Anti-BCMA CAR-T cell-based therapies and bispecific antibodies in the immunotherapy era: are we ready for this?

ABSTRACT

Introduction

Therapeutic strategies against multiple myeloma (MM) have evolved dramatically in recent decades, with unprecedent results in the treatment landscape, culminating in the recent incorporation of novel agents in the anti-myeloma armamentarium.

Areas covered

BCMA represents one of the most promising targets in MM and currently available immune approaches, either approved or under active investigation, are clearly showing their greater potential over standard regimens. In this context, immunotherapies based on chimeric antigen receptor (CAR)-engineered T-cells and bispecific antibodies (BsAbs) have taken center stage, being the ones that are yielding the most promising results in clinical trials. This review focuses on the current landscape of BsAbs and CAR-T, summarizing the latest advances and possible future developments.

Expert opinion

CAR-T and BsAbs anti-BCMA strategies represent breakthrough therapies against MM. However, their inclusion in clinical practice is almost feared, due to the associated limitations, some of which have been addressed here. Meanwhile, all the efforts should be focused on individualizing and choosing the most suitable candidates for each treatment and to understand how to combine, or sequence, these therapies to improve efficacy and minimize toxicity, especially for those patients with limited available treatment options.

KEYWORDS:

• B-cell maturation antigen
• bispecific antibodies
• chimeric antigen receptor T cells therapy
• immunotherapy
• multiple myeloma

1. Introduction

Multiple myeloma (MM) is a clonal plasma cell malignancy accounting for approximately 10% of hematological cancers and 0.9% of all cancers, with an age-standardized incidence of 2.1/100,000 among men and 1.4/100,000 among women [1–3].

In recent decades, the therapeutic landscape has evolved dramatically to include new strategies and treatment approaches, aiming at affording enhanced rates and depth of durable responses. Early advances were established in the 1990s with the introduction of high dose melphalan followed by autologous stem cell transplantation (ASCT). Subsequently, new insights in the biology of the disease led to the discovery of new pathways and targets, culminating in a further expansion and widespread use of new and more effective agents, including proteasome inhibitors (PIs), immunomodulatory drugs (IMiDs), and monoclonal antibodies (MoAbs). The integration of improved diagnostic methods and innovative treatments based on combination therapies and a sequential treatment approach has ensured a significant improvement in the treatment of MM over time, maximizing the depth of response, minimizing residual tumor cells, preventing, or delaying, recurrence, and increasing progression-free survival (PFS) and overall survival (OS). However, patients with MM inevitably relapse and require further treatments, with progressively shorter durations of remission, lesser responses after relapse, and development of treatment resistance [4–6]. Particularly, triple-class exposed (TCE) and penta-refractory patients with relapsed/refractory MM (RRMM) (i.e. received at least a PI, IMiD, and anti-CD38 mAb, or refractory to the two IMiDs lenalidomide and pomalidomide, the two PIs bortezomib and carfilzomib, and the anti-CD38 MoAb daratumumab, respectively) have rapid disease progression after salvage therapy and are characterized by poor prognosis with currently available treatments, with a median PFS (mPFS) of approximately 4.5 months and median OS (mOS) slightly higher than 1 year, stressing the need for alternative and more efficacious therapeutic strategies [6].

B-cell Maturation Antigen (BCMA) is a cell surface protein highly expressed on the surface of MM cell that has emerged as a promising target for MM therapy [7–11]. Notably, BCMA overexpression increases with disease progression and pathogenesis, and BCMA level is considered a negative prognostic marker: the higher BCMA levels, the poorer the outcomes. At present, several therapeutic agents targeting BCMA are under development and various immunotherapeutic strategies, including BCMA-directed MoAb, antibody-drug conjugates, cellular therapy with chimeric antigen receptor (CAR)-engineered T-cell, or bispecific antibodies (BsAbs), are under active investigation worldwide, or have already granted approval by the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) in specific settings, paving the way for an immunotherapy era in MM. Hopefully, emerging anti-BCMA therapies will expand the antimyeloma armamentarium in the near future, with the incorporation of modern treatments that may escape resistance to currently available therapies. In this review, we described the main immunotherapeutic approaches targeting BCMA in MM and reviewed the most recent advancements from ongoing clinical trials to compare limitations and strengths of the major anti-BCMA treatment strategies.

2. Anti-BCMA therapies: CAR-T and BsAbs

Among the most common treatment strategies targeting BCMA, immunotherapies based on CAR-T cells and BsAbs have taken center stage, being the ones that are yielding the most promising and clinically effective results in recent clinical trials. Both these strategies are characterized by a novel mechanism of action based on the activation and redirection of the T-cell compartment of patients’ immune system against neoplastic plasma cells (PCs). Indeed, T-cell activation leads to the release of granzyme B and perforins, which, in turn, lead to the activation of the apoptotic cascade in the neoplastic cells [12,13].

The following paragraphs will describe more in detail the structure and mechanism of action of the main CAR-Ts and BsAbs directed against the BCMA antigen, summarizing the latest advances from clinical trials in the field.

2.1. Anti-BCMA CAR-T therapies

Cellular immunotherapy with engineered T-cells expressing a chimeric antigen receptor (CAR) is a breakthrough strategy widely investigated in the management of various hematologic malignancies, including MM. This innovative strategy is based on the manipulation of patients’ CD3 T lymphocytes to replace the physiological T-Cell Receptor (TCR) with a CAR, with the intention of combining the antigen recognition capabilities of an antibody with the anti-tumor effector action of T lymphocytes, in a manner independent from the major histocompatibility complex (MHC).

