Эволюционный план лечения для пожилых пациентов с множественной миеломой: от квадских режимов до T-Cell Workers и CAR-T.

1. Introduction

Multiple myeloma (MM) is primarily a disease of the elderly, with a median age at diagnosis of 69 years; one-third of newly diagnosed patients are over 75 years and 10% are over 85 years of age [ 1 ]. With the profound shift in the age of the world’s population, the number of MM patients aged ≥ 65 years is expected to rise by more than 36% between 2020 and 2030 [ 2 ]. Despite their growing prevalence, elderly MM patients are underrepresented in clinical trials and their management is largely extrapolated from clinical trials of transplant-ineligible patients, leading to a significant research gap [ 3 , 4 ]. This is relevant because elderly patients are a heterogenous group subject to the effects of frailty, medical comorbidities, and increased susceptibility to adverse treatment effects [ 3 ]. Consequently, treatment strategies for elderly patients must be appropriately tailored, balancing efficacy with quality of life, and aiming to maximize efficacy while preserving function and independence.

Over the past 20 years we have seen an improvement in survival outcomes for older MM patients, driven primarily by the development of immunomodulatory drugs (IMIDs), proteasome inhibitors (PIs), and CD38-directed monoclonal antibodies (mAbs). In the early 2000s, patients ≥ 65 years had a median OS of only 4.6 years, in comparison to modern series where patients ≥ 70 years can expect a median OS beyond 6.5 years [ 5 , 6 , 7 ]. Notably, elderly patients have derived less of a survival benefit over the past two decades compared to the general MM population, and this difference is not clearly explained by differences in age and high-risk disease features [ 8 ]. While some high-risk cytogenetic features are more common in the elderly, their prognostic impact appears to diminish with age, while the impact of patient-related factors is enhanced [ 9 , 10 ]. The reduced benefit of therapeutic advances highlights the need for improved approaches for elderly MM patients, especially as the treatment landscape experiences an unprecedented upheaval following the introduction of T-cell engagers (TCEs) and chimeric antigen receptor T-cells (CAR-T).

The application of immunotherapies to elderly MM patients is a key clinical question and this review will examine modern approaches for newly diagnosed elderly MM patients, focusing on emerging immunotherapeutic strategies. For the purposes of this review we will consider elderly MM patients as those aged ≥ 75 years, as such patients are almost unanimously considered ineligible for intensive therapeutic approaches such as front-line autologous stem-cell transplant (ASCT) [ 11 ].

2. General Considerations in the Treatment of Elderly Myeloma Patients

Frailty is a state of decreased reserve affecting multiple organ systems and is a key determinant of treatment delivery in elderly MM patients [ 12 ]. As a result, several clinical tools have been developed to assess frailty in MM, including the IMWG frailty score, the revised myeloma comorbidity index, the Mayo risk score, and the IFM simplified frailty assessment [ 13 , 14 , 15 , 16 , 17 ]. While such tools have been shown to consistently predict survival, and treatment discontinuation in MM, their adoption in routine clinical practice is limited, primarily due to time constraints. Another limitation of these tools is the omission of physical performance tests, including gait speed, and grip strength. We note that a reduction in gait speed has been associated with increased mortality and a high frequency of hospitalizations in MM [ 18 ]. Irrespective of frailty, age is independently associated with survival and there is a stepwise reduction in PFS and OS with each additional decade of life [ 19 ]. However, age alone should not be considered a marker of frailty, and this remains a limitation of all the aforementioned scores, which include age as a parameter of frailty. Age by itself does not cause frailty [ 13 , 14 , 15 , 16 ].

In addition to existing clinical frailty scores, there is growing interest in incorporating objective biomarkers of frailty, such as sarcopenia, into these frameworks. Sarcopenia refers to the loss of skeletal muscle mass and function, and is associated with increased treatment-related toxicity and reduced tolerance to therapy and inferior survival [ 20 , 21 , 22 ]. Moreover, frailty should be viewed as a dynamic and potentially reversible condition, particularly in the context of clinical improvement or toxicity-related deconditioning [ 14 , 15 ]. Future efforts should prioritize frailty-informed trial designs and tools that can capture real-time changes in patient fitness to better individualize therapy for elderly patients with myeloma [ 23 ].

The approach to elderly and frail patients with MM remains a challenge due to underrepresentation in pivotal clinical trials, a lack of high-quality prospective trials, and absence of standardized treatment recommendations. Although clinical trial design is evolving to incorporate a frailty- or fitness-based approach, many of the contemporary treatment strategies discussed in this review rely on the traditional distinction between transplant-eligible and transplant-ineligible patients [ 24 ].

Several trials have explored frailty-adapted treatment approaches in multiple myeloma. The RV-MM-PI-0752 study compared fixed-duration Rd-R versus continuous Rd in frail patients and demonstrated improved tolerability and outcomes with the fixed-duration approach [ 25 ]. The IFM 2017 trial assessed treatment strategies in frail patients and supported the feasibility of dexamethasone-sparing regimens [ 26 ]. Lastly, the UK FITNESS trial is evaluating Ixazomib-Rd with or without frailty-guided dose modifications, aiming to optimize treatment delivery based on patient fitness [ 27 ].

3. Triplet and Quadruplet Therapy

Historically, transplant-ineligible newly diagnosed MM has been managed with either lenalidomide–dexamethasone (Rd) or an alkylator-based doublet (melphalan-prednisone, MP) or triplet (melphalan-prednisone-thalidomide/bortezomib, MPT, MPV) combination [ 28 , 29 , 30 ], with the former being the preferred regimen in the USA, and the latter often used in Europe. As both PFS and OS were shown to favor Rd over MPT among patients aged ≥ 75 years in the FIRST trial, this became the standard of care regimen in elderly MM patients [ 29 , 31 ].

The benefit of adding daratumumab (D), a monoclonal anti-CD38 directed antibody, to the above regimens was confirmed in two large phase III trials; MAIA (DRd vs. Rd) and ALCYONE (D-VMP vs. VPM), Table 1 . ALCYONE demonstrated that the addition of daratumumab substantially deepened disease responses (CR rate: 43% vs. 24%, MRD negativity 10 −5 : 22% vs. 6%), and that elderly patients ≥ 75 years experienced superior OS, although this did not reach statistical significance [ 32 , 33 ]. Despite these impressive results, the reduced secondary leukemogenicity, incidence of myelosuppression, and neuropathy with Rd compared to VMP means that VMP is no longer a standard-of-care for MM.

It was the MAIA trial which had the most profound impact on contemporary practice: here Rd was compared to DRd until intolerance or disease progression in a cohort of truly transplant-ineligible patients (median age 74 years), producing unprecedented survival outcomes, with median PFS eclipsing 5 years for patients who received DRd [ 7 , 34 ]. Like ALCYONE, deeper CR and MRD negativity rates were observed, and the signal for superior PFS (HR = 0.59, 95%CI = 0.44–0.79) and OS (HR = 0.75, 95%CI 0.55–1.02) was even stronger among patients ≥ 75 years [ 7 , 34 ]. Notably, in both ALCYONE and MAIA, the addition of daratumumab was associated with higher rates of infection, in particularly pneumonia (G3 + ALCYONE: 11% vs. 4%, MAIA: 19% vs. 11%) [ 7 , 32 , 33 , 34 ]. An important insight from MAIA concerns the dose intensity of lenalidomide, which is often poorly tolerated among older individuals due to gastrointestinal effects and fatigue. Patients treated with DRd received a lower median dose intensity of lenalidomide and more frequently discontinued lenalidomide (37% vs. 24%) compared to the Rd arm, but despite this they still experienced superior PFS and OS—implying that the use of this triplet combination permits lower but still effective doses of lenalidomide to be used [ 7 , 34 ].

In 2024 three major phase III clinical trials were published, challenging the dominance of the DRd regimen: these were the CEPHEUS, IMROZ and the BENEFIT trials [ 37 , 38 , 39 ]. All trials investigated a quadruplet regimen containing an anti-CD38 mAb, with the proteasome inhibitors bortezomib, lenalidomide, and dexamethasone (VRd) as the experimental arm. The motivation for the addition of an anti-CD38 mAb to a VRd background in transplant-ineligible MM stems from the SWOG777 study (VRd vs. Rd). While SWOG777 was not a transplant ineligible trial or a trial designed for elderly patients, it nonetheless demonstrated superior OS and PFS with VRd compared to Rd among patients aged ≥ 65 years and so became a standard of care for transplant ineligible patients [ 35 , 36 ]. A major shortcoming of SWOG777 was the use of intravenous bortezomib administered twice weekly, contributing to a higher rate of neuropathy and treatment discontinuation and this has now replaced with subcutaneous dosing [ 40 ]. In the case of all three quadruplet trials, the efficacy of the quadruplet was superior to the triplet comparator [ 37 , 38 , 39 ]. In IMROZ and CEPHEUS (anti-CD38-VRd vs. VRd alone), the MRD negativity rate was significantly higher with the mAb (CEPHEUS: 61% vs. 39%, IMROZ: 58% vs. 44%) and both met their PFS primary endpoints [ 37 , 38 ]. In IMROZ, the 5-year PFS was 63% with isatuximab-VRD (Isa-VRd) compared to 45% with VRd, despite an exceptional performance in the VRd arm.

In contrast to CEPHEUS and IMROZ which examined the benefit of adding an anti-CD38mAb to VRd, the BENEFIT trial (Isa-Rd vs. Isa-VRd) set out to answer the utility of adding a proteasome inhibitor to an Isa-Rd backbone akin to MAIA. BENEFIT confirmed that the addition of bortezomib significantly improved the MRD 10 −5 negativity rate at 18 months from randomization (26% vs. 53%), as well as all other MRD endpoints from 12 months [ 39 ]. The most pertinent finding of BENEFIT was an estimate of the ‘ cost ’ of adding bortezomib when treating elderly MM patients, as assessed through the incidence of peripheral neuropathy (Isa-VRd, any grade: 52%, Grade ≥ 2: 27% vs. Isa-Rd, any grade: 28%, Grade ≥ 2: 10%). While the MRD results are attractive, over one quarter of patients experienced clinically significant peripheral neuropathy with the administration of weekly subcutaneous bortezomib for three out of four weeks, and so this must be evaluated with caution in elderly patients [ 39 ].

