in glioblastoma Neuro-oncol 2015 17 5 697 707 25366336 10.1093/neuonc/nou303 PMC4482855 Green AL, Ramkissoon SH, McCauley D, Jones K, Perry JA, Hsu JH, et al. Preclinical antitumor efficacy of selective exportin 1 inhibitors in glioblastoma. Neuro-oncol. 2015;17(5):697–707. 25366336 10.1093/neuonc/nou303 PMC4482855

107. Bobillo S Abrisqueta P Carpio C Raheja P Castellví J Crespo M Promising activity of selinexor in the treatment of a patient with refractory diffuse large B-cell lymphoma and central nervous system involvement Haematologica 2018 103 2 e92 e93 29242296 10.3324/haematol.2017.181636 PMC5792294 Bobillo S, Abrisqueta P, Carpio C, Raheja P, Castellví J, Crespo M, et al. Promising activity of selinexor in the treatment of a patient with refractory diffuse large B-cell lymphoma and central nervous system involvement. Haematologica. 2018;103(2):e92–3. 29242296 10.3324/haematol.2017.181636 PMC5792294

108. Katodritou E Dalampira D Delimpasi S Ntanasis-Stathopoulos I Karaolidou F Gkioka AI Central nervous system multiple myeloma: A real-world multi-institutional study of the Greek Myeloma Study Group Am J Hematol 2024 99 10 1897 1905 38953456 10.1002/ajh.27425 Katodritou E, Dalampira D, Delimpasi S, Ntanasis-Stathopoulos I, Karaolidou F, Gkioka AI, et al. Central nervous system multiple myeloma: A real-world multi-institutional study of the Greek Myeloma Study Group. Am J Hematol. 2024;99(10):1897–905. 38953456 10.1002/ajh.27425

109. Petersen SL Wagner A Gimsing P Cerebral and meningeal multiple myeloma after autologous stem cell transplantation. A case report and review of the literature Am J Hematol 1999 62 4 228 233 10589078 10.1002/(sici)1096-8652(199912)62:4<228::aid-ajh5>3.0.co;2-3 Petersen SL, Wagner A, Gimsing P. Cerebral and meningeal multiple myeloma after autologous stem cell transplantation. A case report and review of the literature. Am J Hematol. 1999;62(4):228–33. 10589078 10.1002/(sici)1096-8652(199912)62:4<228::aid-ajh5>3.0.co;2-3

110. Gozzetti A Cerase A Novel agents in CNS myeloma treatment Cent Nerv Syst Agents Med Chem 2014 14 1 23 27 25134940 10.2174/1871524914999140818111514 Gozzetti A, Cerase A. Novel agents in CNS myeloma treatment. Cent Nerv Syst Agents Med Chem. 2014;14(1):23–7. 25134940 10.2174/1871524914999140818111514

111. Szita VR Mikala G Kozma A Fábián J Hardi A Alizadeh H Targeted Venetoclax Therapy in t(11;14) Multiple Myeloma: Real World Data From Seven Hungarian Centers Pathol Oncol Res : POR 2022 28 1610276 35295611 10.3389/pore.2022.1610276 PMC8918485 Szita VR, Mikala G, Kozma A, Fábián J, Hardi A, Alizadeh H, et al. Targeted Venetoclax Therapy in t(11;14) Multiple Myeloma: Real World Data From Seven Hungarian Centers. Pathol Oncol Res : POR. 2022;28:1610276. 35295611 10.3389/pore.2022.1610276 PMC8918485

112. Wang Y Zu C Teng X Yang L Zhang M Hong R BCMA CAR-T therapy is safe and effective for refractory/relapsed multiple myeloma with central nervous system involvement J Immunother Hagerstown Md 1997. 2022 45 1 25 34 10.1097/CJI.0000000000000391 34874329 Wang Y, Zu C, Teng X, Yang L, Zhang M, Hong R, et al. BCMA CAR-T therapy is safe and effective for refractory/relapsed multiple myeloma with central nervous system involvement. J Immunother Hagerstown Md 1997. 2022;45(1):25–34. 10.1097/CJI.0000000000000391 34874329

113. Gaballa MR Puglianini OC Cohen A Vogl D Chung A Ferreri CJ BCMA-directed CAR T-cell therapy in patients with multiple myeloma and CNS involvement Blood Adv 2025 9 5 1171 1180 39729503 10.1182/bloodadvances.2024014345 PMC11925525 Gaballa MR, Puglianini OC, Cohen A, Vogl D, Chung A, Ferreri CJ, et al. BCMA-directed CAR T-cell therapy in patients with multiple myeloma and CNS involvement. Blood Adv. 2025;9(5):1171–80. 39729503 10.1182/bloodadvances.2024014345 PMC11925525

114. Egan PA Elder PT Deighan WI O'Connor SJM Alexander HD Multiple myeloma with central nervous system relapse Haematologica 2020 105 7 1780 1790 32414852 10.3324/haematol.2020.248518 PMC7327654 Egan PA, Elder PT, Deighan WI, O’Connor SJM, Alexander HD. Multiple myeloma with central nervous system relapse. Haematologica. 2020;105(7):1780–90. 32414852 10.3324/haematol.2020.248518 PMC7327654

115. Tringale KR Imber BS Cederquist GY Yahalom J Moore ZR Hoppe RT Urgent and emergent radiotherapy for hematologic malignancies of the central nervous system: a review of the literature and practical approach Front Oncol 2025 15 1511261 40231259 10.3389/fonc.2025.1511261 PMC11994676 Tringale KR, Imber BS, Cederquist GY, Yahalom J, Moore ZR, Hoppe RT, et al. Urgent and emergent radiotherapy for hematologic malignancies of the central nervous system: a review of the literature and practical approach. Front Oncol. 2025;15:1511261. 40231259 10.3389/fonc.2025.1511261 PMC11994676

116. Vegivinti CTR Lawrence Alexander Santhi J Liu L Keesari PR Thakur R Hammami MB Efficacy of bispecific antibodies Vs CAR-T in the treatment of extramedullary disease and high-risk cytogenetics in relapsed multiple myeloma: a systematic review and meta-analysis Blood 2023 142 1994 1994 Vegivinti CTR, Lawrence Alexander Santhi J, Liu L, Keesari PR, Thakur R, Hammami MB, et al. Efficacy of bispecific antibodies Vs CAR-T in the treatment of extramedullary disease and high-risk cytogenetics in relapsed multiple myeloma: a systematic review and meta-analysis. Blood. 2023;142:1994–1994.

117. Rees MJ Mammadzadeh A Bolarinwa A Elhaj ME Bohra A Bansal R Clinical features associated with poor response and early relapse following BCMA-directed therapies in multiple myeloma Blood Cancer J 2024 14 1 122 39043638 10.1038/s41408-024-01081-z PMC11266661 Rees MJ, Mammadzadeh A, Bolarinwa A, Elhaj ME, Bohra A, Bansal R, et al. Clinical features associated with poor response and early relapse following BCMA-directed therapies in multiple myeloma. Blood Cancer J. 2024;14(1): 122. 39043638 10.1038/s41408-024-01081-z PMC11266661