First-generation CAR-Ts were thus constructed by combining an extracellular region deputed to antigen recognition, represented by a single chain of the variable region of a monoclonal antibody, with an ζ-chain of the intracellular TCR deputed to signal transduction, joined by an intermediate (hinge) region and a transmembrane region. Although first-generation CAR-Ts have been effective in inducing cytotoxicity, they have not been shown to be as capable of expanding and activating in response to repeated antigen exposure, resulting in a lack of clinical response [14]. To overcome this failure, an attempt was made to introduce a co-stimulation domain in this structural pattern, such as CD28 or 4-1BB [TNFRS9, also known as CD137], thereby allowing CAR-T cells to proliferate and expand in response to repeated exposure to the same antigen by developing the concept of the ‘living-drug’ [15]. These second-generation CAR-Ts have led to the most impressive clinical results achieved so far, determining the approval of autologous CD19-targeting CAR-T cells for the treatment of B-cell malignancies including acute lymphocytic leukemia and diffuse large B-cell lymphoma. As for MM, two second-generation anti-BCMA CAR-T constructs are currently approved by regulatory agencies for the use in heavily pretreated patients: idecabtagene vicleucel and ciltacabtagene autoleucel.

Idecabtagene vicleucel (ide-cel; bb2121, Bristol Myers Squibb, BMS), is composed of autologous T cells transfected with a lentiviral vector for the expression of a murine anti-BCMA fragment, a 4-1BB co-stimulatory domain, and a CD3 activation motif. Thanks to results deriving from the phase II KarMMa trial (NCT03361748) [16], involving patients who had already received at least 3 prior lines of therapy including an IMiD, a PI, and an anti-CD38 monoclonal antibody, ide-cel was approved in the United States for patients with RRMM after exposure to ≥4 prior lines of therapy and granted conditional approval in the European Union for patients with RRMM who received ≥3 therapies and progressed on their last therapy. Results from the KarMMa trial showed an ORR of 73% (complete response, CR, or better: 33%), 8.8 months of disease-free survival (PFS), and 19.4 months of OS in heavily pretreated MM patients [16]. The toxicity profile was characterized by cytokine release syndrome (CRS, 84%, only 5% of grade ≥3), with a median time to onset of 1 day, immune effector cell-associated neurotoxicity syndrome (ICANS, 18%, only 3% of grade ≥3), cytopenia and hypogammaglobulinemia (21%). Hematologic toxicity was mostly of severe grade, with neutropenia in 91% of cases (89% of grade ≥3), anemia in 70% (60% of grade ≥3) and thrombocytopenia in 63% (52% of grade ≥3). Among patients with neutropenia or thrombocytopenia of grade ≥3, the median time to recovery (grade <3) was 2 and 3 months, respectively. In addition, 41% and 48% of patients had delayed recovery of neutropenia and thrombocytopenia (>1 month). Cytopenia and hypogammaglobulinemia were found to be an infectious risk factor: infections occurred in 69% of patients (only 22% grade ≥3) [16]. The excellent results observed in the KarMMa trial [16,17] overall translated into a glimmer of hope for those patients still in remission more than 2 years after ide-cel infusion, who paused from any kind of treatment for the first time in many years, when all previous therapies had failed. As the first CAR T-cell product approved for myeloma, ide-cel is therefore poised to become a practice-changing treatment option, especially for patients relapsing after exposure to the all three major classes of therapy (IMiD, PI, and mAb), also referred to as triple-class refractory patients.

Meanwhile, results on an earlier use of ide-cel in triple-class exposed RRMM patients who have received 2 to 4 prior lines of therapy in the phase 3 KarMMa-3 study (NCT03651128) were recently published, confirming the clinical benefit and significant superiority in terms of response rate, PFS, and minimal residual disease (MRD) negativity, as compared to standard anti-MM regimens [18]. Indeed, ide-cel exposed patients in the KarMMa-3 study showed a significant longer PFS (13.8 vs 4.4 months, respectively) and a higher percentage of patients with a response than standard-regimen-treated patients (71% vs 42%, with 44% vs 6% of complete response or better, respectively) [19]. Comparison had to be chosen among daratumumab (D) associated to pomalidomide and dexamethasone or bortezomib and dexamethasone (DPd, DVd), ixazomib coupled with lenalidomide and dexamethasone (IxaRd), carfilzomib and dexamethasone (Kd), or elotuzumab combined with pomalidomide and dexamethasone (EloPd), as long as the elected treatment was different from the last regimen in use before the trial. Notably, the PFS benefit with a single infusion of ide-cel therapy was consistently observed over time (73% vs 40% at 6 months, 55% vs 30% at 12 months and 41% vs 19% at 18 months for ide-cel and standard-regimen group, respectively), while ide-cel safety profile was consistent with previous studies [16,17,19]. Median time to response was 2.9 months with ide-cel and 2.1 months with standard regimens, while median DOR (mDOR) was 16.6 months vs 9.7 months, respectively [19]. Consistently, MRD-negative CR rate was confirmed in 35% of patients treated with ide-cel and 2% among patients in the standard-regimen group [19]. These data have been further confirmed in a secondary analysis on high-risk patients, in which ide-cell showed a clear superiority in terms of ORR, CR, and significant longer PFS over standard regimens across all high-risk subgroups analyzed, including those with high tumor burden (ORR: 65 vs 53%, ≥CR: 31 vs 9%, mPFS: 11.0 vs 4.9 months, respectively) and triple-class refractory patients (ORR: and 64 vs 31%; ≥CR: and 34 vs 1%, mPFS: and 11.2 vs 3.5 months, respectively) [20]. Ide-cel efficacy and safety profile was also confirmed independently of previous number of lines of therapy, albeit efficacy was greater when administered in earlier lines of therapy, supporting the use in patients with less refractory disease [21]. The impact of bridging therapies was also assessed, showing that decreasing the tumor burden is an important aspect to increase efficacy in TCE RRMM (97% ORR, 56% ≥CR and nearly 2 years mPFS in patients who decreased disease burden vs 56% ORR, 32% ≥CR and 6.9 months mPFS when disease worsened upon bridging therapy) [22].

