Multiple Myeloma: The Role of Autologous Stem Cell Transplantation in the Era of Immunotherapy.

1. Introduction

Multiple myeloma (MM) is the third most common hematological malignancy; it is a clonal plasma cell dyscrasia, accounting for 10% of newly diagnosed hematologic malignancies. Over the past two decades, the expansion of treatment options, including the introduction of targeted therapies and immunomodulatory drugs, has dramatically improved patient outcomes in terms of response rates and survival.

Despite these advancements, autologous stem cell transplantation (ASCT) following high-dose melphalan (HDM) continues to be the standard of care for eligible patients with newly diagnosed MM, showing high response rates and extended survival times. The therapeutic path includes four phases: induction, HDM plus ASCT, consolidation, and maintenance, a model associated with high response rates, prolonged progression-free (PFS), and overall (OS) survival [ 1 , 2 , 3 ].

The latest 2021 European Hematology Association and European Society for Medical Oncology (ESMO) guidelines recommend induction therapy with VTd (bortezomib, thalidomide, dexamethasone) or VRd (bortezomib, lenalidomide, dexamethasone) plus the anti-CD38 monoclonal antibody daratumumab, followed by HDM-ASCT and lenalidomide maintenance [ 4 , 5 ].

The role of ASCT may continue to evolve with the introduction of immunotherapies in a front-line setting.

Immunotherapy in MM has been widely explored in recent years [ 6 , 7 ].

Currently, there are two different approaches, aiming at either passive or active reactivation of the immune system [ 8 ]. Passive immunotherapy includes monoclonal antibodies (MoAbs), both “naked” and conjugated to a cytotoxic agent. Modern strategies of active immunotherapy are represented by bispecific antibodies (BsAbs) and cellular therapy with chimeric antigen receptor (CAR)-T cells, which activate and redirect the T-cell compartment of the immune system against the neoplastic cells, and which have recently revolutionized the therapeutic landscape of MM [ 9 , 10 ]. In both cases, these therapeutic options target surface antigens predominantly expressed on MM cells, with a role in the proliferation and survival of neoplastic plasma cells (PCs), and less represented on other cell types, thus minimizing off-target effects [ 9 ].

These immune-based approaches have shown notable anti-myeloma effects with deep and durable responses in initial clinical trials of heavily pretreated MM patients. Their use in the earlier stages of the disease has produced impressive results, raising the question of how to integrate these drugs into the therapeutic algorithm of transplant-eligible NDMM.

2. Current Consideration on the Role of ASCT in MM

In transplant-eligible NDMM patients, HDM plus ASCT remains the standard of care recommended by international guidelines such as those of the American Society of Clinical Oncology (ASCO), ESMO, and European Bone Marrow Transplantation (EBMT) [ 4 , 11 , 12 , 13 ]. Until a few years ago, regimens for induction therapy commonly included a proteasome inhibitor (PI), an immunomodulatory drug (IMiD), and dexamethasone (a three-drug therapy—triplet). More recently, the introduction of anti-CD38 monoclonal antibodies, daratumumab and isatuximab, has changed the treatment paradigm for transplant-eligible NDMM patients in that quadruplets have supplanted triplets [ 14 , 15 ].

2.1. Daratumumab-Based Induction Regimens

Daratumumab is a human IgG/kappa MoAb directed against targeting CD38 antigen surfaces with different mechanisms of action [ 16 , 17 ]. Daratumumab has been approved for use in combination with various regimens for the treatment of RRMM [ 18 , 19 ] and newly diagnosed transplant-ineligible MM [ 20 , 21 , 22 ].

The addition of daratumumab to standard triplets as induction and consolidation in transplant-eligible NDMM has been extensively evaluated in many randomized controlled clinical trials ( Table 1 ), and now it represents a new standard of care.

The phase 3 CASSIOPEIA trial marked the first evidence of the clinical advantage of incorporating daratumumab into the standard VTd regimen [ 23 ]. This study involved an initial randomization of participants to receive either VTd alone or in combination with daratumumab (D-VTd) across four cycles of pre-transplant induction and two cycles of post-transplant consolidation. Subsequently, responders were randomized again to either continue with maintenance daratumumab or switch to observation. The D-VTd regimen, administered both before and after ASCT, enhanced the primary outcomes of stringent complete response (sCR) and PFS compared to VTd alone. Additionally, 64% of D-VTd patients achieved minimal residual disease (MRD) negativity by day 100 post-transplant, compared to 44% of those on VTd ( p < 0.0001). These findings led to the FDA and EMA’s approval of the four-drug combination D-VTd. Notably, CASSIOPEIA was also the first trial to demonstrate the benefits of daratumumab maintenance over observation following ASCT [ 24 ]. Patients who continued daratumumab treatment beyond two years post-consolidation experienced a median PFS that surpassed that of the observation group (not reached vs. 46.7 months; HR = 0.53, p < 0.0001). While the PFS advantage was apparent in the VTd group with daratumumab maintenance compared to VTd with observation only (HR = 0.32, p < 0.0001), no significant PFS difference was found between the D-VTd induction/consolidation with daratumumab and D-VTd with observation (HR = 1.02, p = 0.91). Moreover, the daratumumab group showed higher rates of complete response (CR) or better (73% vs. 61%, p < 0.0001), improved responses (62% vs. 47%, p < 0.0001), MRD negativity (assessed by next-generation sequencing at 10 −5 ; 59% vs. 47%, p = 0.0001), and conversion to MRD negativity (44% vs. 30%, p = 0.0004) compared to the observation group.

The phase II GRIFFIN study rigorously assessed the impact of adding daratumumab to the VRd regimen (bortezomib, lenalidomide, and dexamethasone) in NDMM [ 25 ]. This randomized trial involved 207 NDMM patients who were divided into groups to receive either D-VRd or VRd for 4 cycles of induction, followed by ASCT, 2 cycles of consolidation with D-VRd or VRd, and 26 cycles of maintenance therapy with either lenalidomide alone or combined with daratumumab. After a median follow-up of 13.5 months, the primary outcome of stringent complete response sCR post-consolidation was reached by 42.4% of patients in the D-VRd group compared to 32.0% in the VRd group ( p = 0.068). Furthermore, the D-VRd group showed superior secondary outcomes, with an ORR of 99.0% compared to 91.8% in the VRd group ( p = 0.0160) and a higher rate of VGPR or better (90.9% vs. 73.2%, p = 0.0014). Over time, these responses deepened, with 62.6% of the D-VRd group achieving sCR by the last follow-up at 22.1 months, compared to 45.4% in the VRd group ( p = 0.0177). Additionally, the rate of complete response (CR) or better was 79.8% in the D-VRd group versus 60.8% in the VRd group ( p = 0.0045). At this follow-up point, the MRD-negativity rate was significantly higher in the D-VRd group than in the VRd group (51.0% vs. 20.4%, p < 0.0001), especially among patients achieving CR or better (62.0% vs. 32.2%, p = 0.0006). Although the median PFS was not reached, the final analysis at 49.6 months demonstrated a 55% reduction in the risk of disease progression (PD) or death in the D-VRd arm compared to the VRd arm (HR, 0.45; 95% CI, 0.21–0.95; p = 0.0324). Importantly, sCR rates increased to 67% for D-VRd and 48% for VRd after two years of maintenance ( p = 0.0079). Given the positive trends in PFS and the high rates of sCR and MRD negativity, the D-VRd quadruplet has become a standard treatment in the US. However, the limitations of the GRIFFIN study, a phase II trial with nearly 200 participants not powered to definitively assess PFS, suggest that further confirmation through larger phase 3 trials is necessary [ 26 ].

The efficacy of the D-VRd regimen has been recently confirmed by the phase 3 PERSEUS study [ 27 ]. 709 transplant-eligible patients with NDMM were randomized to receive either subcutaneous daratumumab plus VRd induction and consolidation regimen and with lenalidomide maintenance (D-VRd group) or VRd induction and consolidation regimen and maintenance with lenalidomide alone (VRd group). Interestingly, in the PERSEUS trial, patients who achieved a CR or better and maintained MRD-negativity (sensitivity at ≤10 −5 ) for at least 12 months stopped daratumumab after 24 months of maintenance and continued with only lenalidomide until disease relapse. At a median follow-up of 47.5 months, PD or death had occurred in 50 of 355 patients (14.1%) in the D-VRd group and 103 of 354 patients (29.1%) in the VRd group. The estimated 48-month PFS rate was 84.3% for the D-VRd group compared to 67.7% for the VRd group (HR 0.42, 95% CI, 0.30 to 0.59; p < 0.001). The D-VRd group also showed higher rates of CR or better (87.9% vs. 70.1%, p < 0.001) and MRD-negative status (75.2% vs. 47.5%, p < 0.001), with 64.8% maintaining MRD-negative status for at least 12 months compared to 29.7% in the VRd group. By the time of analysis, 207 of the 322 patients in the maintenance phase of the D-VRd group had stopped daratumumab as per the protocol. These findings affirm the benefits of incorporating daratumumab into the standard treatment regimen for NDMM.