While all three trials were conducted at an exceptional standard, few patients ≥ 75 years were included and no patients ≥ 80 years were included (19% of MAIA population aged ≥ 80 years), limiting the extrapolation of these results to elderly patients [ 34 , 37 , 38 , 39 ]. Regarding frailty, both CEPHEUS and BENEFIT trials excluded frail patients (frailty score <2 per the Myeloma Geriatric Assessment score) [ 37 , 39 ]. In contrast, IMROZ permitted the inclusion of frail patients, and 27% of patients were classified as frail using the simplified IMWG frailty score [ 41 ]. IMROZ confirmed that even frail patients derived significantly improved PFS with Isa-VRd compared to VRd (HR = 0.52, 95%CI 0.42–0.90, p = 0.023) [ 41 ]. While this is commendable, it is a still significantly lower representation of frail individuals than the MAIA study, in which nearly half of included patients were categorized as frail using the IFM simplified frailty assessment [ 15 , 42 ]. MAIA confirmed that frail patients fared poorly compared to their non-frail counterparts; however, irrespective of frailty status, daratumumab maintained a significant benefit over Rd alone [ 42 ]. In summary, while evidence supports the addition of daratumumab to standard regimens in frail patients, the benefit of incorporating bortezomib in frail patients remains a matter for debate. While bortezomib enhances disease-control, the associated risk of bortezomib-associated peripheral neuropathy, which negatively impacts quality of life and functional independence, needs to be considered carefully.

While carfilzomib (K) appears more effective for high-risk MM [ 43 ], it is associated with higher cardiovascular and renal toxicities [ 44 ], and so there has been less interest in carfilzomib-based quadruplets in elderly multiple myeloma patients. Two phase 2 trials of an anti-CD38-KRd quadruplet (MANHATTAN and GMMG-CONCEPT) found high rates of MRD negativity 10 −5 around 70%; however, both trials had limited numbers of patients ≥ 75 years. Furthermore, in the GMMG-CONCEPT trial the transplant-ineligible cohort had 20% cardiac grade ≥ 3 adverse events, underscoring the risk of this approach in elderly patients [ 45 , 46 ].

4. Immunotherapies

4.1. B-Cell Maturation Antigen

So far, the principal antigenic targets of immunotherapeutic approaches have been the B-cell maturation antigen (BCMA), G-protein coupled receptor, family C, group 5, member D (GPRC5D), and CD38. BCMA is a transmembrane receptor and member of the tumor necrosis factor superfamily [ 47 ]. Several characteristics of BCMA make it an ideal immunotherapeutic target. First, BCMA expression is restricted to plasma cells and terminally differentiated B cells, with higher expression on MM cells compared to normal plasma cells [ 48 ]. Second, BCMA binding activates downstream signaling via mitogen-activated protein kinase (MAPK) and nuclear factor kappa-B (NFKB) pathways that are essential to plasma cell survival [ 49 , 50 ]. Third, membrane bound BCMA may be released from the cell surface by gamma-secretase mediated shedding to produce soluble BCMA (sBCMA), which has emerging roles as a biomarker for disease response, a surrogate for tumor burden, and as an adjunctive therapeutic target through gamma secretase inhibitors [ 51 , 52 , 53 ].

4.2. G-Protein Coupled Receptor, Family C, Group 5, Member D

GPRC5D is expressed on keratinized tissues such as hair follicles, nail beds, and sweat glands, in addition to malignant plasma cells [ 54 , 55 ]. Due to this expression pattern, patients experience a unique set of off-tumor, on-target adverse effects including skin desquamation, nail changes, xerostomia, and dysgeusia [ 56 ]. Recently, cerebellar toxicities have also been reported with both talquetamab and GPRC5d-directed CAR-T potentially due to low-level GPRC5d expression in the cerebellum or inferior olivary nucleus [ 57 , 58 ].

5. T-Cell Engagers

5.1. T-Cell Engager Design

TCEs can bind two or more distinct antigens to simultaneously engage T-cells and tumor cells. This dual binding facilitates an immunological synapse between T-cells and tumors cells [ 59 ], producing T-cell activation independent of major histocompatibility complex (MHC) restriction and without costimulatory signaling [ 59 , 60 , 61 ]. TCEs are generally synthesized as recombinant proteins [ 62 ], and their design has evolved significantly since the original bispecific T-cell engagers (BiTEs), Figure 1 [ 59 ]. Second generation TCEs are characterized by lower affinity CD3 binding to avoid excess T-cell activation and CRS and continued use of Fc-silencing to extend half-life permitting less frequent dosing interval (bi-weekly or monthly). In addition to optimizing pharmacokinetics, further modification of the Fc region can reduce antibody-dependent cellular mediated or complement mediated cytotoxicity, to increase anti-tumor specific T-cell activation [ 63 ].

5.2. FDA-Approved Bispecific Antibodies

An extensive discussion of all investigational TCEs is beyond the scope of this review; instead, we will focus on FDA-approved TCEs and agents approaching registration. Table 2 summarizes the results of key trials for FDA-approved immunotherapies in relapsed myeloma. Teclistamab and elranatamab are both BCMA-directed TCEs with ORRs of ~60% in heavily pretreated patients; of note, the majority of responses are deep, with ~40% of patients obtaining a CR and the median duration of response for both agents being in excess of 18 months [ 64 , 65 ]. Linvoseltamab, another BCMAxCD3 bispecific antibody, received conditional EMA approval in 2025 for relapsed MM and is currently under evaluation by other regulatory agencies. Talquetamab is the only FDA-approved GPRC5D-directed TCE. Although its efficacy is comparable to teclistamab and elranatamab, its side-effect profile is distinctly secondary to on-target off-tumor effects on keratinized tissues and includes skin, nail, and taste-related changes [ 56 ]. While skin and nail changes tend to improve with time, dysgeusia persists and often requires dose reduction in the setting of significant weight loss [ 56 ]. The time to response is rapid for all TCEs around 1–2 months [ 56 , 64 , 65 ]. While the top-line results of the TCE trials are highly promising, frail patients were poorly represented. In MajesTEC-1, MagnetisMM-3, and MontumenTAL-1, only 15%, 23%, and 19% of participants were ≥75 years [ 56 , 64 , 65 ].

Recently, real-world experience suggested similar efficacy when TCEs are applied to elderly patients, with no difference in ORR, PFS, or OS with increasing age [ 66 , 67 ]. In a multicenter U.S. cohort of 83 patients aged ≥ 75 years treated with teclistamab across 13 academic centers, outcomes mirrored those seen in the pivotal MajesTEC-1 trial, with an ORR of 62% and a median PFS of 10.7 months [ 68 ]. Similarly, a multicenter French real-world series of 101 patients receiving elranatamab (median age 68) reported response rates comparable to those observed in the MagnetisMM-3 study, with a manageable safety profile in older adults [ 69 ].

All TCEs are associated with cytokine release syndrome (CRS), which occurs in 60–70% of individuals and is typically low grade (Grade 1–2). Real-world data of elderly and frail patients confirm TCE-associated CRS is manageable even among these vulnerable patient populations [ 67 , 75 ]. The greatest concern of TCEs in elderly patients stems from the high incidence of ≥grade 3 infections, which exceeds 40% with BCMA-directed TCEs [ 56 , 64 , 65 ]. Strategies to mitigate infectious complications include adjusted dosing strategies (time-limited vs. response-adapted), appropriate anti-microbial prophylaxis, and immunoglobulin replacement [ 59 , 76 , 77 , 78 ].

5.3. Trispecific-Antibodies

As design and manufacturing processes evolve, trispecific compounds with two high affinity domains to bind tumor antigens and a single lower affinity domain to CD3 are being investigated [ 79 , 80 ]. Low-affinity CD3 binding appears a promising approach to mitigate CRS and the risk of T-cell exhaustion [ 81 ]. Additionally, by possessing antigen binding domains for two plasma cell-specific antigens, the incidence of on-target, off-tumor effects (such as keratinized tissues for GPRC5d) appears to be reduced [ 80 ]. Notable trispecific compounds include ISB 2001 a CD3xCD38xBCMA-directed trispecific antibody, whose initial phase 1 results obtained an ORR of 83% at its target dose level, despite high rates of prior BCMA-directed CAR-T and TCE exposure [ 82 ]. Equally impressive are the recently presented results of JNJ-79635322 a CD3xBCMAxGPRC5d, which obtained an ORR of 100% at the recommended phase 2 dose (RP2D) in patients naïve to BCMA or GPRC5d directed therapy [ 80 ].

6. CAR-T Therapy

6.1. CAR-T Design and Production

Since their development, there have been several iterations of CAR-T design, Figure 1 . At the most fundamental level, the chimeric antigen receptor is composed of an extracellular domain, containing a single-chain variable fragment (scFv) connected to a transmembrane domain and an intracellular domain [ 83 ]. Nearly all CAR-T utilize a CD3zeta intracellular stimulatory domain to initiate T-cell activation. Successive generation of CARs have incorporated additional intracellular components to enhance persistence, expansion, and tumor-cell killing, including costimulatory domains (CD28 or 4-1BB) and immunomodulatory molecules (IL-7, CCL19) [ 83 ]. Dual-targeting CAR, which express >1 chimeric antigen receptors, appears to provide enhanced MM-cell killing and prevent antigenic escape [ 84 ]. Lastly, innovations of CAR-T production including automated closed-system bioreactors, such as the CliniMACS prodigy and Lonza Cocoon, have been developed to reduce production costs and timelines while maintaining product quality [ 85 , 86 ]. Non-viral gene transfer methods, including transposons and CRISPR genome editing, have also been employed to engineer T cells more efficiently and safely [ 85 , 86 ].