In line with these results, available data on a modified bb2121 product aimed at enriching the final CAR product of memory-like CAR-T cells through the addition of the phosphoinositide 3-kinase (PI3K) inhibitor bb007 (leading to the so-called bb21217) are encouraging, as outlined in the phase I dose escalation CRB-402 (NCT03274219) study, albeit longer follow-up and larger population of patients are needed to establish whether treatment with bb21217 may result in sustained CAR+ T cell persistence and responses [23,24]. Further studies, whose results are eagerly awaited, will tell us more about the role of bb2121 in RRMM patients with fewer prior therapy lines characterized by worse prognosis, such as unsatisfactory response after ASCT, as in the case of the phase 3 KarMMa-9 trial (NCT06045806), comparing the efficacy and safety of ide-cel with lenalidomide maintenance with respect to lenalidomide maintenance therapy alone. In addition, early progression from previous treatment has been addressed in the phase 2 KarMMa-2 trial (NCT03601078, Cohort 2), evaluating bb2121 as second-line treatment in early relapse or suboptimal responders after first-line of therapy, while the efficacy of ide-cel in high-risk NDMM (defined as R-ISS stage III (ISS stage III [serum ß2 microglobulin ≥5.5 mg/L] and cytogenetic abnormalities t(4;14), del(17p), and/or t(14;16) by interphase FISH; or ISS stage III and serum LDH > ULN) upon 3 cycles of standard induction regimen, is being addressed in the phase I KarMMa-4 (NCT04196491) trial.

On the other hand, ciltacabtagene autoleucel (cilta-cel, JNJ-68284528, or JNJ-4528, formerly developed in China as LCAR-B38M) presents two different heavy-chain variable domains recognizing separate epitopes of BCMA antigens and has recently received both FDA and EMA approval in clinical practice, basing on the promising results from the phase Ib/II CARTITUDE-1 study (NCT03548207) [25]. This pilot study showed an ORR of 97% (67% deep responses were sCR, median time 1 month) in a population of patients who had received 3 or more prior lines of therapy (including IMiD, PI, and anti-CD38 Ab) or refractory to at least one IMiD and one PI (double refractory) [26]. Recently, updated data with a longer observation period up to about 2 years [26] and results after almost 3 years [27] from treatment confirmed 98% ORR after a single infusion of cilta-cel in RRMM patients, with an improvement in response over time (response rate of sCR: 83%); mPFS was 34.9 months (estimated 47.5% progression-free and alive at 36 months), while mOS was not reached (estimated 62.9% survival at 36 months) [28]. These efficacy results on patients who are naïve to anti-BCMA therapy are in line with the 4-year follow-up data of LEGEND-2 (NCT03090659) trial, showing a favorable long-term safety profile and a durable response in patients with RRMM treated with cilta-cel [29]. In case of previous exposure to BCMA-targeting therapies, results from the CARTITUDE-2 cohort C suggest that a large proportion (60%) of patients may still respond to cilta-cel, with mDOR of 12.3 months and mPFS of 9.1 months (8.2 and 5.3 months after treatment with BsAbs, respectively) [30]: a proper patient selection and treatment sequencing may contribute to enhance the response rate further. Additionally, cohorts A and B of the CARTITUDE-2 trial showed efficacy even at earlier stages of the disease, with response rates of 95% (90% CR, or more) in lenalidomide-refractory MM patients exposed to 1–3 prior lines of therapy [31] and 100% in patients who failed initial therapy, respectively [32,33]. Similar to ide-cel, the main adverse events associated with the use of cilta-cel in CARTITUDE-1 were found to be CRS (95%, only 4% of grade ≥3), albeit at a later onset than ide-cel (median time to onset: 7 days), ICANS (17%, only 2% of grade ≥3), cytopenia and infections (58%, of which 20% were of grade ≥3) [25]. Of note, in the CARTITUDE-1 trial, a type of neurotoxicity other than ICANS occurred in a small percentage of patients (12%, of which 9% were grade ≥3), all with previous CRS, characterized mainly by polyneuropathy and movement disorders: the etiopathogenetic mechanism is not yet fully known, but was hypothesized to be related to BCMA expression in the basal ganglia of the nuclei [34]. This neurotoxicity, unlike ICANS, showed a very late median time of onset and resolution (27 and 75 days, respectively) [34]. No new safety signals and no additional neurotoxicity events were reported upon 27.7-months of follow-up [27]. Coherently with ide-cel, severe hematologic toxicities were frequent; specifically, grade 3/4 hematologic adverse events included neutropenia (96%), anemia (68%), thrombocytopenia (60%), lymphopenia (50%), and leukopenia (61%). However, time to recover was faster (median: 1 month) than the one reported in the KarMMa trial; also, the percentage of patients with prolonged (>1 month) neutropenia and thrombocytopenia was lower (11% and 26% for cilta-cel vs 41% and 48% reported for ide-cel, respectively) [35]. Notably, lower rates of cytopenia, CRS, and CAR-T – related neurotoxicity were observed when cilta-cel was administered in earlier treatment, thereby suggesting that a use of cilta-cel at earlier stages might be accompanied by a better safety profile [36].