MRD negativity after treatment is linked to improved outcomes in NDMM patients, though its role in guiding therapy adjustments is still being established. In the phase 2 MASTER trial, NDMM patients eligible for transplant underwent four cycles of daratumumab, carfilzomib, lenalidomide, and dexamethasone (Dara-KRd) induction therapy, followed by HDM-ASCT, and up to two cycles of consolidation with Dara-KRd [ 28 ]. The primary goal was to achieve MRD negativity (<10 −5 ). Participants who achieved MRD negativity after or during two subsequent cycles switched to observation with ongoing MRD monitoring, while those without two consecutive MRD-negative determinations continued with lenalidomide maintenance. Of the 123 evaluable patients, 53 (43%) had no high-risk cytogenetic aberrations (HRCAs), 46 (37%) had one HRCA, and 24 (20%) had multiple HRCAs. MRD negativity was achieved in 81% of the study cohort. Eighty-four patients met the criteria for MRD-SURE and entered protocol-directed observation, whereas 24 received ongoing standard lenalidomide maintenance. With a median follow-up of 42.2 months, the 36-month PFS was 88%, 79%, and 50% for participants with no, one, and two or more HRCAs, respectively. This trial exemplifies the potential of MRD-driven therapy to offer a treatment-free state, highlighting the need for further improvements in the prognosis for patients with ultra-high-risk MM.

2.2. Isatuximab-Based Induction Regimens

Isatuximab is a chimeric IgG monoclonal antibody that specifically targets a unique epitope on CD38, exerting its anti-myeloma effects through multiple mechanisms. These include antibody-dependent cellular cytotoxicity, complement-dependent cytotoxicity, antibody-dependent cellular phagocytosis, direct induction of apoptosis, and inhibition of the CD38 enzyme’s intrinsic activity [ 29 ]. Isatuximab has received approval for use in combination with various treatment regimens for RRMM and is also being explored in the initial treatment of transplant-eligible NDMM patients ( Table 1 ) [ 30 , 31 , 32 , 33 ].

In the phase 3 GMMG-HD7 clinical trial, 660 transplant-eligible NDMM patients were randomized to receive three cycles of induction therapy with either isatuximab plus bortezomib, lenalidomide, and dexamethasone (Isa-VRd) or the standard VRd alone. The primary outcome, assessed by flow cytometry, was MRD negativity in the intention-to-treat population. The trial found that 50% of patients in the isatuximab group achieved MRD negativity after induction, compared to 36% in the control group ( p = 0.00017) [ 34 ].

Furthermore, isatuximab’s efficacy was under evaluation in the phase 2 GMMG-CONCEPT trial, combined with carfilzomib, lenalidomide, and dexamethasone (KRd) in cytogenetically high-risk, both young (≤70 years) and elderly (>70 years) NDMM patients [ 35 ]. This study classified patients as high-risk based on the International Staging System (ISS) stages II/III and specific cytogenetic abnormalities such as del17p, t(4;14), t(14;16), or more than three copies of 1q21. These transplant-eligible NDMM patients received Isa-KRd for induction/consolidation and continued with Isa-KR for maintenance. The primary endpoint of the study was achieving MRD negativity at the end of the consolidation phase, and the secondary endpoint was PFS. By the end of consolidation, 72.8% of patients achieved a complete or stringent complete response, and 18.2% reached a very good partial response, with an overall response rate of 94.9%. At this stage, 67.7% of patients were MRD-negative, and 81.8% reached MRD negativity at some point during the treatment. Sustained MRD-negative status for at least 6 and 12 months was achieved by 72 and 62 patients, respectively, corresponding to sustained MRD negativity rates of 72.7% and 62.6%. With a median follow-up of 44 months, the median PFS had not been reached, underscoring Isa-KRd’s potential to significantly impact MRD negativity and improve outcomes in high-risk NDMM populations.

2.3. Stem Cell Mobilization and Harvesting

Mobilization of CD34+ stem cells from the bone marrow to the peripheral blood is a prerequisite for harvesting an adequate number of hematopoietic stem cells (HSC). A minimum of 2 × 10 6 /kg CD34+ cells is required to perform ASCT, while the ideal target for 1 ASCT is >3 × 10 6 /kg CD34+ cells, and that for 2 ASCT is >6 × 10 6 /kg CD34+ cells. The optimal stem cell mobilization strategy remains a matter of debate [ 36 , 37 , 38 ]. Currently, stem cell mobilization can be performed with granulocyte colony-stimulating factor (G-CSF), preceded or not by chemotherapy with Cyclophosphamide (Cy) at a variable dose of 1.5–4 g/m 2 . Recently, plerixafor (scissor enzyme selective and reversible antagonist of CXCR4) has been approved, which is particularly effective in reducing the failure rate of the procedure by preventing the adherence of HSCs to the marrow matrix and thus increasing their release into the circulation. After its approval, the chemotherapy-free protocol has been adopted by many centers because of the less adverse event rates, such as neutropenia or infections.

Recent data seem to indicate that the introduction of anti-CD38 monoclonal antibodies in the induction therapy of NDMM is associated with a lower capacity to mobilize and collect HSC. The biological reasons for these findings have yet to be clarified. An important role could be played by the expression of CD38 on normal bone marrow and mobilized hematopoietic progenitor [ 39 , 40 , 41 ].

In the phase 3 CASSIOPEIA trial, stem cell collection was notably less efficient following the D-VTd regimen compared to VTd (6.7 vs. 10.0 × 10 −6 /kg), with higher usage of plerixafor (21.7% vs. 7.9%) and increased rates of collection failures (defined as collections <5 × 10 −6 /kg, 24.6% vs. 11.4%) [ 42 ]. Further analysis in the phase 2 MASTER and GRIFFIN trials sought to assess the impact of the daratumumab, PI, and IMID combination on hematopoietic stem cell mobilization [ 43 ]. Within these studies, up to 97% of D-KRd patients and 72% of the D-VRd cohort needed the use of plerixafor. The median total CD34+ cell yield was 6.0 × 10 −6 /kg in the MASTER trial, 8.3 × 10 −6 /kg for D-VRd, and 9.4 × 10 −6 /kg for VRd in the GRIFFIN study. Among those mobilized, the rate of needing to remobilize was 7% for D-KRd, 2% for D-VRd, and 6% for VRd. Despite the lower yields and increased plerixafor use in the daratumumab-containing regimens in the NDMM setting across the MASTER, GRIFFIN, and CASSIOPEIA trials, the integration of daratumumab into the PI-IMIds triplet therapy did not negatively affect the feasibility and safety of conducting ASCT or hinder successful engraftment. Several retrospective clinical trials have described HSC mobilization and collection in patients receiving daratumumab-based induction regimens [ 44 , 45 , 46 ].

A German retrospective single-center study evaluated 179 transplant-eligible NDMM patients treated according to the GMMG-HD6 and GMMG-HD7 clinical trials with respect to PBSC mobilization and collection [ 47 ]. Patients were grouped according to induction therapy: VRd (6 cycles: 44 patients, 4 cycles: 51 patients), Isa-VRd (35 patients), or elotuzumab-VRd (49 patients). All 179 patients received a chemotherapy-based mobilization. Leukapheresis collection was considered successful if a target dose of >6 × 10 6 /kg CD34+ cells was reached. The addition of isatuximab to VRd had no significant negative impact on HSC mobilization, considering mean peripheral blood CD34 + cell count, number of leukapheresis sessions, plerixafor use, and overall CD34+ cell collection results. Multivariable logistic regression analysis confirmed these results.

3. T Cell Redirecting Therapy in MM

3.1. T Cell Redirecting Therapy Targeting BCMA

As previously mentioned, active immunotherapy works against specific targets on MM cells, activating and redirecting the T cell compartment of the immune system [ 9 , 10 ].