6.2. FDA-Approved CAR-T

The introduction of CAR-T therapy to relapsed myeloma led to unprecedented results in extensively treated patients, Table 2 . While the uptake of CAR-T in elderly patients has been tempered by concerns for excessive toxicity in the form of CRS, immune effector cell-associated neurotoxicity syndrome (ICANS), and delayed neurological toxicity, they remain highly effective in this population. Recently, long-term follow-up from CARTITUDE-1 demonstrated that one-third of patients who were infused with cilta-cel remain alive and progression-free at ≥5 years since treatment [ 73 ]. A subset of these patients additionally had serial MRD and PET-CT assessment and all remain MRD-negative at year 5 or later following cilta-cel [ 73 ]. These unmatched results suggest that cilta-cel is potentially curative in relapsed MM, or at the very least a means of functional cure for elderly patients. However, both the CARTITUDE-1 and KarMMa-1 studies included limited numbers of elderly individuals (<10%). An older patient subgroup analysis of the KarMMa study demonstrated that treatment outcomes were similar in patients aged ≥ 70 years and those that were younger [ 87 ].

Despite the growing role of CAR-T cell therapies in relapsed MM, data specific to elderly and frail patients are limited. A single-center real-world series demonstrated patients ≥ 70 years vs. <70 years had no difference in OS, PFS, or CRS incidence (79% vs. 86%, Grade ≥ 2: 2% vs. 5%) [ 88 ]. But, they did experience more ICANS (13% vs. 21%) and infections (all grades; 18% vs. 29%), which was associated with higher healthcare utilization through ED visitations and unplanned hospitalizations [ 88 ]. Retrospective real-world series have reported encouraging outcomes in older adults, but also a potentially increased risk of prolonged cytopenias, infections, and delayed functional recovery [ 89 ]. Frailty-specific data remain scarce, underscoring the need for prospective studies incorporating geriatric assessments to better understand tolerability and long-term outcomes of CAR-T in this population.

Emerging predictive models for CAR-T-related toxicity may assist in patient selection and risk stratification. Biomarkers such as albumin, CRP, and ferritin, as well as sBCMA and tumor volume all influence CAR-T outcomes in MM [ 90 , 91 , 92 ]. Their application may be particularly valuable in elderly or borderline-fit patients, where careful risk–benefit assessment is essential.

7. Strengths and Weaknesses of T-Cell Redirecting Therapies

Due to the co-emergence of CAR-T and TCEs into the field of relapsed MM, their comparative strengths and weaknesses deserve special mention. Key characteristics of FDA-approved cellular therapies and TCEs, including their weaknesses and strengths are summarized in Table 3 . Undoubtedly, cilta-cel has demonstrated the most impressive single agent efficacy to date, the seminal CARTITUDE-1 demonstrating an ORR of 98% median PFS of 34.9 months [ 73 ]. However, this efficacy is associated with increased immediate toxicity compared to TCEs, with higher rates and more severe CRS and ICANS than TCEs [ 56 , 65 , 74 , 93 ]. Although the time frame of these toxicities is predictable and risk factors for their occurrence (i.e., tumor burden) and strategies for their management have all improved with increasing physician familiarization, their management in frail patients remains a concern [ 94 ]. Idiosyncratic toxicities more frequent with certain CAR-T products such as cilta-cel have also been reported, including the delayed onset of neurocognitive events (tremors, psychomotor retardation, inattention, micrographia) [ 95 , 96 ]. Lastly, the potential for fatal complication like immune effector cell-associated hemophagocytic lymphohistiocytosis-like syndrome (IEC-HS) is troubling, particularly in medically frail individuals [ 97 , 98 ].

CAR-T is also limited by manufacturing constraints (including production failures and delays) and a limited number of accredited centers; however, with greater experience and streamlined production processes, the detriment of these factors has been lessened [ 99 ]. For instance, in the KarMMa-3 and CARTITUDE-4 studies, 10% and 15% of patients did not receive CAR-T infusion due to disease progression prior to produce availability [ 95 , 100 ]. Improved manufacturing processes, in vivo CAR-T products and allogeneic products may also reduce the period between apheresis and product administration, reducing the need for bridging therapies. The other major strength of CAR-T is the potential for time-off therapy, the so-called ‘ one-and-done ’ approach. While the introduction of post CAR-T maintenance strategies threatens this situation [ 101 ], having time free from treatment is associated with improved quality of life, as well as physical and psychological benefits [ 102 ]. While the potential for time-limited therapy is being explored with TCEs, this currently remains investigational [ 103 ].

By comparison, TCEs offer a highly effective, ‘ off-the-shelf ’ therapy, fulfilling a critical role for patients with a rapid tempo of relapse. CRS and neurological toxicities are less frequent and severe, so much so, that many institutions have implemented or are in the process of adopting an outpatient step-up schedule, obviating the need for inpatient admission. The reduced upfront toxicities also make this therapeutic class more appealing for elderly and frail patients, with no perceived ‘ upper-age threshold ’ to their administration. But undoubtedly the single greatest advantage of TCEs is their readiness to pair with other conventional or investigational TCEs to augment efficacy and permit a reduction in TCE dosing longer term [ 104 , 105 , 106 ]. The redirecTT study, which investigated the combination of talquetamab and teclistamab in patients with relapsed MM, obtained an ORR of 80% in a cohort with true extra-medullary disease (EMD); moreover, responses were sustained with 86% of patients remaining in response at 18 months [ 104 ]. Similarly, the TRIMM-2 study which evaluated the combination of talquetamab and daratumumab in relapsed MM obtained a similar ORR of 78% with median PFS of 19.4 months [ 106 ].

In contrast to CAR-T, whose risk profile is high in the period immediately following infusion and which then gradually diminishes, the adverse effect profile of TCEs persists with their ongoing administration. The infectious risk associated with BCMA-directed TCEs, as well as dysgeusia and weight loss associated with GPRC5d-directed therapies, remains troublesome for many patients [ 58 , 65 , 107 ]. Another important consideration physicians must contemplate is the ideal sequencing of these therapies in MM. Prior BCMA-directed therapy exposure negatively impacts both TCE and CAR-T efficacy, but the magnitude of effect is most pronounced for CAR-T, suggesting CAR-T should be used first when it is being considered [ 66 , 107 , 108 , 109 , 110 , 111 ].

8. Moving Immunotherapy into the Front Line

Treatment attrition, that is the fallout of patients prior to subsequent lines of therapy is a major issue for elderly MM patients. Data from Europe and the USA indicated that less than half of newly diagnosed MM patients will receive a third line of therapy [ 112 , 113 ]. And this attrition rate is likely to be even higher among elderly patients for whom competing causes of mortality are more prominent. In light of this, there is a strong imperative to utilize the most-effective treatment options upfront in elderly MM patients. A summary of phase III trials investigating T-cell redirecting therapy in transplant ineligible MM is shown, Table 4 [ 3 , 78 ]. While the results of these trials are eagerly anticipated, early data from TCEs in newly diagnosed MM appear extremely promising. MajesTEC-5 examined DRd and DVRd in combination with teclistamab in transplant-eligible newly diagnosed MM; here, 100% of participants had obtained MRD negativity (10 −5 threshold) following only three cycles of treatment [ 114 ]. Likewise, MagnetisMM-6, which is examining elranatamab in combination with lenalidomide and daratumumab in transplant-ineligible newly diagnosed MM, has an ORR of 92% with 81% of patients, reaching a very good partial response or better [ 115 ].

9. Future Directions

With the results of the IMROZ, CEPHEUS, and BENEFIT trials, quadruplet therapy is the new standard of care for newly diagnosed transplant ineligible MM, with DRd or Isa-Rd remaining preferred options for frail individuals [ 37 , 38 , 39 ]. However, the introduction of TCEs and their rapid transition to the newly diagnosed setting means this current standard of care may not endure for long [ 115 , 119 ]. It remains to be seen whether an upper age limit exists for the administration of CAR-T or TCEs in MM, or whether their toxicity profile will continue to improve with increased familiarization. Mitigating infectious complications appears to be the greatest challenge to the introduction of TCEs in the newly diagnosed setting and may be overcome with fixed-duration therapy or an MRD-guided approach.

Importantly, for many elderly patients, especially those with favorable cytogenetic features and indolent disease biology, TCEs and CAR-T offer the possibility of an ‘operational cure’ with one or two lines of therapy. In this setting, a continuous suppressive therapeutic approach leads to unnecessary toxicity, increases healthcare burden, increases cost, and reduces quality of life. Consequently time-limited or response-adapted approaches for elderly and frail patients may mitigate toxicity, improve treatment adherence, and enhance patient satisfaction.

Besides upfront-combination therapy with TCEs and CAR-T, another potent combination treatment is with the cereblon E3 ligase modulators (CELMoDs), iberdomide, and mezigdomide. Mezigdomide has demonstrated immune-stimulator effects in preclinical studies via enhanced T-cell and NK cell activity, which would synergize with an immunotherapeutic approach [ 120 ]. Additionally, CELMoDs have been shown to activate specific T-cell subsets, such as Vγ9Vδ2 T cells, which are crucial for anti-tumor immunity and which have the capacity to reverse immune exhaustion [ 121 ]. Other logistic considerations for future research include outpatient step-up dosing for TCEs, and whether the prophylactic use of interventions to reduce CRS can facilitate this including tocilizumab [ 122 ].