Against this background, the recently published impressive results of the phase III CARTITUDE-4 (NCT04181827), comparing cilta-cel with conventional treatments (PVd: pomalidomide + bortezomib + dexamethasone; or DPd: daratumumab + pomalidomide + dexamethasone) in RRMM should not come as much of a surprise, though exceeding any expectation, thereby emphasizing the potential of using of cilta-cel in MM already at first relapse. At a median follow-up of 15.9 months the CARTITUDE-4 trial showed a significantly lower risk (hazard ratio, 0.26) of disease progression, or death, in the experimental arm than standard-care receiving patients, in which the median duration of PFS (not reached in the cilta-cel arm) was 11.8 months. In the intention-to-treat population, 12-months PFS was 75.9% in the cilta-cel group and 48.6% in the standard-care group, independently of the regimen used (i.e. DPd or PVd), with 73.1% and 21.8% of patients achieving a complete response or better (ORR being 84.6% and 67.3), and MRD-negativity found in 60.6% vs 15.6%, respectively [36]. Additional analysis in subgroups of patients who have indicators of poor prognosis, such as high-risk cytogenetics, soft tissue plasmacytomas, ISS stage III and prior triple-class exposure, confirmed high rates of PFS at 12 months [37]. With these promising findings, it is conceivable that the application for approval in early lines of therapy may be on the way.

Future developments based on the results of CARTITUDE-5 (NCT04923893) and CARTITUDE-6 (NCT05257083) trials in NDMM patients, comparing the efficacy of cilta-cel after bortezomib, lenalidomide and dexamethasone (VRd) induction vs VRd induction followed by Rd maintenance in participants for whom ASCT is not planned as initial therapy (CARTITUDE-5), and of cilta-cel following D-VRd induction vs D-VRd followed by ASCT in transplant-eligible naïve MM patients (CARTITUDE-6), will provide additional insights into the use of JNJ-4528 in earlier phases of the disease, but the very recent data available are so encouraging as to justify an application for authorization as a new therapeutic indication soon.

The promising efficacy demonstrated by both ide-cel and cilta-cel has triggered fervent clinical research with other products almost everywhere in the world, and research with numerous CAR-T cell-based products with different constructs and mechanisms of action, targets, and application settings, as listed in Table 1, are underway. As an instance, durcabtagene autoleucel (PHE885, Durca-cel, Novartis) is an autologous, fully human, BCMA-directed CAR T-cell therapy composed of a significantly greater proportion of naive-like memory T-cells (CCR7+/CD45RO-) and its administration has been explored in the phase 1 CADPT07A12101 (NCT04318327) in adult MM participants relapsed and/or refractory to at least 2 or 3 prior treatment regimens (in escalation and expansion cohorts, respectively), with 97% of ORR (41% of CR, or better) and high MRD-negativity rates, with similar safety profile to that seen in other CAR-T studies [38]. Interestingly, this product relies on a T-Charge platform for manufacturing, that reduces time for production and preserves T-cells stemness, while granting a rapid and robust expansion, with a peak on day 14, and durable persistence in vivo after 1 year post administration, along with sBCMA suppression [38,39]. Further evaluations are underway in the phase II CPHE885B12201 (NCT05172596) trial, enrolling RRMM who have failed three or more lines of therapy (including an IMiD, a PI and an anti-CD38 agent), and evaluation in earlier lines of therapy is set to begin.

Table 1. Anti-BCMA CAR-T cell clinical trials.

CAR-T product	Clinical trial	Phase	Therapy	MM population	Status of the trial
Idecabtagene Vicleucel (bb2121)	NCT02658929 (CRB-401)	1	bb2121 (150–450 × 10^6 CAR+ T cells)	RRMM ≥3 lines	Completed
	NCT03361748 (KarMMa)	2	bb2121	RRMM ≥3 lines	Active, not recruiting
	NCT03601078 (KarMMa-2)	2	bb2121	HR*-RRMM	Active, not recruiting
	NCT03651128 (KarMMa-3)	3	Bb2121 vs standard regimen (DPd, DVd, Ixa-Rd, Kd, or EloPd)	RRMM 2–4 lines	Active, not recruiting
	NCT04196491 (KarMMa-4)	1	bb2121	HR*-NDMM	Active, not recruiting
	NCT06045806 (KarMMa-9)		ide-cel + lena vs lena	NDMM	Recruiting
	KarMMa-8°			RRMM 1–3 Lines	Upcoming
bb21217	CRB-402 (NCT03274219)	1	bb21217	RRMM ≥3 lines	Active, not recruiting
Ciltacabtagene Autoleucel (JNJ-68284528, LCAR-B38M)	NCT03090659 (LEGEND-2)	1/2	LCAR-B38M CAR-T	RRMM ≥3 lines	Active, not recruiting
	NCT03548207 (CARTITUDE-1)	1b/2	JNJ-68284528	RRMM ≥3 lines	Active, not recruiting
	NCT03758417 (CARTIFAN-1)	2	LCAR-B38M CAR-T	RRMM ≥3 lines	Recruiting
	NCT04133636 (CARTITUDE-2)	2	Various cohorts administering cilta cel ± others (lena in D and E; D-VRd in E)	A: PD after 1–3 LOT B: Early relapse after 1^st line C: TCE and anti-BCMA RRMM D: suboptimal responders after ASCT E: HR-NDMM TNP F: SR-NDMM	Active, not recruiting
	NCT05201781 (CARTINUE)	4	Cilta-cel	long-term study of CARTITUDE-1 enrolled pts	Recruiting
	NCT04181827 (CARTITUDE-4)	3	Cilta-cel vs Dara-VD/PD	RRMM 1–3 lines	Active, not recruiting
	NCT04923893 (CARTITUDE-5)	3	VRD + Cilta-cel vs VRD + RD	TNP MM Unfit patients	Recruiting
	NCT05257083 (CARTITUDE-6)	3	Dara-VRD + Cilta-cel vs Dara-VRD + ASCT	TNP MM	Recruiting
PHE885	CADPT07A12101 (NCT04318327)	1	PHE885	RRMM ≥3 lines	Recruiting
	NCT05172596	2	PHE885	RRMM ≥3 lines	Recruiting
CT053	NCT03975907 (LUMMICAR)	1/2	Zevor-cel (CT053)	RRMM ≥3 lines	Recruiting
	NCT03915184 (LUMMICAR-2)	1/2	Zevor-cel (CT053)	RRMM ≥3 lines	Active, not recruiting
JCARH125	NCT03430011 (EVOLVE)	1/2	JCARH125 ± anakinra	RRMM ≥3 lines	Active, not recruiting
CART-BCMA	NCT02546167	1	CART-BCMA	RRMM ≥3 lines	Completed
p-BCMA-101 (PRIME)	NCT03288493	1/2	p-BCMA-101	RRMM	Terminated (Phase 1 completed; Phase 2 early terminated)
CT103	ChiCTR1800018137	1	CT103A	RRMM	Active, not recruiting
	NCT05066646 (FUMANBA-1)	1/2	CT103A	RRMM ≥3 lines	Recruiting
	NCT05181501 (FUMANBA-2)	1	CT103A	HR-TNP MM	Not yet recruiting
MCARH171	NCT03070327	1	EGFRt/BCMA-41BBz ± Lena	RRMM ≥2 lines	Active, not recruiting
KITE-585	NCT03318861	1	KITE-585	RRMM ≥3 lines	Active, not recruiting
CART-ddBCMA	NCT04155749	1	A: CART-ddBCMA B: ARC-T + SPRX00	RRMM ≥3 lines	Recruiting
FasT CAR-T GC012F	NCT04236011	1	GC012F	RRMM ≥3 lines	Unknown
	NCT04182581	1	GC012F	RRMM ≥3 lines	Unknown
ALLO-715	NCT04093596 (UNIVERSAL)	1	ALLO-715 ± Nirogacestat	RRMM ≥3 lines	Active, not recruiting
BMS-986354	NCT04394650	1	CC-98633	RRMM ≥3 lines	Active, not recruiting
ARI0002h	NCT04309981	1/2	ARI0002h	RRMM ≥2 lines	Active, not recruiting