In the search for ideal targets over the years, B-cell Maturation Antigen (BCMA) has emerged as a milestone in MM treatment [ 48 ]. BCMA, also known as TNFRSF17, is a member of the tumor necrosis factor receptor (TNFR) superfamily, which binds B-cell activating factor (BAFF) and a proliferation-inducing ligand (APRIL), activating the NF-κB signaling pathway and, consequently, playing a key role in B-cell maturation and differentiation [ 49 , 50 ]. BCMA is mainly expressed on mature B cell surfaces, leading to the survival of long-lived PCs, with minimal expression on other hematopoietic and non-hematopoietic cells and overexpression in MM cells [ 50 , 51 ]. Moreover, BCMA expression increases as the disease progresses, making it a promising therapeutic target [ 48 ].

Considering these findings, two new anti-BCMA immunotherapeutic approaches have emerged: CAR-T cells and BsAbs. The results of the main clinical trials are shown in Table 2 .

Among anti-BCMA CAR-T cells, idecabtagene vicleucel (ide-cel or bb2121) and ciltacabtagene autoleucel (cilta-cel or JNJ-4528), both with the 4-1BB co-stimulation domain, showed encouraging results in phase 2 and 1b/2 studies for RRMM patients, thus leading to their approval in clinical practice [ 52 , 53 , 54 ]. In the KarMMa and CARTITUDE-1 trials, the ORR was approximately 73% and 98%, with a high rate of CR and MRD-negativity (CR: 33% and 83%, respectively; MRD-negativity in evaluable patients: 28% and 92%, respectively). Moreover, median PFS and OS were 8.8 months and 19.4 months in the KarMMa trial, respectively [ 50 ], and they were not reached in the updated analysis of the CARTITUDE-1 study (27-month PFS: 55%; 27-month OS: 70%) [ 54 ]. The most frequent adverse events with ide-cel and cilta-cel were cytokine release syndrome (CRS) (84% and 95%, respectively, mostly of grade 1–2) and hematological toxicity (91% and 96%, respectively, mostly of grade ≥ 3). The incidence of neurological toxicity associated with effector cells of the immune system (ICANS) was low (18% and 17%, respectively, only ≤3% of grade ≥ 3). The main differences in the safety profile between the two constructs were the onset time of CRS (1 day for ide-cel versus 7 days for cilta-cel) and a different kind of neurotoxicity with cilta-cel. This neurological adverse event was mainly characterized by polyneuropathy and movement disorders with a delayed median onset and resolution time (27 days and 75 days, respectively) compared to ICANS, which was observed in a small percentage of patients in the CARTITUDE-1 study (12%, of which 9% were grade ≥ 3) [ 54 ]. The pathogenic mechanism of this type of neurotoxicity is not yet fully understood, but it has been hypothesized to be related to the expression of BCMA in the basal ganglia [ 55 , 56 ].

These great results for RRMM patients (with at least 3 previous lines of therapy, including an IMiD, a PI, and an anti-CD38 monoclonal antibody) have laid the basis for further studies in earlier lines of therapy and disease setting, such as KarMMa-2 ( NCT03601078 ), KarMMa-3 ( NCT03651128 ), KarMMa-4 ( NCT04196491 ), CARTITUDE-2 ( NCT04133636 ), CARTITUDE-4 ( NCT04181827 ), CARTITUDE-5 ( NCT04923893 ), and CARTITUDE-6 ( NCT05257083 ) clinical trials.

The phase 3 KarMMa-3 trial focused on patients with RRMM who had previously undergone two to four treatment regimens, including IMiDs, PIs, and daratumumab, and were refractory to their last regimen. Participants were randomly assigned at a 2:1 ratio to receive either ide-cel or one of five standard treatment regimens [ 57 ]. The primary outcome measured was PFS. At a median follow-up of 18.6 months, the ide-cel group demonstrated a significantly longer PFS compared to those on standard regimens, with medians of 13.3 months versus 4.4 months, respectively ( p < 0.001). Treatment with ide-cel also led to a higher response rate, with an overall response rate (ORR) of 71% compared to 42% in the standard regimen group; the percentage achieving stringent complete response (sCR) or complete response (CR) was 39% versus 5%. Additionally, minimal residual disease (MRD) negativity was confirmed in 51 patients (20%) in the ide-cel group compared to just 1 patient (1%) in the standard regimen group. Cytokine release syndrome (CRS) occurred in 88% of the ide-cel-treated patients, primarily in grades 1 or 2 (83%), with grade 3 or higher events in 5% of patients, including two fatalities. Immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in 15% of patients, mostly in grades 1 or 2. The phase 3 CARTITUDE-4 trial targeted patients with multiple myeloma (MM) who were refractory to lenalidomide and had undergone one to three prior treatment lines. Participants were randomized to receive either cilta-cel or the physician’s choice of standard care deemed effective [ 58 ]. The primary endpoint assessed was progression-free survival (PFS). The results showed that cilta-cel significantly reduced the risk of PD or death compared to standard care (hazard ratio, 0.26; 95% confidence interval [CI], 0.18 to 0.38; p < 0.001). A higher proportion of patients in the cilta-cel group achieved a stringent complete response (sCR) or complete response (CR) compared to those in the standard care group (73.1% vs. 21.8%). Additionally, MRD negativity at any point during the study was observed in 60.6% of cilta-cel patients versus 15.6% of standard-care patients. Cytokine release syndrome (CRS) occurred in 76.1% of cilta-cel recipients, mostly in grades 1 or 2. CAR-T cell-related neurotoxic events were reported in 20.5% of patients, with one instance of grade 1 movement and neurocognitive adverse events. Cranial nerve palsies predominantly affecting cranial nerve VII occurred in 16 patients (9.1%), and CAR-T-related peripheral neuropathies were noted in 5 patients (2.8%). Recently, other anti-BCMA CAR-T cell products have been studied [ 59 , 60 ]. Orvacabtagene autoleucel (orva-cel) has been investigated in the phase 1/2 EVOLVE study ( NCT03430011 ) for patients with RRMM: the most common adverse events were hematologic toxicities and CRS (any grade), with an ORR of 92% for all dose groups (≥VGPR: 68%) [ 61 ]. Bb21217, like ide-cel cultured with a PI3K inhibitor to enrich for T cells with memory-like phenotype, is under evaluation for heavily pretreated patients with RRMM in the ongoing first-in-human phase 1 CRB-402 trial ( NCT03274219 ) with promising and updated safety and efficacy data for durable response [ 62 ]. FHVH33-CD8BBZ, Zevorcabtagene autoleucel (Zevor-cel, CT053), and P-BCMA-101 are novel anti-BCMA CAR-T therapies studied in phase 1/2 clinical trials [ 63 , 64 , 65 ]. Additional strategies include dual CAR-T cells targeting both BCMA and CD19 ( NCT04236011 ; NCT04182581 ) [ 66 ].

Bispecific antibodies are another strategy of active immunotherapy thanks to their double antigenic specificity, which promotes cell-to-cell interaction. In fact, their mechanism of action is based on the binding between the CD3 antigen, mostly expressed by T lymphocytes, and a surface antigen expressed by MM neoplastic cells, creating an immunological synapse. This cellular interaction leads to the activation of T cells in the immune system independently of antigen presentation on the major histocompatibility complex (MHC) class 1, which releases substances, including granzyme B and perforins, subsequently initiating the apoptotic cascade within the neoplastic PC and resulting in cell death. This class of drugs has demonstrated high efficacy in terms of ORR, ranging from 65% to 79%, with a manageable safety profile [ 10 , 67 , 68 , 69 , 70 ].