10. Conclusions

The introduction of anti-CD38 monoclonal antibodies, TCEs, and CAR-T therapy has ushered in a transformative era for elderly patients with multiple myeloma. With effective triplet and quadruplet approaches, many elderly MM patients can expect an ‘ operational cure’ with one to two lines of therapy. As TCEs and CAR-T are moved earlier in the treatment algorithm, it is conceivable that select patients will only need a single line of treatment. However, as efficacy improves, minimizing treatment-related toxicities is paramount. This is especially critical in frail patients, who are more vulnerable to the infectious complications of prolonged TCE therapy and delayed neurotoxicity associated with CAR-T. For elderly frail individuals, finite-duration TCE therapy or CAR-T products with more favorable toxicity profiles may represent appropriate therapeutic strategies.

Indeed, among elderly patients (both frail and non-frail) for whom competing causes of non-myeloma mortality are common—and the need for subsequent lines of therapy therefore limited—the initial treatment choice is critical. The challenge ahead lies in individualizing therapy: selecting the right treatment for the right patient at the right time. This requires a nuanced approach that distinguishes between frail and non-frail individuals, balances efficacy with tolerability, avoids overtreating those with low-risk disease, and ensures high-risk patients are not undertreated.

To support this, prospective studies focused specifically on elderly and frail populations are urgently needed, including risk- and dose-adapted strategies to appropriately address the heterogeneity of this subpopulation.

Acknowledgments

The authors have no acknowledgements.

Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.

Author Contributions

H.Q. and M.J.R. both conceived and wrote the manuscript. Both authors critically reviewed the manuscript and approved the final version. All authors have read and agreed to the published version of the manuscript.

Conflicts of Interest

The authors report no competing interests to declare.

References

1. National Cancer Institute Cancer Stat Facts: Myeloma Available online: https://seer.cancer.gov/statfacts/html/mulmy.html (accessed on 2 May 2025)

2. Smith B.D. Smith G.L. Hurria A. Hortobagyi G.N. Buchholz T.A. Future of cancer incidence in the United States: Burdens upon an aging, changing nation J. Clin. Oncol. 2009 27 2758 2765 10.1200/JCO.2008.20.8983 19403886

3. Facon T. Leleu X. Manier S. How I treat multiple myeloma in geriatric patients Blood 2024 143 224 232 10.1182/blood.2022017635 36693134 PMC10808246

4. Zweegman S. Engelhardt M. Larocca A. Elderly patients with multiple myeloma: Towards a frailty approach? Curr. Opin. Oncol. 2017 29 315 321 10.1097/CCO.0000000000000395 28763310

5. Kumar S.K. Dispenzieri A. Lacy M.Q. Gertz M.A. Buadi F.K. Pandey S. Kapoor P. Dingli D. Hayman S.R. Leung N. Continued improvement in survival in multiple myeloma: Changes in early mortality and outcomes in older patients Leukemia 2014 28 1122 1128 10.1038/leu.2013.313 24157580 PMC4000285

6. Shpitzer D. Cohen Y.C. Shragai T. Grossberger O. Amsterdam D. Reiner-Benaim A. Avivi I. Clinical Outcomes in Elderly Patients Treated Outside Clinical Studies: Highlighting the Octogenarian Experience Blood Adv. 2025 9 2677 2685 10.1182/bloodadvances.2025015968 40048737 PMC12155550

7. Facon T. Moreau P. Weisel K. Goldschmidt H. Usmani S.Z. Chari A. Plesner T. Orlowski R.Z. Bahlis N. Basu S. Daratumumab/lenalidomide/dexamethasone in transplant-ineligible newly diagnosed myeloma: MAIA long-term outcomes Leukemia 2025 39 942 950 10.1038/s41375-024-02505-2 40016302 PMC11976258

8. Costa L.J. Brill I.K. Omel J. Godby K. Kumar S.K. Brown E.E. Recent trends in multiple myeloma incidence and survival by age, race, and ethnicity in the United States Blood Adv. 2017 1 282 287 10.1182/bloodadvances.2016002493 29296944 PMC5727774

9. Pawlyn C. Cairns D. Kaiser M. Striha A. Jones J. Shah V. Jenner M. Drayson M. Owen R. Gregory W. The relative importance of factors predicting outcome for myeloma patients at different ages: Results from 3894 patients in the Myeloma XI trial Leukemia 2020 34 604 612 10.1038/s41375-019-0595-5 31611625 PMC7214257

10. Rees M.J. Kumar S. High-risk multiple myeloma: Redefining genetic, clinical, and functional high-risk disease in the era of molecular medicine and immunotherapy Am. J. Hematol. 2024 99 1560 1575 10.1002/ajh.27327 38613829

11. Mikhael J. Ismaila N. Cheung M.C. Costello C. Dhodapkar M.V. Kumar S. Lacy M. Lipe B. Little R.F. Nikonova A. Treatment of Multiple Myeloma: ASCO and CCO Joint Clinical Practice Guideline J. Clin. Oncol. 2019 37 1228 1263 10.1200/JCO.18.02096 30932732

12. Kyle R.A. Gertz M.A. Witzig T.E. Lust J.A. Lacy M.Q. Dispenzieri A. Fonseca R. Rajkumar S.V. Offord J.R. Larson D.R. Review of 1027 patients with newly diagnosed multiple myeloma Mayo Clin. Proc. 2003 78 21 33 10.4065/78.1.21 12528874

13. Engelhardt M. Domm A.S. Dold S.M. Ihorst G. Reinhardt H. Zober A. Hieke S. Baayen C. Müller S.J. Einsele H. A concise revised Myeloma Comorbidity Index as a valid prognostic instrument in a large cohort of 801 multiple myeloma patients Haematologica 2017 102 910 921 10.3324/haematol.2016.162693 28154088 PMC5477610

14. Palumbo A. Bringhen S. Mateos M.-V. Larocca A. Facon T. Kumar S.K. Offidani M. McCarthy P. Evangelista A. Lonial S. Geriatric assessment predicts survival and toxicities in elderly myeloma patients: An International Myeloma Working Group report Blood 2015 125 2068 2074 10.1182/blood-2014-12-615187 25628469 PMC4375104

15. Facon T. Dimopoulos M.A. Meuleman N. Belch A. Mohty M. Chen W.M. Kim K. Zamagni E. Rodriguez-Otero P. Renwick W. A simplified frailty scale predicts outcomes in transplant-ineligible patients with newly diagnosed multiple myeloma treated in the FIRST (MM-020) trial Leukemia 2020 34 224 233 10.1038/s41375-019-0539-0 31427722 PMC7214253

16. Milani P. Vincent Rajkumar S. Merlini G. Kumar S. Gertz M.A. Palladini G. Lacy M.Q. Buadi F.K. Hayman S.R. Leung N. N-terminal fragment of the type-B natriuretic peptide (NT-proBNP) contributes to a simple new frailty score in patients with newly diagnosed multiple myeloma Am. J. Hematol. 2016 91 1129 1134 10.1002/ajh.24532 27508522 PMC5129512

17. Sim S. Kalff A. Tuch G. Mollee P. Ho P.J. Harrison S. Gibbs S. Prince H.M. Spencer A. Joshua D. The importance of frailty assessment in multiple myeloma: A position statement from the Myeloma Scientific Advisory Group to Myeloma Australia Intern. Med. J. 2023 53 819 824 10.1111/imj.16049 36880355

18. Liu M.A. DuMontier C. Murillo A. Hshieh T.T. Bean J.F. Soiffer R.J. Stone R.M. Abel G.A. Driver J.A. Gait speed, grip strength, and clinical outcomes in older patients with hematologic malignancies Blood 2019 134 374 382 10.1182/blood.2019000758 31167800 PMC6659254

19. Chang-Chan D.Y. Ríos-Tamayo R. Rodríguez Barranco M. Redondo-Sánchez D. González Y. Marcos-Gragera R. Sánchez M.J. Trends of incidence, mortality and survival of multiple myeloma in Spain. A twenty-three-year population-based study Clin. Transl. Oncol. 2021 23 1429 1439 10.1007/s12094-020-02541-1 33433836

20. Dac D.T. Koshihara H. Cho M. Inaoka P.T. Nguyen H.T.G. Espinoza J.L. Sarcopenia and clinical outcomes in lymphoma and multiple myeloma patients receiving hematopoietic cell transplantation: A systematic review and meta-analysis Int. J. Hematol. 2025 122 25 34 10.1007/s12185-025-03998-y 40358877

21. Cruz-Jentoft A.J. Bahat G. Bauer J. Boirie Y. Bruyère O. Cederholm T. Cooper C. Landi F. Rolland Y. Sayer A.A. Sarcopenia: Revised European consensus on definition and diagnosis Age Ageing 2019 48 601 10.1093/ageing/afz046 PMC6593317 31081853

22. Nandakumar B. Baffour F. Abdallah N.H. Kumar S.K. Dispenzieri A. Buadi F.K. Dingli D. Lacy M.Q. Hayman S.R. Kapoor P. Sarcopenia identified by computed tomography imaging using a deep learning-based segmentation approach impacts survival in patients with newly diagnosed multiple myeloma Cancer 2023 129 385 392 10.1002/cncr.34545 36413412 PMC9822865

23. Wildes T.M. Rosko A. Tuchman S.A. Multiple myeloma in the older adult: Better prospects, more challenges J. Clin. Oncol. 2014 32 2531 2540 10.1200/JCO.2014.55.1028 25071143 PMC4129503

24. Stege C.A.M. Nasserinejad K. van der Spek E. Bilgin Y.M. Kentos A. Sohne M. van Kampen R.J.W. Ludwig I. Thielen N. Durdu-Rayman N. Ixazomib, Daratumumab, and Low-Dose Dexamethasone in Frail Patients With Newly Diagnosed Multiple Myeloma: The Hovon 143 Study J. Clin. Oncol. 2021 39 2758 2767 10.1200/JCO.20.03143 33945289