*High-risk defined as R-ISS Stage III per IMWG criteria.

°Registrational.

Abbreviations: ASCT: autologous stem cell transplantation; BCMA: B-cell maturation antigen; HR: high-risk; IMWG: International Myeloma Working Group; LOT: lines of therapy; MM: multiple myeloma; NDMM: newly diagnosed MM; PD: progressive disease; pts: patients; RRMM: relasped or refractory MM; SR: standard-risk; TCE: triple-class-exposed (including PI, IMiD and anti-CD38 agents); TNP: transplant not planned.

Furthermore, dual-targeting CARs have investigated various other antigens alongside BCMA. As an example, BCMA/CD19 Dual-Targeting CAR-T GC012F, whose manufacturing time is assessed in the range of 22–36 hours, exploiting the FasT platform, is showing promising results in RRMM patients (NCT04236011; NCT04182581 trials), with an ORR of 93.1% (sCR rate 82.8%), mPFS of 38.0 months and a mDoR of 37.0 months [40].

Other CAR-T products include CART-ddBCMA, consisting of autologous T cells genetically modified to express a 73 amino acid BCMA-binding domain (d-domain) able to induce BCMA-specific cytotoxicity in tumor cell lines. Results from the phase I study (NCT04155749) conducted in RRMM patients who were TCE or ‘triple-refractory’ following treatment with a PI, an IMiD, and anti-CD38 antibody (as part of the same or different regimens) showed a response rate of 100% across both dose levels (100 or 300 × 10⁶ CART-ddBCMA), ≥67% being CR or better in each dose level, along with a favorable toxicity profile, consistent with what has been observed previously in BCMA CAR T-cell trials [41].

In addition, results from the pilot study CARTBCMA-HCB-01 (NCT04309981), performed in five academic centers in Spain, on the use of ARI0002h (anti-BCMA CAR-T product developed by academia) showed deep and sustained responses in TCE RRMM patients. The ORR during the first 100 days from infusion among the 30/35 patients who received ARI0002h (administered as initial fractionated infusion of 3 × 10⁶ CAR T cells/kg and a non-fractionated booster dose after >3 months from the first infusion) was 100%, with 50% CR. These results were coupled with low toxicities, especially in terms of neurological events [42].

The next-generation CAR T-cell product BMS-986354, manufactured with a next generation process aimed at improving potency while reducing time of production, is being evaluated in the ongoing phase I CC-98633-MM-001 trial (NCT04394650). Initial results have shown BMS-986354 to have a favorable safety profile and promising efficacy in RRMM [43].

Notably, allogeneic CAR T cell therapy may present meaningful advantages over autologous CAR T products, including the ease of manufacturing and administration. In this sense, interim results from the ongoing phase I UNIVERSAL study (NCT04093596), evaluating escalating doses of ALLO-715 in heavily pretreated MM patients, are encouraging. This first-in-class, allogeneic, anti-BCMA CAR-T has been engineered to abrogate graft-versus-host disease and minimize CAR T rejection and initial results support the feasibility and safety of allogeneic CAR T cell therapy for myeloma, with an ORR of 55.8%, mDOR of 8.3 months, and a safety profile in line with other anti-BCMA autologous-targeted cell therapies [44].

Other anti-BCMA CAR T-cell products with different mechanism of action, are under development or being tested in preclinical and clinical models, as reviewed elsewhere [45,46]. Furthermore, natural killer (NK) cells may be valid alternatives for the production of ‘off-the-shelf’ CAR products, well tolerated and affordable as compared to CAR-T cells-based therapies [47]. However, fewer data have been so far reported and later studies will likely determine whether target other than BCMA may be more efficient for CAR-NK-based immunotherapy in MM [48].