The first anti-BCMA BsAb entering clinical practice is teclistamab, due to the promising results of the MajesTEC-1 phase 1/2 trial ( NCT03145181 , NCT04557098 ): at the dose of 1.5 mg/kg once a week, the ORR was 63% (≥VGPR: 59%) and the median PFS was 11 months for heavily pretreated MM patients (triple-refractory: 78%, penta-refractory: 30%), without unexpected adverse events (CRS, mostly of grade 1–2: 72%; hematological toxicity: 71%, grade ≥ 3: 65%; infections: 76%, grade ≥ 3: 45%; ICANS: 5%, grade ≥ 3: <1%) [ 69 , 70 , 71 , 72 ]. Recently, results from the MajesTEC-1 study’s cohort C were also reported, evaluating teclistamab in patients previously exposed to anti-BCMA therapy: once again, the responses were profound (ORR 53%, ≥VGPR: 48%), with a toxicity profile similar to that of the general study population, supporting the use of teclistamab even for patients who had relapsed after anti-BCMA targeted treatments [ 73 ]. Considering these results from the MajesTEC-1 trial, teclistamab as a single agent has been approved by the FDA and EMA for RRMM. Ongoing studies are evaluating teclistamab, both in earlier stages of the disease ( NCT04722146 or MajesTEC-2, NCT05083169 or MajesTEC-3, NCT05243797 or MajesTEC-4 or EMN30, NCT05695508 or MajesTEC-5, NCT05552222 or MajesTEC-7, NCT05572515 or MajesTEC-9, NCT05849610 or GEM-TECTAL, NCT05231629 or MASTER-2, NCT05572229 or IFM2021-01, NCT05469893 or immune-PRISM) and in combination with other MoAbs, including daratumumab ( NCT04108195 or TRIMM-2) and talquetamab ( NCT04586426 or RedirecTT-1, TRIMM-2, NCT05338775 or TRIMM-3).

Elranatamab is another humanized IgG-like bispecific antibody targeting BCMA × CD3, evaluated in the phase 1 dose-finding and expansion MagnetisMM-1 trial ( NCT03269136 ) in a setting of heavily pretreated patients with RRMM, showing as a single agent or in combination with lenalidomide or pomalidomide a high ORR (70%, ≥CR 30%), with a CRS rate of 83% (all grade 1–2) [ 74 ]. The phase 2 MagnetisMM-3 trial ( NCT04649359 ) further supported the preliminary safety and efficacy data of elranatamab. This study reported results from cohort A, which included patients who had not previously received BCMA-directed therapy, totaling 123 participants [ 75 ]. The primary endpoint of a confirmed ORR was successfully achieved with an ORR of 61.0% and 35.0% of patients reaching CR or better, as assessed by a blinded independent central review. Among the responders, 50 transitioned from weekly to biweekly dosing, with 40 (80.0%) maintaining or improving their response for six months or longer. At a median follow-up of 14.7 months, the median durations of response, PFS, and OS had not yet been reached. The fifteen-month rates for the duration of response, PFS, and OS were 71.5%, 50.9%, and 56.7%, respectively. The most common adverse events included infections (69.9% any grade, 39.8% grade 3–4), CRS (57.7%, all grades 1–2), and ICANS (3.4%, all grades 1–2), highlighting a manageable safety profile. Based on these positive results, elranatamab as a single agent has been approved by the FDA and EMA for RRMM. Elranatamab is currently evaluated in several clinical studies, both in combination with other therapeutic agents and in earlier stages of the disease ( NCT05090566 or MagnetisMM-4, NCT03269136 , NCT05020236 or MagnetisMM-5, NCT05623020 or MagnetisMM-6, NCT05317416 or MagnetisMM-7, NCT05014412 or MagnetisMM-9, NCT05675449 or MagnetisMM-20, NCT05927571 ) [ 76 ].

Other anti-BCMA BsAbs under investigation are linvoseltamab ( NCT03761108 , NCT05730036 , NCT05137054 , NCT05955508 ), ABBV383 ( NCT03933735 ), alnuctamab ( NCT03486067 ) and HPN217 ( NCT04184050 ) [ 77 , 78 , 79 , 80 , 81 ].

3.2. T Cell Redirecting Therapy Targeting Non-BCMA Antigens

The increasingly extensive use of anti-BCMA therapies, even in the early stages of the disease, has opened the debate on what the optimal choice should be at the time of relapse. Therefore, new alternative targets to BCMA, such as G protein-coupled receptor, family C, group 5, member D (GPRC5D), and Fc receptor homolog 5 (FcRH5), have been studied, with promising data even in the setting of patients who have already received anti-BCMA therapy ( Table 2 ).

Novel therapeutic anti-GPRC5D strategies, such as CAR-T cells and the first-in-class BsAb talquetamab, showed great efficacy with acceptable toxicity [ 82 , 83 , 84 , 85 ]. Regarding talquetamab, the updated results from the phase 1/2 MonumenTAL-1 trial ( NCT03399799 / NCT04634552 ) showed a high and rapid ORR in the pivotal cohorts (74%, ≥VGPR: 59% at the dose of 405 μg/kg; 73%, ≥VGPR: 57% at the dose of 800 μg/kg), as well as in patients who had received prior T cell redirecting therapy (63%, ≥VGPR: 53%), without new safety concerns [ 83 , 86 ]. Based on these positive results, talquetamab as a single agent has been approved by the FDA and EMA for RRMM. Talquetamab is currently explored in further clinical studies ( NCT04586426 or RedirecTT-1, TRIMM-2, NCT05050097 or MonumenTAL-2, NCT05455320 or MonumenTAL-3, NCT05461209 or MonumenTAL-5, NCT05338775 or TRIMM-3, the previously mentioned MajesTEC-7 and GEM-TECTAL). Forimtamig (RG6234) is a novel T cell-redirecting bispecific antibody designed to bind CD3 on T cells and GPRC5D on plasma cells [ 87 , 88 , 89 ]. It features a distinctive 2:1 (GPRC5D:CD3) configuration, which is theorized to enhance its potency compared to a conventional 1:1 configuration. This dual-binding mechanism facilitates the targeted destruction of plasma cells by T cells. Preclinical studies have shown that forimtamig effectively kills all tested GPRC5D+ MM cell lines. Additionally, in an autologous ex vivo model using total bone marrow aspirates from newly diagnosed MM patients, forimtamig demonstrated increased cytotoxic effectiveness. A phase 1 clinical trial ( NCT04557150 ) is currently in progress to further investigate its efficacy and safety. The humanized bispecific antibody FcRH5 × CD3 cevostamab has been developed and studied in vivo in an ongoing phase 1 dose-finding trial ( NCT03275103 ). Preliminary efficacy data showed promising results in heavily pre-treated patients (ORR: 57%, ≥VGPR: 33% at the target dose of 132–198 mg) with a good safety profile (CRS: 81%, mostly of grade 1–2 with early resolution within 48 h in 85% of patients) [ 90 ]. Additional studies with cevostamab, both as monotherapy and in combination with other anti-MM agents, are currently ongoing ( NCT04910568 or CAMMA 1, NCT05801939 , NCT05535244 or CAMMA 2, NCT05646836 , NCT05583617 or PLYCOM, NCT05927571 ).

4. Discussion

Currently, ASCT remains the standard of care for NDMM patients eligible for high-dose chemotherapy. Improved response rates and PFS were obtained thanks to the incorporation of anti-CD38 monoclonal antibodies in the frontline setting. The striking efficacy of the new T cell redirecting therapies has raised the question of where to place them in the treatment algorithm of NDMM. About this debate, there are several ongoing studies evaluating the role of ASCT in the era of immunotherapy ( Table 3 ). Particularly, these clinical trials should answer some open issues: will ASCT remain the first-line choice for young and fit patients compared to CAR-T cell therapy? Will integrating immunotherapy Yes I agree into transplantation, such as consolidation with CAR-T cells or maintenance with BsAbs, increase the rate of MRD-negativity and, consequently, improve survival?

The phase 1 KarMMa-4 trial ( NCT04196491 ) explores the optimal target dose and the safety profile of ide-cel in high-risk NDMM patients. The two phase 3 studies, CARTITUDE-5 ( NCT04923893 ) and CARTITUDE-6 ( NCT05257083 ) are planned to evaluate the efficacy of cilta-cel in patients with NDMM. Particularly, the CARTITUDE-6 trial compares CAR-T cell therapy versus ASCT after induction with D-VRd in transplant-eligible NDMM patients. Another phase ½ study ( NCT01352286 ) is evaluating the role of engineered T cell immunotherapy as a consolidation strategy after ASCT for high-risk MM patients [ 91 ].

The phase 2 MajesTEC-5 trial ( NCT05695508 ) is recruiting NDMM patients to evaluate the safety and tolerability of teclistamab both as induction therapy in combination with VRd and D-VRd and as maintenance therapy post-ASCT. The phase 3 MajesTEC-4 study ( NCT05243797 or EMN30) is exploring the use of teclistamab as maintenance after ASCT. Among the MRD-driven multi-cohort MASTER-2 study ( NCT05231629 ) MRD-positive NDMM patients will receive teclistamab plus daratumumab as post-ASCT consolidation and maintenance. Again, the ongoing phase 3 MagnetisMM-7 study ( NCT05317416 ) investigates elranatamab versus lenalidomide as maintenance after ASCT [ 92 ]. The phase 2 GEM-TECTAL ( NCT05849610 ) study will assess the efficacy and safety of teclistamab and talquetamab combined with daratumumab in de novo high-risk MM in both transplant-eligible and -ineligible patients.