25. Larocca A. Salvini M. De Paoli L. Cascavilla N. Benevolo G. Galli M. Montefusco V. Caravita di Toritto T. Baraldi A. Spada S. Efficacy and Feasibility of Dose/Schedule-Adjusted Rd-R Vs. Continuous Rd in Elderly and Intermediate-Fit Newly Diagnosed Multiple Myeloma (NDMM) Patients: RV-MM-PI-0752 Phase III Randomized Study Blood 2018 132 305 10.1182/blood-2018-99-111796

26. Manier S. Lambert J. Hulin C. Laribi K. Araujo C. Pica G.M. Touzeau C. Godmer P. Slama B. Karlin L. The IFM2017-03 Phase 3 Trial: A Dexamethasone Sparing-Regimen with Daratumumab and Lenalidomide for Frail Patients with Newly-Diagnosed Multiple Myeloma Blood 2024 144 774 10.1182/blood-2024-203045 41038184

27. Coulson A.B. Royle K.L. Pawlyn C. Cairns D.A. Hockaday A. Bird J. Bowcock S. Kaiser M. de Tute R. Rabin N. Frailty-adjusted therapy in Transplant Non-Eligible patients with newly diagnosed Multiple Myeloma (FiTNEss (UK-MRA Myeloma XIV Trial)): A study protocol for a randomised phase III trial BMJ Open 2022 12 e056147 10.1136/bmjopen-2021-056147 PMC9163533 35654466

28. San Miguel J.F. Schlag R. Khuageva N.K. Dimopoulos M.A. Shpilberg O. Kropff M. Spicka I. Petrucci M.T. Palumbo A. Samoilova O.S. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma N. Engl. J. Med. 2008 359 906 917 10.1056/NEJMoa0801479 18753647

29. Benboubker L. Dimopoulos M.A. Dispenzieri A. Catalano J. Belch A.R. Cavo M. Pinto A. Weisel K. Ludwig H. Bahlis N. Lenalidomide and dexamethasone in transplant-ineligible patients with myeloma N. Engl. J. Med. 2014 371 906 917 10.1056/NEJMoa1402551 25184863

30. Palumbo A. Bringhen S. Rossi D. Cavalli M. Larocca A. Ria R. Offidani M. Patriarca F. Nozzoli C. Guglielmelli T. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial treatment of multiple myeloma: A randomized controlled trial J. Clin. Oncol. 2010 28 5101 5109 10.1200/JCO.2010.29.8216 20940200

31. Facon T. Dimopoulos M.A. Dispenzieri A. Catalano J.V. Belch A. Cavo M. Pinto A. Weisel K. Ludwig H. Bahlis N.J. Final analysis of survival outcomes in the phase 3 FIRST trial of up-front treatment for multiple myeloma Blood 2018 131 301 310 10.1182/blood-2017-07-795047 29150421 PMC5774211

32. Mateos M.V. Cavo M. Blade J. Dimopoulos M.A. Suzuki K. Jakubowiak A. Knop S. Doyen C. Lucio P. Nagy Z. Overall survival with daratumumab, bortezomib, melphalan, and prednisone in newly diagnosed multiple myeloma (ALCYONE): A randomised, open-label, phase 3 trial Lancet 2020 395 132 141 10.1016/S0140-6736(19)32956-3 31836199

33. Mateos M.V. Dimopoulos M.A. Cavo M. Suzuki K. Jakubowiak A. Knop S. Doyen C. Lucio P. Nagy Z. Kaplan P. Daratumumab plus Bortezomib, Melphalan, and Prednisone for Untreated Myeloma N. Engl. J. Med. 2018 378 518 528 10.1056/NEJMoa1714678 29231133

34. Facon T. Kumar S.K. Plesner T. Orlowski R.Z. Moreau P. Bahlis N. Basu S. Nahi H. Hulin C. Quach H. Daratumumab, lenalidomide, and dexamethasone versus lenalidomide and dexamethasone alone in newly diagnosed multiple myeloma (MAIA): Overall survival results from a randomised, open-label, phase 3 trial Lancet Oncol. 2021 22 1582 1596 10.1016/S1470-2045(21)00466-6 34655533

35. Durie B.G.M. Hoering A. Abidi M.H. Rajkumar S.V. Epstein J. Kahanic S.P. Thakuri M. Reu F. Reynolds C.M. Sexton R. Bortezomib with lenalidomide and dexamethasone versus lenalidomide and dexamethasone alone in patients with newly diagnosed myeloma without intent for immediate autologous stem-cell transplant (SWOG S0777): A randomised, open-label, phase 3 trial Lancet 2017 389 519 527 10.1016/S0140-6736(16)31594-X 28017406 PMC5546834

36. Durie B.G.M. Hoering A. Sexton R. Abidi M.H. Epstein J. Rajkumar S.V. Dispenzieri A. Kahanic S.P. Thakuri M.C. Reu F.J. Longer term follow-up of the randomized phase III trial SWOG S0777: Bortezomib, lenalidomide and dexamethasone vs. lenalidomide and dexamethasone in patients (Pts) with previously untreated multiple myeloma without an intent for immediate autologous stem cell transplant (ASCT) Blood Cancer J. 2020 10 53 10.1038/s41408-020-0311-8 32393732 PMC7214419

37. Usmani S.Z. Facon T. Hungria V. Bahlis N.J. Venner C.P. Braunstein M. Pour L. Martí J.M. Basu S. Cohen Y.C. Daratumumab plus bortezomib, lenalidomide and dexamethasone for transplant-ineligible or transplant-deferred newly diagnosed multiple myeloma: The randomized phase 3 CEPHEUS trial Nat. Med. 2025 31 1195 1202 10.1038/s41591-024-03485-7 39910273 PMC12003169

38. Facon T. Dimopoulos M.A. Leleu X.P. Beksac M. Pour L. Hájek R. Liu Z. Minarik J. Moreau P. Romejko-Jarosinska J. Isatuximab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma N. Engl. J. Med. 2024 391 1597 1609 10.1056/NEJMoa2400712 38832972

39. Leleu X. Hulin C. Lambert J. Bobin A. Perrot A. Karlin L. Roussel M. Montes L. Cherel B. Chalopin T. Isatuximab, lenalidomide, dexamethasone and bortezomib in transplant-ineligible multiple myeloma: The randomized phase 3 BENEFIT trial Nat. Med. 2024 30 2235 2241 10.1038/s41591-024-03050-2 38830994 PMC11333283

40. O'Donnell E.K. Laubach J.P. Yee A.J. Redd R. Huff C.A. Basile F. Wade P.M. Paba-Prada C.E. Ghobrial I.M. Schlossman R.L. Updated Results of a Phase 2 Study of Modified Lenalidomide, Bortezomib, and Dexamethasone (RVd-lite) in Transplant-Ineligible Multiple Myeloma Blood 2019 134 3178 10.1182/blood-2019-128000 PMC6074026 29740809

41. Manier S. Dimopoulos M.A. Leleu X.P. Moreau P. Cavo M. Goldschmidt H. Orlowski R.Z. Tron M. Tekle C. Brégeault M.F. Isatuximab plus bortezomib, lenalidomide, and dexamethasone for transplant-ineligible newly diagnosed multiple myeloma patients: A frailty subgroup analysis of the IMROZ trial Haematologica 2025 10.3324/haematol.2024.287200 PMC12399942 40109195

42. Facon T. Cook G. Usmani S.Z. Hulin C. Kumar S. Plesner T. Touzeau C. Bahlis N.J. Basu S. Nahi H. Daratumumab plus lenalidomide and dexamethasone in transplant-ineligible newly diagnosed multiple myeloma: Frailty subgroup analysis of MAIA Leukemia 2022 36 1066 1077 10.1038/s41375-021-01488-8 34974527 PMC8979809

43. Costa B.A. Costa T.A. Pak K. Patel A. Felix N. Mouhieddine T.H. Richter J. Comparative efficacy of carfilzomib, lenalidomide, and dexamethasone (KRd) versus bortezomib, lenalidomide, and dexamethasone (VRd) in newly-diagnosed multiple myeloma: A systematic review and meta-analysis Am. J. Hematol. 2024 99 1411 1414 10.1002/ajh.27314 38606993

44. Kumar S.K. Jacobus S.J. Cohen A.D. Weiss M. Callander N. Singh A.K. Parker T.L. Menter A. Yang X. Parsons B. Carfilzomib or bortezomib in combination with lenalidomide and dexamethasone for patients with newly diagnosed multiple myeloma without intention for immediate autologous stem-cell transplantation (ENDURANCE): A multicentre, open-label, phase 3, randomised, controlled trial Lancet Oncol. 2020 21 1317 1330 10.1016/s1470-2045(20)30452-6 32866432 PMC7591827

45. Leypoldt L.B. Tichy D. Besemer B. Hänel M. Raab M.S. Mann C. Munder M. Reinhardt H.C. Nogai A. Görner M. Isatuximab, Carfilzomib, Lenalidomide, and Dexamethasone for the Treatment of High-Risk Newly Diagnosed Multiple Myeloma J. Clin. Oncol. 2024 42 26 37 10.1200/JCO.23.01696 37753960 PMC10730063

46. Landgren O. Hultcrantz M. Diamond B. Lesokhin A.M. Mailankody S. Hassoun H. Tan C. Shah U.A. Lu S.X. Salcedo M. Safety and Effectiveness of Weekly Carfilzomib, Lenalidomide, Dexamethasone, and Daratumumab Combination Therapy for Patients With Newly Diagnosed Multiple Myeloma: The MANHATTAN Nonrandomized Clinical Trial JAMA Oncol. 2021 7 862 868 10.1001/jamaoncol.2021.0611 33856405 PMC8050789

47. Rees M.J. Kumar S. BCMA-directed therapy, new treatments in the myeloma toolbox, and how to use them Leuk. Lymphoma 2024 65 287 300 10.1080/10428194.2023.2284088 38354090