Overall, data from clinical trials are heterogeneous and come from different products, patients, and settings. Despite results seem promising, suggesting a propensity for massive entry of CAR-T cell-based therapies in clinical practice soon, upcoming, or ongoing randomized trials are needed to assess whether a combinatorial, or ‘armored’ approach may be superior to single-BCMA targeting CAR-T products and, above all, to confirm sustained remissions in RRMM patients and/or efficacy as earlier treatment. More importantly, data on the use of CAR-T in real-life, with a broader use of these products in all MM patients with different baseline characteristics, comorbidities, and various grades of disease, are urgently needed to assess the real impact of these therapies in MM, but few data have been reported so far, overall showing comparable efficacy and safety outcomes with results observed in clinical trial settings, despite wider use in non-trial-eligible MM patients, thereby indicating that CAR T administration in the real world is feasible, safe, and effective, even among patients with comorbidities [49,50].

2.2. Anti-BCMA bispecific antibodies

Recently, the antibody strategies targeting BCMA have been enriched by the introduction of bispecific antibodies (BsAbs), artificially engineered antibodies able to bind two different antigens, that represent a novel therapeutic option for patients with MM [51]. Unlike monoclonal antibodies, specifically directed against a single antigen, BsAbs are designed to bind concomitantly a target on the malignant plasma cells and on cytotoxic immune effector cells, to facilitate an anti-tumor cytotoxic activity mediated by T-cells. Indeed, the creation of the immunologic synapse activates T cells, and this is followed by degranulation, granzymes and perforins release, and tumor cell lysis [52].

Several different structures have been made to design BsAbs and many of them have already been investigated in recent clinical trials. The first BsAbs were generated by conjugation of two different purified MoAbs [53], whereas recent advances in genetic engineering ensured the availability of new generation BsAbs for therapeutic and diagnostic applications. Overall, a major classification can be made on the presence, or absence, of a fragment-crystallizable (Fc) region. Among the BsAbs investigated in recent MM trials, IgG-like BiTEs® (Amgen, Thousand Oaks, CA, U.S.A.), consisting of two single-chain variable fragments (scFv) with unique antigen specificities, each consisting of a heavy chain and a light chain of the variable region, fused with a short flexible linker, and DuoBody® BsAbs (Genmab A/S, Copenhagen, Denmark) with a fragment antigen-binding (Fab) domain connected to a fragment-crystallizable (Fc) region can be counted. Although molecules lacking an Fc region can be easily modified to add another scFv (creating a trivalent molecule) and have been shown to easily penetrate tumors, due to their small size, the short half-life of this type of construct plagues patients with frequent, or continuous, infusions. On the contrary, the presence of the Fc region extends the half-life of the product and ensures less frequent dosing, supporting the decision to include an Fc region in the structure of most BsAbs under investigation.

To maximize their efficacy, BsAbs should be directed against MM-specific antigens, having minimal or no expression in healthy tissues, making BCMA the target of choice for MM patients, with about 10 different anti-BCMA BsAbs currently under active investigation, as listed in Table 2.

Table 2. Bispecific antibodies targeting T-cell and BCMA currently under investigation to treat MM.