5. Conclusions

The field of immunotherapy in MM is rapidly evolving, with an impressive number of ongoing clinical trials. Considering the latest data, active immunotherapy with CAR-T cells and BsAbs will soon revolutionize the therapeutic landscape of MM; thus, the state-of-the-art frontline treatment, including the transplant program, is expected to change in the next few years. Indeed, considering on one hand both the acute toxicities of HDM, such as hematologic and gastrointestinal toxicity, infections, and the long-term toxicities, such as secondary neoplasms [ 93 ], and considering also the significant increase in deep responses with quadruplet induction therapy and the great results of CAR-T cells and BsAbs treatment (see Table 2 ), it is likely that in the near future HDM-ASCT will be deferred or reserved for selected cases, leading to a risk- and a response-adapted therapy, improving the patient’s quality of life and survival.

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.

Conflicts of Interest

Rocchi S. declares the following conflicts of interest: Amgen, Pfizer, GSK, BMS, Sanofi; Zannetti, B.A. and Marconi, G. declare no conflicts of interest; Lanza, F. declares the following conflicts of interest: Pfizer, Amgen, Abvvie, Sobi.

References

1. Bazarbachi A.H. Al Hamed R. Malard F. Bazarbachi A. Harousseau J.L. Mohty M. Induction therapy prior to autologous stem cell transplantation (ASCT) in newly diagnosed multiple myeloma: An update Blood Cancer J. 2022 12 47 10.1038/s41408-022-00645-1 35347107 PMC8960754

2. Goel U. Usmani S. Kumar S. Current approaches to management of newly diagnosed multiple myeloma Am. J. Hematol. 2022 97 (Suppl. S1) S3 S25 10.1002/ajh.26512 35234302

3. Perrot A. How I treat frontline transplantation-eligible multiple myeloma Blood 2022 139 2882 2888 10.1182/blood.2020008735 34788422

4. Dimopoulos M.A. Moreau P. Terpos E. Mateos M.V. Zweegman S. Cook G. Delforge M. Hájek R. Schjesvold F. Cavo M. EHA Guidelines Committee. Multiple myeloma: EHA-ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up Ann. Oncol. 2021 32 309 322 10.1016/j.annonc.2020.11.014 33549387

5. Dimopoulos M.A. Moreau P. Terpos E. Mateos M.V. Zweegman S. Cook G. Delforge M. Hájek R. Schjesvold F. Cavo M. Multiple Myeloma: EHA-ESMO Clinical Practice Guidelines for Diagnosis, Treatment and Follow-up Hemasphere 2021 5 e528 10.1097/HS9.0000000000000528 33554050 PMC7861652

6. Mohan M. Hari P. Dhakal B. Immunotherapy in Multiple Myeloma-Time for a Second Major Paradigm Shift JCO Oncol. Pract. 2021 17 405 413 10.1200/OP.21.00032 34003675

7. Holstein S.A. Grant S.J. Wildes T.M. Chimeric Antigen Receptor T-Cell and Bispecific Antibody Therapy in Multiple Myeloma: Moving Into the Future J. Clin. Oncol. 2023 41 4416 4429 10.1200/JCO.23.00512 37471687 PMC10522112

8. Galluzzi L. Vacchelli E. Bravo-San Pedro J.M. Buqué A. Senovilla L. Baracco E.E. Bloy N. Castoldi F. Abastado J. Agostinis P. Classification of current anticancer immunotherapies Oncotarget 2014 5 12472 12508 10.18632/oncotarget.2998 25537519 PMC4350348

9. Lakshman A. Kumar S.K. Chimeric antigen receptor T-cells, bispecific antibodies, and antibody-drug conjugates for multiple myeloma: An update Am. J. Hematol. 2022 97 99 118 10.1002/ajh.26379 34661922

10. Lancman G. Sastow D.L. Cho H.J. Jagannath S. Madduri D. Parekh S.S. Richard S. Richter J. Sanchez L. Chari A. Bispecific Antibodies in Multiple Myeloma: Present and Future Blood Cancer Discov. 2021 2 423 433 10.1158/2643-3230.BCD-21-0028 34661161 PMC8510808

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. Snowden J.A. Sánchez-Ortega I. Corbacioglu S. Basak G.W. Chabannon C. de la Camara R. Dolstra H. Duarte R.F. Glass B. Greco R. for the European Society for Blood and Marrow Transplantation (EBMT). Indications for haematopoietic cell transplantation for haematological diseases, solid tumours and immune disorders: Current practice in Europe, 2022 Bone Marrow Transplant. 2022 57 1217 1239 10.1038/s41409-022-01691-w 35589997 PMC9119216

13. Mohty M. Hübel K. Kröger N. Aljurf M. Apperley J. Basak G.W. Bazarbachi A. Douglas K. Gabriel I. Garderet L. Autologous haematopoietic stem cell mobilisation in multiple myeloma and lymphoma patients: A position statement from the European Group for Blood and Marrow Transplantation Bone Marrow Transplant. 2014 49 865 872 10.1038/bmt.2014.39 24686988

14. Lonial S. Bowser A.D. Chari A. Costello C. Krishnan A. Usmani S.Z. Expert Consensus on the Incorporation of Anti-CD38 Monoclonal Antibody Therapy Into the Management of Newly Diagnosed Multiple Myeloma Clin. Lymphoma Myeloma Leuk. 2023 23 815 824 10.1016/j.clml.2023.07.001 37516547

15. Devasia A.J. Lancman G.S. Stewart A.K. Management of Newly Diagnosed Multiple Myeloma Today, and in the Future Hematol. Oncol. Clin. N. Am. 2024 38 441 459 10.1016/j.hoc.2023.12.007 38171937

16. Overdijk M.B. Verploegen S. Bögels M. van Egmond M. van Bueren J.J.L. Mutis T. Groen R.W. Breij E. Martens A.C. Bleeker W.K. Antibody-mediated phagocytosis contributes to the anti-tumor activity of the therapeutic antibody daratumumab in lymphoma and multiple myeloma mAbs 2015 7 311 321 10.1080/19420862.2015.1007813 25760767 PMC4622648

17. Krejcik J. Casneuf T. Nijhof I.S. Verbist B. Bald J. Plesner T. Syed K. Liu K. van de Donk N.W.C.J. Weiss B.M. Daratumumab depletes CD38+ immune regulatory cells, promotes T-cell expansion, and skews T-cell repertoire in multiple myeloma Blood 2016 128 384 394 10.1182/blood-2015-12-687749 27222480 PMC4957162

18. Dimopoulos M.A. Oriol A. Nahi H. San-Miguel J. Bahlis N.J. Usmani S.Z. Rabin N. Orlowski R.Z. Suzuki K. Plesner T. Overall Survival with Daratumumab, Lenalidomide, and Dexamethasone in Previously Treated Multiple Myeloma (POLLUX): A Randomized, Open-Label, Phase III Trial J. Clin. Oncol. 2023 41 1590 1599 10.1200/JCO.22.00940 36599114 PMC10022849

19. Sonneveld P. Chanan-Khan A. Weisel K. Nooka A.K. Masszi T. Beksac M. Spicka I. Hungria V. Munder M. Mateos M.V. Overall Survival with Daratumumab, Bortezomib, and Dexamethasone in Previously Treated Multiple Myeloma (CASTOR): A Randomized, Open-Label, Phase III Trial J. Clin. Oncol. 2023 41 1600 1609 10.1200/JCO.21.02734 36413710 PMC10022857

20. Facon T. Kumar S.K. Plesner T. Orlowski R.Z. Moreau P. Bahlis N. Basu S. Nahi H. Hulin C. et. al. 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

21. 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

22. San-Miguel J. Avet-Loiseau H. Paiva B. Kumar S. Dimopoulos M.A. Facon T. Mateos M.V. Touzeau C. Jakubowiak A. Usmani S.Z. Sustained minimal residual disease negativity in newly diagnosed multiple myeloma and the impact of daratumumab in MAIA and ALCYONE Blood 2022 139 492 501 10.1182/blood.2020010439 34269818 PMC8796656

23. Moreau P. Attal M. Hulin C. Arnulf B. Belhadj K. Benboubker L. Béné M.C. Broijl A. Caillon H. Caillot D. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): A randomised, open-label, phase 3 study Lancet 2019 394 29 38 10.1016/S0140-6736(19)31240-1 31171419