48. Dogan A. Siegel D. Tran N. Fu A. Fowler J. Belani R. Landgren O. B-cell maturation antigen expression across hematologic cancers: A systematic literature review Blood Cancer J. 2020 10 73 10.1038/s41408-020-0337-y 32606424 PMC7327051

49. Tai Y.T. Acharya C. An G. Moschetta M. Zhong M.Y. Feng X. Cea M. Cagnetta A. Wen K. van Eenennaam H. APRIL and BCMA promote human multiple myeloma growth and immunosuppression in the bone marrow microenvironment Blood 2016 127 3225 3236 10.1182/blood-2016-01-691162 27127303 PMC4920023

50. Sanchez E. Gillespie A. Tang G. Ferros M. Harutyunyan N.M. Vardanyan S. Gottlieb J. Li M. Wang C.S. Chen H. Soluble B-Cell Maturation Antigen Mediates Tumor-Induced Immune Deficiency in Multiple Myeloma Clin. Cancer Res. 2016 22 3383 3397 10.1158/1078-0432.CCR-15-2224 26960399

51. Sanchez E. Li M. Kitto A. Li J. Wang C.S. Kirk D.T. Yellin O. Nichols C.M. Dreyer M.P. Ahles C.P. Serum B-cell maturation antigen is elevated in multiple myeloma and correlates with disease status and survival Br. J. Haematol. 2012 158 727 738 10.1111/j.1365-2141.2012.09241.x 22804669

52. Ghermezi M. Li M. Vardanyan S. Harutyunyan N.M. Gottlieb J. Berenson A. Spektor T.M. Andreu-Vieyra C. Petraki S. Sanchez E. Serum B-cell maturation antigen: A novel biomarker to predict outcomes for multiple myeloma patients Haematologica 2017 102 785 795 10.3324/haematol.2016.150896 28034989 PMC5395119

53. Lonial S. Grosicki S. Hus M. Song K.W. Facon T. Callander N.S. Ribrag V. Uttervall K. Quach H. Vorobyev V.I. Synergistic effects of low-dose belantamab mafodotin in combination with a gamma-secretase inhibitor (nirogacestat) in patients with relapsed/refractory multiple myeloma (RRMM): DREAMM-5 study J. Clin. Oncol. 2022 40 8019 10.1200/JCO.2022.40.16_suppl.8019

54. Inoue S. Nambu T. Shimomura T. The RAIG Family Member, GPRC5D, Is Associated with Hard-Keratinized Structures J. Investig. Dermatol. 2004 122 565 573 10.1046/j.0022-202X.2004.12628.x 15086536

55. Smith E.L. Harrington K. Staehr M. Masakayan R. Jones J. Long T.J. Ng K.Y. Ghoddusi M. Purdon T.J. Wang X. GPRC5D is a target for the immunotherapy of multiple myeloma with rationally designed CAR T cells Sci. Transl. Med. 2019 11 485 10.1126/scitranslmed.aau7746 PMC7508042 30918115

56. Chari A. Minnema M.C. Berdeja J.G. Oriol A. van de Donk N.W.C.J. Rodríguez-Otero P. Askari E. Mateos M.-V. Costa L.J. Caers J. Talquetamab, a T-Cell–Redirecting GPRC5D Bispecific Antibody for Multiple Myeloma N. Engl. J. Med. 2022 387 2232 2244 10.1056/NEJMoa2204591 36507686

57. Mailankody S. Devlin S.M. Landa J. Nath K. Diamonte C. Carstens E.J. Russo D. Auclair R. Fitzgerald L. Cadzin B. GPRC5D-Targeted CAR T Cells for Myeloma N. Engl. J. Med. 2022 387 1196 1206 10.1056/NEJMoa2209900 36170501 PMC10309537

58. Chari A. Touzeau C. Schinke C. Minnema M.C. Berdeja J.G. Oriol A. van de Donk N.W.C.J. Rodríguez-Otero P. Morillo D. Martinez-Chamorro C. 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 e269 e281 10.1016/S2352-3026(24)00385-5 40090350

59. Rees M. Abdallah N. Yohannan B. Gonsalves W.I. Bispecific antibody targets and therapies in multiple myeloma Front. Immunol. 2024 15 1424925 10.3389/fimmu.2024.1424925 39450163 PMC11499143

60. Brischwein K. Parr L. Pflanz S. Volkland J. Lumsden J. Klinger M. Locher M. Hammond S.A. Kiener P. Kufer P. Strictly Target Cell-dependent Activation of T Cells by Bispecific Single-chain Antibody Constructs of the BiTE Class J. Immunother. 2007 30 798 807 10.1097/CJI.0b013e318156750c 18049331

61. Offner S. Hofmeister R. Romaniuk A. Kufer P. Baeuerle P.A. Induction of regular cytolytic T cell synapses by bispecific single-chain antibody constructs on MHC class I-negative tumor cells Mol. Immunol. 2006 43 763 771 10.1016/j.molimm.2005.03.007 16360021

62. Nuñez-Prado N. Compte M. Harwood S. Álvarez-Méndez A. Lykkemark S. Sanz L. Álvarez-Vallina L. The coming of age of engineered multivalent antibodies Drug Discov. Today 2015 20 588 594 10.1016/j.drudis.2015.02.013 25757598

63. Wang S. Chen K. Lei Q. Ma P. Yuan A.Q. Zhao Y. Jiang Y. Fang H. Xing S. Fang Y. The state of the art of bispecific antibodies for treating human malignancies EMBO Mol. Med. 2021 13 e14291 10.15252/emmm.202114291 34431224 PMC8422067

64. Lesokhin A.M. Tomasson M.H. Arnulf B. Bahlis N.J. Miles Prince H. Niesvizky R. Rodrίguez-Otero P. Martinez-Lopez J. Koehne G. Touzeau C. Elranatamab in relapsed or refractory multiple myeloma: Phase 2 MagnetisMM-3 trial results Nat. Med. 2023 29 2259 2267 10.1038/s41591-023-02528-9 37582952 PMC10504075

65. Moreau P. Garfall A.L. van de Donk N.W.C.J. Nahi H. San-Miguel J.F. Oriol A. Nooka A.K. Martin T. Rosinol L. Chari A. Teclistamab in Relapsed or Refractory Multiple Myeloma N. Engl. J. Med. 2022 387 495 505 10.1056/NEJMoa2203478 35661166 PMC10587778

66. Rees M.J. Mammadzadeh A. Bolarinwa A. Elhaj M.E. Bohra A. Bansal R. Ailawadhi S. Parrondo R. Chhabra S. Khot A. Clinical features associated with poor response and early relapse following BCMA-directed therapies in multiple myeloma Blood Cancer J. 2024 14 122 10.1038/s41408-024-01081-z 39043638 PMC11266661

67. Tan C.R. Asoori S. Huang C.Y. Brunaldi L. Popat R. Kastritis E. Martinez-Lopez J. Bansal R. Silva Corraes A.D.M. Chhabra S. Real-world evaluation of teclistamab for the treatment of relapsed/refractory multiple myeloma (RRMM): An International Myeloma Working Group Study Blood Cancer J. 2025 15 53 10.1038/s41408-025-01259-z 40175336 PMC11965530

68. Pasvolsky O. Dima D. Feng L. Dong W. Richards T. Davis J.A. Afrough A. Vazquez-Martinez M.A. Sannareddy A. Goel U. Outcomes of Elderly Patients with Relapsed Refractory Multiple Myeloma (RRMM) Treated with Teclistamab: A Multicenter Study from the U.S. Multiple Myeloma Immunotherapy Consortium Blood 2024 144 934 10.1182/blood-2024-205989 PMC12064690 40346049

69. Malard F. Bobin A. Labopin M. Karlin L. Frenzel L. Roussel M. Vignon M. Godet S. Chalopin T. Moyer P. Elranatamab monotherapy in the real-word setting in relapsed-refractory multiple myeloma: Results of the French compassionate use program on behalf of the IFM Blood Cancer J. 2024 14 219 10.1038/s41408-024-01200-w 39695076 PMC11655550

70. Garfall A.L. Nooka A.K. van de Donk N.W.C.J. Moreau P. Bhutani M. Oriol A. Martin T.G. Rosiñol L. Mateos M.V. Bahlis N.J. Long-term follow-up from the phase 1/2 MajesTEC-1 trial of teclistamab in patients with relapsed/refractory multiple myeloma J. Clin. Oncol. 2024 42 7540 10.1200/JCO.2024.42.16_suppl.7540

71. Tomasson M.H. Iida S. Niesvizky R. Mohty M. Bahlis N.J. Martinez-Lopez J. Koehne G. Rodriguez-Otero P. Miles Prince H. Viqueira A. Long-term survival and safety of elranatamab in patients with relapsed or refractory multiple myeloma: Update from the MagnetisMM-3 study Hemasphere 2024 8 e136 10.1002/hem3.136 39055646 PMC11269363

72. Berdeja J.G. Madduri D. Usmani S.Z. Jakubowiak A. Agha M. Cohen A.D. Stewart A.K. Hari P. Htut M. Lesokhin A. 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 2021 398 314 324 10.1016/S0140-6736(21)00933-8 34175021

73. Jagannath S. Martin T.G. Lin Y. Cohen A.D. Raje N. Htut M. Deol A. Agha M. Berdeja J.G. Lesokhin A.M. Long-Term (≥5-Year) Remission and Survival After Treatment With Ciltacabtagene Autoleucel in CARTITUDE-1 Patients With Relapsed/Refractory Multiple Myeloma J. Clin. Oncol. 2025 JCO-25-00760 10.1200/JCO-25-00760 40459151 PMC12393059