BsAb name	Clinical trials	Phase	Therapy	MM population	Status of the trial
Teclistamab	NCT04557098 (MajesTEC-1)	1/2	Teclistamab SC/IV	RRMM ≥3 LOT	Recruiting
	NCT03145181 (MajesTEC-1)	1/2	Teclistamab SC/IV	RRMM ≥3 LOT	Recruiting
	NCT04696809(Japanese cohort)	1/2	Teclistamab SC	RRMM	Recruiting
	NCT04722146 (MajesTEC-2)	1	Tec + other tp: A: Tec-DP B: Tec-DRV (21-day) C: Tec-Niro D: Tec-lena E: Tec-DR F: Tec-DRV (28-day)	RRMM/NDMM	Active, not recruiting
	NCT05083169 (MajesTEC-3)	3	Tec-Dara vs DPd/DVd	RRMM	Active, not recruiting
	NCT05243797 (MajesTEC-4)	3	Tec vs lena Tec-lena vs lena	Maint in NDMM post ASCT	Recruiting
	NCT05695508 (MajesTEC-5)	2	A: Tec-DRd + Tec-DR (maint) B: Tec-DVRd + Tec-DR (maint) C: Tec-DR (maint)	NDMM TE	Recruiting
	NCT05552222 (MajesTEC-7)	3	Tec-DR/Tal-DR vs DRd	NDMM TNE	Recruiting
	NCT05572515 (MajesTEC-9)	3	Tec vs PVd/Kd	RRMM	Recruiting
	NCT05932680	2	Teclistamab (limited-duration regimen)	Pts ≥VGPR upon 6–9 mos teclistamab	Recruiting
	NCT05231629 (MASTER-2)	2	MRD-Guided Sequential Therapy	NDMM	Recruiting
	NCT05572229 (IFM 2021–01)	2	Tec-dara vs Tec-lena	NDMM (elderly MM, TNE)	Not yet recruiting
	NCT05469893 (Imuno-PRISM)	2	Tec vs lena-dex	SMM	Recruting
	NCT05338775 (TRIMM-3)*	1	Teclistamab + talquetamab (± PD-1 inhibitor)	RRMM	Recruiting
	NCT04586426 (RedirecTT-1)*	1b/2	Teclistamab + talquetamab (± dara)	RRMM	Recruiting
	NCT04108195* (TRIMM-2)	1b	Dara-Tec Dara-Tal Dara-Tec-poma Dara-Tal-poma	RRMM ≥3 LOT	Active, not recruiting
	NCT05849610 (GEM-TECTAL)*	2	Dara-VRD (ind) + Tec-dara (int) + Tec-dara (maint) + ERI Tal-dara	HR-NDMM	Recruting
Elranatamab	NCT03269136 (MagnetisMM-1)	1	Elranatamab IV vs SC	RRMM ≥3 LOT	Active, not recruiting
	NCT04798586 (MagnetisMM-2)	1	Elranatamab	RRMM ≥3 LOT	Active, not recruiting
	NCT04649359 (MagnetisMM-3)	2	Elranatamab	RRMM ≥3 LOT	Active, not recruiting
	NCT05090566 (MagnetisMM-4)	2	Elranatamab + Niro	RRMM ≥3 LOT	Recruiting
	NCT05020236 (MagnetisMM-5)	3	Elranatamab ± Dara vs Dara-Pd	RRMM 1–3 LOT (PI and lena based, no anti-CD38 refractory)	Recruiting
	NCT05623020 (MagnetisMM-6)	3	Elranatamab + DR ± dex	Part1: RRMM 1–2 LOT Part2: NDMM TNE	Recruiting
	NCT05317416 (MagnetisMM-7)	3	Elranatamab vs lena	NDMM (MRD+ after ASCT)	Recruiting
	NCT05228470 (MagnetisMM-8)	2	Elranatamab	RRMM ≥3 LOT	Active, not recruiting
	NCT05014412 (MagnetisMM-9)	2	Elranatamab ± dex	RRMM TCR	Active, not recruiting
	NCT05675449(MagnetisMM-20)	1	Elranatamab + Kd/Maplirpacept	RRMM ≥3 LOT	Recruiting
	NCT05927571 (GO43979)	1b	Cevostamab + Elranatamab	RRMM	Recruiting
Linvoseltamab (REGN 5458)	NCT03761108 (LINKER-MM1)	1/2	REGN 5458	RRMM ≥3 LOT	Recruiting
	NCT05137054	1	REGN5458+dara/K/lena/bort/poma/isa/REGN3767/cemiplimab/Niro	RRMM ≥2 LOT	Recruiting
	NCT05730036 (R5458-ONC-2245, LINKER-MM3)	3	REGN 5458 vs EloPd	RRMM 1–4 LOT	Recruiting
	NCT05828511 (LINKER-MM4)	1/2	REGN 5458	NDMM TE/TNE	Recruiting
REGN 5459	NCT04083534	1/2	REGN 5459	RRMM ≥3 LOT	Active, not recruiting
Pacanalotamab (AMG 420)	NCT02514239	1	AMG 420	RRMM ≥2 LOT	Recruitment completed
	NCT03836053	1	AMG 420	RRMM ≥3 LOT	Recruitment completed
Pavuratamab (AMG 701)	NCT03287908 (ParadigMM-1B)	1	AMG 701 ± poma ± dex	RRMM ≥3 LOT	Early termination°
TNB-383B	NCT03933735	1/2	TNB-383B	RRMM ≥3 LOT	Active, not recruiting
Alnuctamab (CC-93269)	NCT03486067	1	CC-93269	RRMM	Recruiting
ABBV-383	NCT05650632	1	ABBV-383	RRMM ≥3 LOT	Recruiting
	NCT05286229	1	ABBV-383	RRMM ≥3 LOT	Active, not recruiting
	NCT05259839 (M22–947)	1	ABBV-383 + Pd/Rd/Dd/Niro	RRMM	Recruiting
	NCT05650632	1b	ABBV-383	RRMM	Recruiting
RO729089	NCT04434469	1	RO7297089	RRMM	Recruitment Completed
WVT078	NCT04123418	1	WVT078 ± WHG626	RRMM ≥2 LOT	Active, not recruiting

*Trials including teclistamab (JNJ-64007957) and talquetamab (JNJ-64407564).

°Early termination of the study due to business decision, not safety reasons.

Abbreviations: ASCT: autologous stem cell transplantation; D, Dara: daratumumab; d, dex: dexamethasone; HR: high-risk; ind: induction; int: intensification; isa: isatuximab; elo: elotuzumab; IV: intravenously; K: carfilzomib; LOT: lines of therapy; maint: maintenance; MM: multiple myeloma; Mos: months; MRD: minimal residual disease; NDMM: newly diagnosed MM; Niro: nirogacestat; P, poma: pomalidomide; PD-1: Programmed cell death protein 1; Pts: patients; R, lena: lenalidomide; RRMM: relapsed/refractory MM; SC: subcutaneous; SMM: smoldering MM; Tal: talquetamab; TCR: triple-class refractory; TE: transplant-eligible; Tec: teclistamab; TNE: transplant-not eligible; tp: terapies; V, bort: bortezomib.

2.2.1. Teclistamab (JNJ-64007957)

Teclistamab (JNJ-64007957, Janssen), a full-size, immunoglobin G4 proline, alanine, alanine (IgG4-PAA) bispecific antibody targeting BCMA and the cluster of differentiation 3 (CD3) receptor, expressed on the surface of T cells, is the first BsAb approved as monotherapy for the treatment of adult patients with RRMM who are TCE and have received at least three (EMA) or four (FDA) previous therapies, including a PI, an IMiD and an anti-CD38 mAb, and who showed disease progression during the last therapy [54]. Conditional approval of teclistamab (24 August 2022) was based on the first-in-human phase I/II trial MajesTEC-1 (NCT04557098, NCT03145181) showing deep and durable responses in RRMM patients (77.6% of whom were triple-class refractory, 26% with high-risk cytogenetics and 17% having extramedullary disease, EMD), with an ORR of 63.0%, mostly achieving a very good partial response (VGPR), or better (≥CR found in 39.4% of patients, 46% of whom showing MRD-negativity). The median DOR and PFS were 18.4 and 11.3 months, respectively [55–57]. Dosing schedule of teclistamab is the recommended phase 2 dose (RP2D), consisting of 1.5 mg/kg by subcutaneous injection (SC) weekly, preceded by step-up doses of 0.06 mg/kg and 0.3 mg/kg, to reduce the incidence and severity of adverse events like CRS, until unacceptable toxicity or disease progression. As a further precaution, patients may be hospitalized during a step-up dosing window and should however be instructed to remain within proximity of a healthcare facility and monitored daily for signs and symptoms for 48 hours after drug administration, to reduce complications. Common adverse events associated with the use of teclistamab include CRS, neutropenia, anemia, and thrombocytopenia. Also, hypogammaglobulinemia and infections are frequent, while neurotoxic events comprise ICANS [55,56].