24. Moreau P. Hulin C. Perrot A. Arnulf B. Belhadj K. Benboubker L. Béné M.C. Zweegman S. Caillon H. Caillot D. Maintenance with daratumumab or observation following treatment with bortezomib, thalidomide, and dexamethasone with or without daratumumab and autologous stem-cell transplant in patients with newly diagnosed multiple myeloma (CASSIOPEIA): An open-label, randomised, phase 3 trial Lancet Oncol. 2021 22 1378 1390 10.1016/S1470-2045(21)00428-9 34529931

25. Voorhees P.M. Kaufman J.L. Laubach J.P. Sborov D.W. Reeves B. Rodriguez C. Chari A. Silbermann R. Costa L.J. Anderson L.D. Jr. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: The GRIFFIN trial Blood 2020 136 936 945 10.1182/blood.2020005288 32325490 PMC7441167

26. Voorhees P.M. Sborov D.W. Laubach J. Kaufman J.L. Reeves B. Rodriguez C. Chari A. Silbermann R. Costa L.J. Anderson L.D. Addition of daratumumab to lenalidomide, bortezomib, and dexamethasone for transplantation-eligible patients with newly diagnosed multiple myeloma (GRIFFIN): Final analysis of an open-label, randomised, phase 2 trial Lancet Haematol. 2023 10 e825 e837 10.1016/S2352-3026(23)00217-X 37708911

27. Sonneveld P. Dimopoulos M.A. Boccadoro M. Quach H. Ho P.J. Beksac M. Hulin C. Antonioli E. Leleu X. Mangiacavalli S. Daratumumab, Bortezomib, Lenalidomide, and Dexamethasone for Multiple Myeloma N. Engl. J. Med. 2024 390 301 313 10.1056/NEJMoa2312054 38084760

28. Costa L.J. Chhabra S. Medvedova E. Dholaria B.R. Schmidt T.M. Godby K.N. Silbermann R. Dhakal B. Bal S. Giri S. Minimal residual disease response-adapted therapy in newly diagnosed multiple myeloma (MASTER): Final report of the multicentre, single-arm, phase 2 trial Lancet Haematol. 2023 10 e890 e901 10.1016/S2352-3026(23)00236-3 37776872 PMC10836587

29. Moreno L. Perez C. Zabaleta A. Manrique I. Alignani D. Ajona D. Blanco L. Lasa M. Maiso P. Rodriguez I. The Mechanism of Action of the Anti-CD38 Monoclonal Antibody Isatuximab in Multiple Myeloma Clin. Cancer Res. 2019 25 3176 3187 10.1158/1078-0432.CCR-18-1597 30692097

30. Attal M. Richardson P.G. Rajkumar S.V. San-Miguel J. Beksac M. Spicka I. Leleu X. Schjesvold F. Moreau P. Dimopoulos M.A. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): A randomised, multicentre, open-label, phase 3 study Lancet 2019 394 2096 2107 10.1016/S0140-6736(19)32556-5 31735560

31. Richardson P.G. Perrot A. San-Miguel J. Beksac M. Spicka I. Leleu X. Schjesvold F. Moreau P. Dimopoulos M.A. Huang J.S.-Y. Isatuximab plus pomalidomide and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed and refractory multiple myeloma (ICARIA-MM): Follow-up analysis of a randomised, phase 3 study Lancet Oncol. 2022 23 416 427 10.1016/S1470-2045(22)00019-5 35151415

32. Moreau P. Dimopoulos M.-A. Mikhael J. Yong K. Capra M. Facon T. Hajek R. Baker R. Kim K. Martinez G. Isatuximab, carfilzomib, and dexamethasone in relapsed multiple myeloma (IKEMA): A multicentre, open-label, randomised phase 3 trial Lancet 2021 397 2361 2371 10.1016/S0140-6736(21)00592-4 34097854

33. Martin T. Dimopoulos M.-A. Mikhael J. Yong K. Capra M. Facon T. Hajek R. Spicka I. Baker R. Kim K. Isatuximab, carfilzomib, and dexamethasone in patients with relapsed multiple myeloma: Updated results from IKEMA, a randomized Phase 3 study Blood Cancer J. 2023 13 72 10.1038/s41408-023-00797-8 37156782 PMC10166682

34. Goldschmidt H. Mai E.K. Bertsch U. Fenk R. Nievergall E. Tichy D. Besemer B. Dürig J. Schroers R. von Metzler I. Addition of isatuximab to lenalidomide, bortezomib, and dexamethasone as induction therapy for newly diagnosed, transplantation-eligible patients with multiple myeloma (GMMG-HD7): Part 1 of an open-label, multicentre, randomised, active-controlled, phase 3 trial Lancet Haematol. 2022 9 e810 e821 10.1016/S2352-3026(22)00263-0 36328040

35. 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

36. Lanza F. Saccardi R. Seghatchian J. New Horizons on stem cell cryopreservation through the artificial eyes of CD 34+, using modern flow cytometry tools Transfus. Apher. Sci. 2020 59 102785 10.1016/j.transci.2020.102785 32340812

37. Lanza F. Marchetti M. Zannetti B.A. Overview on novel strategies and current guidelines for hematopoietic stem cell mobilisation and collection Transfus. Apher. Sci. 2023 62 103830 10.1016/j.transci.2023.103830 37867056

38. Zannetti B.A. Saraceni F. Cellini C. Fabbri E. Monaco F. Guarini A. Laszlo D. Martino M. Olivieri A. Imola M. Low Dose Cyclophosphamide versus Intermediate-High Dose Cyclophosphamide versus G-CSF alone for Stem Cell Mobilization in Multiple Myeloma in the Era of Novel Agents: A Multicenter Retrospective Study Transplant. Cell Ther. 2021 27 244.e1 244.e8 10.1016/j.jtct.2020.12.009 33781522

39. Seth A. Murray D. Buadi F.K. Gertz M.A. Yadav U. Kumar S.K. Gonsalves W.I. Failure of mobilization of hematopoietic stem cells associated with elevated serum levels of anti-CD38 monoclonal antibody Eur. J. Haematol. 2023 111 318 321 10.1111/ejh.14008 37209032 PMC10524502

40. Ma X. Wong S.W. Zhou P. Chaulagain C.P. Doshi P. Klein A.K. Sprague K. Kugelmass A. Toskic D. Warner M. Daratumumab binds to mobilized CD34+ cells of myeloma patients in vitro without cytotoxicity or impaired progenitor cell growth Exp. Hematol. Oncol. 2018 7 27 10.1186/s40164-018-0119-4 30356940 PMC6192105

41. Zappaterra A. Civettini I. Cafro A.M. Pezzetti L. Pierini S. Anghilieri M. Bellio L. Bertazzoni P. Grillo G. Minga P. Anti-CD38 monoclonal antibody impairs CD34+ mobilization and affects clonogenic potential in multiple myeloma patients Blood Transfus 2024 ahead of print 10.2450/BloodTransfus.667 PMC11251823 38315530

42. Hulin C. Offner F. Moreau P. Roussel M. Belhadj K. Benboubker L. Caillot D. Facon T. Garderet L. Kuhnowski F. Stem cell yield and transplantation in transplant-eligible newly diagnosed multiple myeloma patients receiving daratumumab + bortezomib/thalidomide/dexamethasone in the phase 3 CASSIOPEIA study Haematologica 2021 106 2257 2260 10.3324/haematol.2020.261842 33657786 PMC8327738

43. Chhabra S. Callander N. Watts N.L. Costa L.J. Thapa B. Kaufman J.L. Laubach J. Sborov D.W. Reeves B. Rodriguez C. Stem Cell Mobilization Yields with Daratumumab- and Lenalidomide-Containing Quadruplet Induction Therapy in Newly Diagnosed Multiple Myeloma: Findings from the MASTER and GRIFFIN Trials Transplant. Cell Ther. 2023 29 e1 e174 10.1016/j.jtct.2022.11.029 36494017

44. Sauer S. Hieke L. Brandt J. Müller-Tidow C. Schmitt A. Kauer J. Kriegsmann K. Impact of Clinical Parameters and Induction Regimens on Peripheral Blood Stem-Cell Mobilization and Collection in Multiple Myeloma Patients Transfus. Med. Hemother. 2023 50 382 395 10.1159/000530056 37899996 PMC10601599