74. Munshi N.C. Anderson L.D. Jr. Shah N. Madduri D. Berdeja J. Lonial S. Raje N. Lin Y. Siegel D. Oriol A. Idecabtagene Vicleucel in Relapsed and Refractory Multiple Myeloma N. Engl. J. Med. 2021 384 705 716 10.1056/NEJMoa2024850 33626253

75. Abdallah N. Rees M. Gupta S. Elhaj M. Bansal R. Menser T. Schaeferle G. Cook J. Kourelis T. Warsame R.M. Frailty-Based Outcomes with Bispecific Antibodies in Older Patients with Multiple Myeloma Blood 2024 144 4695 10.1182/blood-2024-211768

76. Raje N. Anderson K. Einsele H. Efebera Y. Gay F. Hammond S.P. Lesokhin A.M. Lonial S. Ludwig H. Moreau P. Monitoring, prophylaxis, and treatment of infections in patients with MM receiving bispecific antibody therapy: Consensus recommendations from an expert panel Blood Cancer J. 2023 13 116 10.1038/s41408-023-00879-7 37528088 PMC10394080

77. Ludwig H. Terpos E. van de Donk N. Mateos M.V. Moreau P. Dimopoulos M.A. Delforge M. Rodriguez-Otero P. San-Miguel J. Yong K. Prevention and management of adverse events during treatment with bispecific antibodies and CAR T cells in multiple myeloma: A consensus report of the European Myeloma Network Lancet Oncol. 2023 24 e255 e269 10.1016/S1470-2045(23)00159-6 37269857

78. McLoughlin A. Rees M.J. Minimising Toxicity and Maximising Response: T-Cell Engagers for Elderly Patients with Multiple Myeloma Lymphatics 2025 3 14 10.3390/lymphatics3020014

79. Carretero-Iglesia L. Hall O.J. Berret J. Pais D. Estoppey C. Chimen M. Monney T. Loyau J. Dreyfus C. Macoin J. ISB 2001 trispecific T cell engager shows strong tumor cytotoxicity and overcomes immune escape mechanisms of multiple myeloma cells Nat. Cancer 2024 5 1494 1514 10.1038/s43018-024-00821-1 39261676 PMC11505469

80. van de Donk N.W.C.J. Vega G. Perrot A. Anguille S. Oriol A. Minnema M. Kaiser M.F. Lee H.C. Garfall A. Matous J.V. First-in-human study of JNJ-79635322 (JNJ-5322), a novel, next-generation trispecific antibody (TsAb), in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Initial phase 1 results J. Clin. Oncol. 2025 43 7505 10.1200/JCO.2025.43.16_suppl.7505

81. Sharon D. Robinson V. Hecquet C. Calabrese K. Cosgrove C. Mantis C. Bueno O. Ahsan A. Chervin A. Epling-Burnette P.K. Bivalent BCMA Binding and Low Affinity CD3 T-Cell Engagement By Abbv-383 Drives Sustained Activation with Reduced T-Cell Exhaustion in Preclinical Models of Multiple Myeloma Blood 2023 142 4666 10.1182/blood-2023-179039

82. Quach H. Augustson B. Sia H. Shah N. Lichtman E.I. Liedtke M. Martinet C. Menon V. Garton A. Pihlgren M. First Results of a Phase 1, First-in-Human, Dose Escalation Study of ISB 2001, a BCMAxCD38xCD3 Targeting Trispecific Antibody in Patients with Relapsed/Refractory Multiple Myeloma (RRMM) Blood 2024 144 1026 10.1182/blood-2024-208189

83. Sheykhhasan M. Ahmadieh-Yazdi A. Vicidomini R. Poondla N. Tanzadehpanah H. Dirbaziyan A. Mahaki H. Manoochehri H. Kalhor N. Dama P. CAR T therapies in multiple myeloma: Unleashing the future Cancer Gene Ther. 2024 31 667 686 10.1038/s41417-024-00750-2 38438559 PMC11101341

84. Qiang W. Lu J. Jia Y. Liu J. Liu J. He H. Wang X. Fan X. Jin L. Ruan Q. B-Cell Maturation Antigen/CD19 Dual-Targeting Immunotherapy in Newly Diagnosed Multiple Myeloma JAMA Oncol. 2024 10 1259 1263 10.1001/jamaoncol.2024.2172 39052306 PMC11273281

85. Wang J. Caimi P.F. CAR assembly line: Taking CAR T-cell manufacturing to the next level Best Pract. Res. Clin. Haematol. 2024 37 101595 10.1016/j.beha.2024.101595 40074509

86. Ramamurthy A. Tommasi A. Saha K. Advances in manufacturing chimeric antigen receptor immune cell therapies Semin. Immunopathol. 2024 46 12 10.1007/s00281-024-01019-4 39150566 PMC12054169

87. Berdeja J.G. Raje N.S. Siegel D.S. Lin Y. Anderson L.D. Rodriguez-Otero P. Manier S. Einsele H. Cavo M. Truppel-Hartmann A. Efficacy and Safety of Idecabtagene Vicleucel (ide-cel, bb2121) in Elderly Patients with Relapsed and Refractory Multiple Myeloma: KarMMa Subgroup Analysis Blood 2020 136 16 17 10.1182/blood-2020-134322

88. Abdallah N. Elhaj M. Gupta S. Rees M. Atallah-Yunes S.A. Menser T. Bansal R. Schaeferle G. Knepper C. Warsame R. P-001 Impact of Age and Frailty on Outcomes of Patients with Multiple Myeloma Receiving CAR T-Cell Therapies–A Single Center Experience Clin. Lymphoma Myeloma Leuk. 2024 24 S40 10.1016/S2152-2650(24)01904-9

89. Hansen D.K. Sidana S. Peres L.C. Colin Leitzinger C. Shune L. Shrewsbury A. Gonzalez R. Sborov D.W. Wagner C. Dima D. Idecabtagene Vicleucel for Relapsed/Refractory Multiple Myeloma: Real-World Experience From the Myeloma CAR T Consortium J. Clin. Oncol. 2023 41 2087 2097 10.1200/JCO.22.01365 36623248 PMC10082273

90. Freeman C.L. Noble J. Menges M. Villanueva R. Nakashima J.Y. Figura N.B. Tonseth R.P. Werner Idiaquez D. Skelson L. Smith E. Tumor burden quantified by soluble B-cell maturation antigen and metabolic tumor volume determines myeloma CAR-T outcomes Blood 2025 145 1645 1657 10.1182/blood.2024024965 39652773

91. Akhtar O.S. Modi K. Kim J. Skelson L. Smith E. Al-Jumayli M.A. Extermann M. De Avila G. Parker N. Castaneda Puglianini O. Simple Score of Albumin and CRP Predicts High-Grade Toxicity in Patients with Multiple Myeloma Receiving CAR-T Therapy Transpl. Cell Ther. 2024 30 283.e1–283.e10 10.1016/j.jtct.2023.12.010 38123069

92. Rejeski K. Hansen D.K. Bansal R. Sesques P. Ailawadhi S. Logue J.M. Bräunlein E. Cordas Dos Santos D.M. Freeman C.L. Alsina M. The CAR-HEMATOTOX score as a prognostic model of toxicity and response in patients receiving BCMA-directed CAR-T for relapsed/refractory multiple myeloma J. Hematol. Oncol. 2023 16 88 10.1186/s13045-023-01465-x 37525244 PMC10391746

93. Lin Y. Martin T.G. Usmani S.Z. Berdeja J.G. Jakubowiak A.J. Agha M.E. Cohen A.D. Deol A. Htut M. Lesokhin A.M. CARTITUDE-1 final results: Phase 1b/2 study of ciltacabtagene autoleucel in heavily pretreated patients with relapsed/refractory multiple myeloma J. Clin. Oncol. 2023 41 8009 10.1200/JCO.2023.41.16_suppl.8009

94. Jain M.D. Smith M. Shah N.N. How I treat refractory CRS and ICANS after CAR T-cell therapy Blood 2023 141 2430 2442 10.1182/blood.2022017414 36989488 PMC10329191

95. San-Miguel J. Dhakal B. Yong K. Spencer A. Anguille S. Mateos M.V. Fernández de Larrea C. Martínez-López J. Moreau P. Touzeau C. Cilta-cel or Standard Care in Lenalidomide-Refractory Multiple Myeloma N. Engl. J. Med. 2023 389 335 347 10.1056/NEJMoa2303379 37272512

96. Cohen A.D. Parekh S. Santomasso B.D. Gállego Pérez-Larraya J. van de Donk N. Arnulf B. Mateos M.V. Lendvai N. Jackson C.C. De Braganca K.C. Incidence and management of CAR-T neurotoxicity in patients with multiple myeloma treated with ciltacabtagene autoleucel in CARTITUDE studies Blood Cancer J. 2022 12 32 10.1038/s41408-022-00629-1 35210399 PMC8873238

97. Hines M.R. Knight T.E. McNerney K.O. Leick M.B. Jain T. Ahmed S. Frigault M.J. Hill J.A. Jain M.D. Johnson W.T. Immune Effector Cell-Associated Hemophagocytic Lymphohistiocytosis-Like Syndrome Transplant. Cell. Ther. 2023 29 438.e1–438.e16 10.1016/j.jtct.2023.03.006 36906275 PMC10330221

98. Leung N. Alkhateeb H.B. Atallah-Yunes S.A. Durani U. Moraes A.G.D. Gupta S. Hayman S.R. Herrmann J. Johnston P.B. Kenderian S. Outcomes of patients who received CAR T cell therapy and developed IEC-HS treated with cytokine directed therapy J. Clin. Oncol. 2024 42 7516 10.1200/JCO.2024.42.16_suppl.7516

99. Kourelis T. Bansal R. Berdeja J. Siegel D. Patel K. Mailankody S. Htut M. Shah N. Wong S.W. Sidana S. Ethical Challenges with Multiple Myeloma BCMA Chimeric Antigen Receptor T Cell Slot Allocation: A Multi-Institution Experience Transpl. Cell Ther. 2023 29 255 258 10.1016/j.jtct.2023.01.012 PMC10040426 36681151