45. Papaiakovou E.E. Terpos E. Kanellias N. Migkou M. Gavriatopoulou M. Ntanasis-Stathopoulos I. Fotiou D. Malandrakis P. Theodorakakou F. Spiliopoulou V. Impact of daratumumab on stem cell mobilization and collection, engraftment and early post-transplant complications among multiple myeloma patients undergoing autologous stem cell transplantation Leuk. Lymphoma. 2023 64 2140 2147 10.1080/10428194.2023.2253479 37655597

46. Thurlapati A. Roubal K. Davis J.A. Shah S.Z. Smith D. McGann M. Gaffney K. Cendagorta A. Maldonado A. Weeda E. Stem Cell Mobilization for Multiple Myeloma Patients Receiving Daratumumab-Based Induction Therapy: A Real- World Experience Transplant. Cell Ther. 2023 29 340.e1 340.e4 10.1016/j.jtct.2023.02.013 36804934

47. Kauer J. Freundt E.P. Schmitt A. Weinhold N. Mai E.K. Müller-Tidow C. Goldschmidt H. Raab M.S. Kriegsmann K. Sauer S. Stem cell collection after lenalidomide, bortezomib and dexamethasone plus elotuzumab or isatuximab in newly diagnosed multiple myeloma patients: A single centre experience from the GMMG-HD6 and -HD7 trials BMC Cancer 2023 23 1132 10.1186/s12885-023-11507-9 37990162 PMC10664363

48. Kleber M. Ntanasis-Stathopoulos I. Terpos E. BCMA in Multiple Myeloma—A Promising Key to Therapy J. Clin. Med. 2021 10 4088 10.3390/jcm10184088 34575199 PMC8472544

49. 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

50. Novak A.J. Darce J.R. Arendt B.K. Harder B. Henderson K. Kindsvogel W. Gross J.A. Greipp P.R. Jelinek D.F. Expression of BCMA, TACI, and BAFF-R in multiple myeloma: A mechanism for growth and survival Blood 2004 103 689 694 10.1182/blood-2003-06-2043 14512299

51. Shah N. Chari A. Scott E. Mezzi K. Usmani S.Z. B-cell maturation antigen (BCMA) in multiple myeloma: Rationale for targeting and current therapeutic approaches Leukemia 2020 34 985 1005 10.1038/s41375-020-0734-z 32055000 PMC7214244

52. 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

53. 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

54. Martin T. Usmani S.Z. Berdeja J.G. Agha M. Cohen A.D. Hari P. Avigan D. Deol A. Htut M. Lesokhin A. Ciltacabtagene Autoleucel, an Anti-B-cell Maturation Antigen Chimeric Antigen Receptor T-Cell Therapy, for Relapsed/Refractory Multiple Myeloma: CARTITUDE-1 2-Year Follow-Up J. Clin. Oncol. 2023 41 1265 1274 10.1200/JCO.22.00842 35658469 PMC9937098

55. Van Oekelen O. Aleman A. Upadhyaya B. Schnakenberg S. Madduri D. Gavane S. Teruya-Feldstein J. Crary J.F. Fowkes M.E. Stacy C.B. Neurocognitive and hypokinetic movement disorder with features of parkinsonism after BCMA-targeting CAR-T cell therapy Nat. Med. 2021 27 2099 2103 10.1038/s41591-021-01564-7 34893771 PMC8678323

56. Cohen A.D. Parekh S. Santomasso B.D. Pérez-Larraya J.G. van de Donk N.W.C.J. 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

57. 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

58. San-Miguel J. Dhakal B. Yong K. Spencer A. Anguille S. Mateos M.-V. de Larrea C.F. Martinez-Lopez 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

59. Manier S. Ingegnere E. Escure G. Prodhomme C. Nudel M. Mitra S. Facon T. Current state and next-generation CAR-T cells in multiple myeloma Blood Rev. 2022 54 100929 10.1016/j.blre.2022.100929 35131139

60. Mishra A.K. Gupta A. Dagar G. Das D. Chakraborty A. Haque S. Prasad C.P. Singh A. Bhat A.A. Macha M.A. CAR-T-Cell Therapy in Multiple Myeloma: B-Cell Maturation Antigen (BCMA) and Beyond Vaccines 2023 11 1721 10.3390/vaccines11111721 38006053 PMC10674477

61. Mailankody S. Jakubowiak A.J. Htut M. Costa L.J. Lee K. Ganguly S. Kaufman J.L. Siegel D.S. Bensinger W. Cota M. Orvacabtageneautoleucel (orva-cel), a B-cell maturation antigen (BCMA)-directed CAR T cell therapy for patients (pts) with relapsed/refractory multiple myeloma (RRMM): Update of the phase 1/2 EVOLVE study ( NCT03430011 ) J. Clin. Oncol. 2020 38 (Suppl. S15) 8504 10.1200/JCO.2020.38.15_suppl.8504

62. Alsina M. Shah N. Raje N.S. Jagannath S. Madduri D. Kaufman J.L. Siegel D.S. Munshi N.C. Updated Results from the Phase I CRB-402 Study of Anti-Bcma CAR-T Cell Therapy bb21217 in Patients with Relapsed and Refractory Multiple Myeloma: Correlation of Expansion and Duration of Response with T Cell Phenotypes Blood 2020 136 25 26 10.1182/blood-2020-140410

63. Mikkilineni L. Manasanch E.E. Natrakul D. Weissler K. Brudno J.N. Mann J. Goff S.L. Yang J.C. Lam N. Maric I. T Cells Expressing a Fully-Human Anti-BCMA Chimeric Antigen Receptor with a Heavy-Chain-Only Antigen-Recognition Domain Exhibit Rapid and Durable Activity Against Multiple Myeloma Blood 2022 140 7433 7434 10.1182/blood-2022-159156

64. Chen W. Fu C. Fang B. Liang A. Xia Z. He Y. Lu J. Liu H. Hou M. Cai Z. Phase II Study of Fully Human BCMA-Targeting CAR-T Cells (Zevorcabtagene Autoleucel) in Patients with Relapsed/Refractory Multiple Myeloma Blood 2022 140 4564 4565 10.1182/blood-2022-168610

65. Costello C.L. Cohen A.D. Patel K.K. Ali S.S. Berdeja J.G. Shah N. Ganguly S. Kocoglu M.H. Abedi M. Ostertag E.M. Phase 1/2 Study of the Safety and Response of P-BCMA-101 CAR-T Cells in Patients with Relapsed/Refractory (r/r) Multiple Myeloma (MM) (PRIME) with Novel Therapeutic Strategies Blood 2020 136 (Suppl. S1) 29 30 10.1182/blood-2020-142695

66. Du J. Fu W. Jiang H. Dong B. Gao L. Liu L. Ge J. He A. Li L. Lu J. Updated results of a phase I, open-label study of BCMA/CD19 dual-targeting fast CAR-T GC012F for patients with relapsed/refractory multiple myeloma (RRMM) J. Clin. Oncol. 2023 41 8005 10.1200/JCO.2023.41.16_suppl.8005

67. Hosny M. Verkleij C.P.M. van der Schans J. Frerichs K.A. Mutis T. Zweegman S. van de Donk N.W.C.J. Current State of the Art and Prospects of T Cell-Redirecting Bispecific Antibodies in Multiple Myeloma J. Clin. Med. 2021 10 4593 10.3390/jcm10194593 34640611 PMC8509238

68. Topp M.S. Duell J. Zugmaier G. Attal M. Moreau P. Langer C. Krönke J. Facon T. Salnikov A.V. Lesley R. Anti-B-Cell Maturation Antigen BiTE Molecule AMG 420 Induces Responses in Multiple Myeloma J. Clin. Oncol. 2020 38 775 783 10.1200/JCO.19.02657 31895611

69. Usmani S.Z. Garfall A.L. van de Donk N.W.C.J. Nahi H. San-Miguel J.F. Oriol A. Rosinol L. Chari A. Bhutani M. Karlin L. Teclistamab, a B-cell maturation antigen × CD3 bispecific antibody, in patients with relapsed or refractory multiple myeloma (MajesTEC-1): A multicentre, open-label, single-arm, phase 1 study Lancet 2021 398 665 674 10.1016/S0140-6736(21)01338-6 34388396