100. Rodriguez-Otero P. Ailawadhi S. Arnulf B. Patel K. Cavo M. Nooka A.K. Manier S. Callander N. Costa L.J. Vij R. Ide-cel or Standard Regimens in Relapsed and Refractory Multiple Myeloma N. Engl. J. Med. 2023 388 1002 1014 10.1056/NEJMoa2213614 36762851

101. Yan Y. Tu Y. Cheng Q. Zhang J. Wang E. Deng Z. Yu Y. Wang L. Liu R. Chu L. BCMA CAR-T therapy combined with pomalidomide is a safe and effective treatment for relapsed/refractory multiple myeloma J. Transl. Med. 2024 22 1087 10.1186/s12967-024-05772-w 39614361 PMC11607906

102. Delforge M. Shah N. Miguel J.S.F. Braverman J. Dhanda D.S. Shi L. Guo S. Yu P. Liao W. Campbell T.B. Health-related quality of life with idecabtagene vicleucel in relapsed and refractory multiple myeloma Blood Adv. 2022 6 1309 1318 10.1182/bloodadvances.2021005913 34933328 PMC8864645

103. Lesokhin A.M. Richter J. Trudel S. Cohen A.D. Spencer A. Forsberg P.A. Laubach J.P. Thomas S.K. Bahlis N.J. Costa L.J. Enduring Responses after 1-Year, Fixed-Duration Cevostamab Therapy in Patients with Relapsed/Refractory Multiple Myeloma: Early Experience from a Phase I Study Blood 2022 140 4415 4417 10.1182/blood-2022-157547

104. Cohen Y.C. Magen H. Gatt M. Sebag M. Kim K. Min C.K. Ocio E.M. Yoon S.S. Chu M.P. Rodríguez-Otero P. Talquetamab plus Teclistamab in Relapsed or Refractory Multiple Myeloma N. Engl. J. Med. 2025 392 138 149 10.1056/NEJMoa2406536 39778168

105. Matous J. Biran N. Perrot A. Berdeja J.G. Dorritie K. Elssen J.V. Searle E. Touzeau C. Anguille S. Vishwamitra D. Talquetamab + Pomalidomide in Patients with Relapsed/Refractory Multiple Myeloma: Safety and Preliminary Efficacy Results from the Phase 1b MonumenTAL-2 Study Blood 2023 142 1014 10.1182/blood-2023-187706

106. Dholaria B.R. Weisel K. Mateos M.-V. Goldschmidt H. Martin T.G. Morillo D. Reece D.E. Rodríguez-Otero P. Bhutani M. D'Souza A. Talquetamab (tal) + daratumumab (dara) in patients (pts) with relapsed/refractory multiple myeloma (RRMM): Updated TRIMM-2 results J. Clin. Oncol. 2023 41 8003 10.1200/JCO.2023.41.16_suppl.8003

107. Bahlis N.J. Costello C.L. Raje N.S. Levy M.Y. Dholaria B. Solh M. Tomasson M.H. Damore M.A. Jiang S. Basu C. Elranatamab in relapsed or refractory multiple myeloma: The MagnetisMM-1 phase 1 trial Nat. Med. 2023 29 2570 2576 10.1038/s41591-023-02589-w 37783970 PMC10579053

108. Bansal R. Corraes A.D.M.S. Brunaldi L. Sandahl T.B. Rees M.J. Hayman S.R. Binder M. Abdallah N. Dingli D. Cook J. Real world outcome of patients with multiple myeloma who received bispecific antibodies after CAR-T therapy J. Clin. Oncol. 2024 42 7520 10.1200/JCO.2024.42.16_suppl.7520

109. Cohen A.D. Mateos M.V. Cohen Y.C. Rodriguez-Otero P. Paiva B. van de Donk N. Martin T. Suvannasankha A. De Braganca K.C. Corsale C. Efficacy and safety of cilta-cel in patients with progressive multiple myeloma after exposure to other BCMA-targeting agents Blood 2023 141 219 230 10.1182/blood.2022015526 36095849 PMC10562529

110. Ferreri C.J. Hildebrandt M.A.T. Hashmi H. Shune L.O. McGuirk J.P. Sborov D.W. Wagner C.B. Kocoglu M.H. Rapoport A. Atrash S. Real-world experience of patients with multiple myeloma receiving ide-cel after a prior BCMA-targeted therapy Blood Cancer J. 2023 13 117 10.1038/s41408-023-00886-8 37558706 PMC10412575

111. Touzeau C. Krishnan A.Y. Moreau P. Perrot A. Usmani S.Z. Manier S. Cavo M. Martinez-Chamorro C. Nooka A.K. Martin T.G. Efficacy and safety of teclistamab (tec), a B-cell maturation antigen (BCMA) x CD3 bispecific antibody, in patients (pts) with relapsed/refractory multiple myeloma (RRMM) after exposure to other BCMA-targeted agents J. Clin. Oncol. 2022 40 8013 10.1200/JCO.2022.40.16_suppl.8013

112. Yong K. Delforge M. Driessen C. Fink L. Flinois A. Gonzalez-McQuire S. Safaei R. Karlin L. Mateos M.-V. Raab M.S. Multiple myeloma: Patient outcomes in real-world practice Br. J. Haematol. 2016 175 252 264 10.1111/bjh.14213 27411022 PMC5096152

113. Kanas G. Clark O. Keeven K. Nersesyan K. Sansbury L. Hogea C. Estimate of multiple myeloma patients by line of therapy in the USA: Population-level projections 2020–2025 Future Oncol. 2021 17 921 930 10.2217/fon-2020-0970 33200616

114. Raab M.S. Weinhold N. Kortüm K.M. Krönke J. Podola L. Bertsch U. Frenking J.H. Mersi J. Huhn S. Hundemer M. Phase 2 Study of Teclistamab-Based Induction Regimens in Patients with Transplant-Eligible (TE) Newly Diagnosed Multiple Myeloma (NDMM): Results from the GMMG-HD10/DSMM-XX (MajesTEC-5) Trial Blood 2024 144 493 10.1182/blood-2024-206003

115. Quach H. Pour L. Grosicki S. Sia H. Minarik J. Byun J.M. Touzeau C. Liberatore C. Sullivan S.T. Leip E. Elranatamab in combination with daratumumab and lenalidomide (EDR) in patients with newly diagnosed multiple myeloma (NDMM) not eligible for transplant: Initial results from MagnetisMM-6 part 1 J. Clin. Oncol. 2025 43 7504 10.1200/JCO.2025.43.16_suppl.7504

116. Dytfeld D. Dhakal B. Agha M. Manier S. Delforge M. Kuppens S. Afifi S. Deraedt W. Taraseviciute-Morris A. Schecter J.M. Bortezomib, Lenalidomide and Dexamethasone (VRd) Followed By Ciltacabtagene Autoleucel Versus Vrd Followed By Lenalidomide and Dexamethasone (Rd) Maintenance in Patients with Newly Diagnosed Multiple Myeloma Not Intended for Transplant: A Randomized, Phase 3 Study (CARTITUDE-5) Blood 2021 138 1835 10.1182/blood-2021-146210

117. Krishnan A.Y. Manier S. Terpos E. Usmani S. Khan J. Pearson R. Girgis S. Guo Y. McAleer D. Olyslager Y. MajesTEC-7: A Phase 3, Randomized Study of Teclistamab + Daratumumab + Lenalidomide (Tec-DR) Versus Daratumumab + Lenalidomide + Dexamethasone (DRd) in Patients with Newly Diagnosed Multiple Myeloma Who Are Either Ineligible or Not Intended for Autologous Stem Cell Transplant Blood 2022 140 10148 10149 10.1182/blood-2022-160173

118. Grosicki S. Yeh S.P. Huang S.Y. Byun J.M. Dirienzo C. Viqueira A. Pb2130: MagnetisMM-6: A phase 3 study of elranatamab + daratumumab + lenalidomide vs daratumumab + lenalidomide + dexamethasone in transplant ineligible patients with newly diagnosed multiple myeloma Hemasphere 2023 7 e039274c 10.1097/01.HS9.0000975284.03927.4c

119. Touzeau C. Beksac M. Terpos E. Usmani S.Z. Krishnan A.Y. Nijhof I.S. Janowski W. Hulin C. Grosicki S. Delforge M. Safety results from the phase 3 MajesTEC-7 study in patients (pts) with transplant ineligible/not intended newly diagnosed multiple myeloma (NDMM) J. Clin. Oncol. 2024 42 7506 10.1200/JCO.2024.42.16_suppl.7506

120. Hartley-Brown M.A. Mo C.C. Nadeem O. Midha S. Laubach J.P. Richardson P.G. Mezigdomide-A Novel Cereblon E3 Ligase Modulator under Investigation in Relapsed/Refractory Multiple Myeloma Cancers 2024 16 1166 10.3390/cancers16061166 38539501 PMC10969776

121. Inoue Y. Oda A. Maeda Y. Sumitani R. Oura M. Sogabe K. Maruhashi T. Takahashi M. Fujii S. Nakamura S. Ex vivo expansion and activation of Vγ9Vδ2 T cells by CELMoDs in combination with zoledronic acid Int. J. Hematol. 2024 119 626 630 10.1007/s12185-024-03763-7 38581458

122. van de Donk N.W.C.J. Garfall A.L. Benboubker L. Uttervall K. Groen K. Rosiñol L. Hodin C. Stephenson T. Trancucci D. Perales-Puchalt A. Evaluation of prophylactic tocilizumab (toci) for the reduction of cytokine release syndrome (CRS) to inform the management of patients (pts) treated with teclistamab in MajesTEC-1 J. Clin. Oncol. 2023 41 8033 10.1200/JCO.2023.41.16_suppl.8033