70. Moreau P. Garfall A.L. van de Donk N.W. 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

71. Moreau P. van de Donk N.W.C.J. Nahi H. Oriol A. Nooka A.K. Martin T. Rosinol L. Karlin L. Benboubker L. Mateos M.V. Plain language summary of the MajesTEC-1 study of teclistamab for the treatment of people with relapsed or refractory multiple myeloma Future Oncol. 2023 19 811 818 10.2217/fon-2023-0171 37492991

72. Martin T.G. Mateos M.V. Nooka A. Banerjee A. Kobos R. Pei L. Qi M. Verona R. Doyle M. Smit J. Detailed overview of incidence and management of cytokine release syndrome observed with teclistamab in the MajesTEC-1 study of patients with relapsed/refractory multiple myeloma Cancer 2023 129 2035 2046 10.1002/cncr.34756 36991547

73. Touzeau C. Krishnan A. Moreau P. Perrot A. Usmani S.Z. Manier S. Cavo M. Martinez-Chamorro C. Nooka A.K. Martin T. Evaluating Teclistamab in patients with relapsed/refractory Multiple Myeloma following exposure to other B-Cell Maturation Antigen (BCMA)-Targeted agents HemaSphere 2022 6 85 86 10.1097/01.HS9.0000843628.63947.e4

74. 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

75. Lesokhin A.M. Tomasson M.H. Arnulf B. Bahlis N.J. Prince H.M. 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

76. Grosicki S. Yeh S.P. Huang S.Y. Byun J.M. DiRienzo C. Viqueira A. MagnetisMM-6: A phase 3 study of Elranatanab + Daratumumab + Lenalidomide vs Daratumumab + Lenalidomide + Dexamethasone in transplant ineligible patients with Newly Diagnosed Multiple Myeloma J. Clin. Oncol. 2023 41 TPS8065 10.1200/JCO.2023.41.16_suppl.TPS8065

77. Jagannath S. Richter J. Dhodapkar M.V. Hoffman J.E. Lee H. Suvannasankha A. Shah M.R. Lentzsch S. Zonder J.A. Baz R. Patterns of Response to 200 Mg Linvoseltamab in Patients with Relapsed/Refractory Multiple Myeloma: Longer Follow-Up of the Linker-MM1 Study Blood 2023 142 4746 10.1182/blood-2023-177968

78. Rodriguez-Otero P. Mateos M.V. Aina O. Sinha A. Steele A.J. Hazra A. Rodriguez Lorenc K. Kroog G.S. Sarkaria S.M. San Miguel J. Trial in Progress: A Phase 2 Study of Linvoseltamab for the Treatment of High-Risk Smoldering Multiple Myeloma (LINKER-SMM1) Blood 2023 142 3393 10.1182/blood-2023-179356

79. Vij R. Kumar S.K. D’Souza A. Mckay J.T. Voorhees P.M. Chung A. Tuchman S.A. Korde N. Weisel K. Teipel R. Updated Safety and Efficacy Results of Abbv-383, a BCMA x CD3 Bispecific T-Cell Redirecting Antibody, in a First-in-Human Phase 1 Study in Patients with Relapsed/Refractory Multiple Myeloma Blood 2023 142 3378 10.1182/blood-2023-182388

80. Bar N. Mateos M.V. Ribas P. Hansson M. Paris L. Hofmeister C.C. Rodriguez Otero P. Aranzazu Bermúdez M. Martin T. Santoro A. Alnuctamab (ALNUC.; BMS-986349; CC-93269), a 2+1 B-Cell Maturation Antigen (BCMA) × CD3 T-Cell Engager (TCE), Administered Subcutaneously (SC) in Patients (Pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from a Phase 1 First-in-Human Clinical Study Blood 2023 142 (Suppl. S1) 2011

81. Madan S. Costello C.L. Lipe B. Cowan A.J. Medvedova E. Hillengass J. Bergsagel P.L. Leleu X. Touzeau C. Morillo D. Results from the Completed Dose Escalation Portion of the Phase 1 Study of HPN217, a Half-Life Extended Tri-Specific T Cell Activating Construct (TriTAC ® ) Targeting B Cell Maturation Antigen (BCMA) for Relapsed/Refractory Multiple Myeloma (MM) Blood 2023 142 (Suppl. S1) 1012 10.1182/blood-2023-182345

82. 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

83. 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

84. Zhang M. Wei G. Zhou L. Zhou J. Chen S. Zhang W. Wang D. Luo X. Cui J. Huang S. 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 e107 e116 10.1016/S2352-3026(22)00372-6 36725117

85. Rodriguez-Otero P. van de Donk N.W.C.J. Pillarisetti K. Cornax I. Vishwamitra D. Gray K. Hilder B. Tolbert J. Renaud T. Masterson T. GPRC5D as a novel target for the treatment of multiple myeloma: A narrative review Blood Cancer J. 2024 14 24 10.1038/s41408-023-00966-9 38307865 PMC10837198

86. Jakubowiak A.J. Anguille S. Karlin L. Chari A. Schinke C. Rasche L. San-Miguel J. Campagna M. Hilder B.W. Masterson T.J. Updated Results of Talquetamab, a GPRC5D×CD3 Bispecific Antibody, in Patients with Relapsed/Refractory Multiple Myeloma with Prior Exposure to T-Cell Redirecting Therapies: Results of the Phase 1/2 MonumenTAL-1 Study Blood 2023 142 (Suppl. S1) 3377 10.1182/blood-2023-187242

87. Hasselbalch Riley C. Hutchings M. Yoon S.-S. Koh Y. Manier S. Facon T. Harrison S.J. Er J. Volzone F. Pinto A. S180: RG6234, a novel GPRC5D T-cell engaging bispecific antibody, induces rapid responses in patients with relapsed /refractory multiple myeloma: Preliminary results from a first-in-human trial HemaSphere 2022 6 81 82 10.1097/01.HS9.0000843612.41180.42

88. Carlo-Stella C. Mazza R. Manier S. Facon T. Yoon S.-S. Koh Y. Harrison S.J. Er J. Pinto A. Volzone F. RG6234, a GPRC5DxCD3 T-Cell Engaging Bispecific Antibody, Is Highly Active in Patients (pts) with Relapsed/Refractory Multiple Myeloma (RRMM): Updated Intravenous (IV) and First Subcutaneous (SC) Results from a Phase I Dose-Escalation Study Blood 2022 140 (Suppl. S1) 397 399 10.1182/blood-2022-157988

89. Dekhtiarenko I. Lelios I. Jacob E. Schneider M. Weisser M. Carlo-Stella C. Manier S. Harrison S.J. Popat R. Hasselbalch Riley A.C. MD8* Co-Expression of GPRC5D, FcRH5 and BCMA Suggests That Targeting More Than One Cell Surface Marker May be a Viable Strategy in Relapsed/Refractory Multiple Myeloma (RRMM): Biomarker Results from the Phase I Study of Forimtamig, a GPRC5DxCD3 Bispecific Antibody Blood 2023 142 1948

90. Trudel S. Cohen A.D. Krishnan A.Y. Fonseca R. Spencer A. Berdeja J.G. Lesokhin A. Forsberg P.A. Laubach J.P. Costa L.J. Cevostamab Monotherapy Continues to Show Clinically Meaningful Activity and Manageable Safety in Patients with Heavily Pre-Treated Relapsed/Refractory Multiple Myeloma (RRMM): Updated Results from an Ongoing Phase I Study Blood 2021 138 157 10.1182/blood-2021-147983

91. Stadtmauer E.A. Faitg T.H. Lowther D.E. Badros A.Z. Chagin K. Dengel K. Iyengar M. Melchiori L. Navenot J.M. Norry E. Long-term safety and activity of NY-ESO-1 SPEAR T cells after autologous stem cell transplant for myeloma Blood Adv. 2019 3 2022 2034 10.1182/bloodadvances.2019000194 31289029 PMC6616263

92. Mateos M.V. Grosicki S. Kim K. Negre E. Vandendries E. MagnetisMM-7: An open-label, multicenter, randomized phase 3 study of Elranatanab versus Lenalidomide in post-transplant patients with Newly Diagnosed Multiple Myeloma J. Clin. Oncol. 2023 41 TPS8066 10.1200/JCO.2023.41.16_suppl.TPS8066

93. Mo C.C. Hartley-Brown M.A. Midha S. Richardson P.G. Upfront or Deferred Autologous Stem Cell Transplantation for Newly Diagnosed Multiple Myeloma in the Era of Triplet and Quadruplet Induction and Minimal Residual Disease/Risk-Adapted Therapy Cancers 2023 15 5709 10.3390/cancers15245709 38136255 PMC10741557