At present, investigation on the use of teclistamab after 1–3 prior lines of therapy in MM are under way and results in this setting are highly awaited, with a view to improving the therapeutic armamentarium in MM as early as the early stages of the disease. Moreover, several trials are currently ongoing to evaluate the efficacy and safety of teclistamab in combination with other agents [58]. Among these, the phase Ib MajesTEC-2 trial (NCT04722146) is evaluating the combination of teclistamab with bortezomib, daratumumab, pomalidomide, lenalidomide, and/or nirogacestat, while the phase Ib TRIMM-3 (NCT05338775) and RedirecTT-1 (NCT04586426) are exploring the anticancer activity mediated by the combination of teclistamab and talquetamab in participants with RRMM, aiming at overcoming mechanisms of resistance due to antigen escape. Of note, recent preliminary data on 63 heavily pretreated RRMM patients (5 prior median treatments) reported an ORR of 84% across all dose levels (92% at the recommended phase 2 regimen, RP2R, with 31% ≥CR), and 73% ORR (83% at the RP2R ≥ CR 33%) in the proportion of patients (43%) with EMD, demonstrating the feasibility of combining two BsAbs directed against two different targets and suggesting that this combination deserves further study in patients with high-risk EMD, for whom treatment options are currently limited [59]. Further details on this combination in high-risk NDMM may be added in the future by the GEM-TECTAL (NCT05849610) trial. In parallel, phase Ib TRIMM-2 study (NCT04108195) is evaluating safety and antitumor activity of teclistamab associated with daratumumab, with or without pomalidomide, and early results seem to support the addition of daratumumab for the treatment of triple- and penta-refractory MM patients, with durable and deepened over time responses [60]. However, when administering teclistamab in combination with other agents, the risk of infective toxicity should be considered. Indeed, hypogammaglobulinemia may commonly occur when teclistamab is combined with daratumumab and the administration of intravenous immunoglobulin (IVIG) in case of severe or recurrent/chronic infections is advised, while strongly recommended to consider regular prophylactic administration of IVIG.

Besides these promising results, non-trial populations represent a substantial proportion of patients seen in clinics, and data collected on the compassionate use of teclistamab in Expanded-Access Program (EAP, NCT05463939) or Pre-approval Access Single Patient Request (NCT05161598) may bring useful additional information to complement data from clinical trials, as well as results from the upcoming REALiTEC study, including even all those under-represented MM patients treated in real-life settings. Currently available data on the real-world use of teclistamab on 56 RRMM treated at Dana Farber showed similar efficacy to that reported in the MajesTEC-1 trial (ORR 53,6%). Notably, these real-world patients had poorer PFS and higher ISS and patients with central nervous system involvement, high-risk cytogenetics, and prior exposure to anti-BCMA treatments were also included, resulting in approximately 80% of them who would have been ineligible for participation in the trial. Nonetheless, the study demonstrated similar toxicity, with infectious complications remaining a significant concern, while prior use of BCMA-directed therapy led to inferior response rates (ORR of 45% in patients with prior BCMA therapy and of 30,8% with prior CAR-T therapy). Also, in univariate analysis, a lack of response in higher ISS, EMD, poor renal function and high-risk cytogenetics was reported [61].

2.2.2. Elranatamab (PF-06863135)

Elranatamab (PF-06863135, Pfizer) is a novel heterodimeric humanized full-length bispecific IgG2 kappa antibody derived from 2 MoAbs directed against BCMA and CD3, able to form a trimeric synapse between T-cell and BCMA+ myeloma cells. The binding affinities of elranatamab for BCMA and CD3 have been engineered to elicit potent T-cell-mediated anti-myeloma activity via IFN-γ-perforin and granzymes pathways. Elranatamab is currently being investigated in multiple clinical trials (Table 2), and preliminary results seem to be very encouraging. Results from the first-in-human phase I trial MagnetisMM-1 (NCT03269136) on 58 RRMM patients (91% triple-class relapsed/refractory, median age 64 years) receiving elranatamab SC as single agent (n = 55), at doses starting from 215 up to 1000 µg/kg either weekly (QW), or every 2 weeks (Q2W), showed this agent to achieve durable clinical and molecular responses, with a confirmed ORR of 64% and CR/sCR rate of 38% (100% MRD negativity in evaluable pts), mDOR of 17.1 months and mPFS of 11.8 months, along with a manageable safety profile [62,63]. Also, emerging data from the ongoing phase II trial MagnetisMM-3 (NCT0469359) [64,65] on 123 heavily pretreated RRMM patients (anti-BCMA naïve) receiving elranatamab as monotherapy at the RP2D (76 mg QW, SC) showed an ORR of approximately 61% (55.2% VGPR or better, 27.6% CR or sCR), with mPFS and mDOR not reached at 14.7 months median follow-up, granting elranatamab the Breakthrough Therapy Designation and Fast Track Designation for the treatment of RRMM from FDA. The combination of elranatamab plus daratumumab is being investigated in the MagnetisMM-5 (NCT05020236, part 1) trial, showing promising results [66]. Notably, the MagnetisMM-1 study included RRMM patients priorly exposed to anti-BCMA and 54% of these responded to elranatamab. Updated results on patients enrolled in different studies of the MagnetisMM program showed an ORR of 46% (sCR 4.6%, CR 13.8%, VGPR 24.1% and PR 3.4%) in patients receiving elranatamab after any prior BCMA-directed therapy (n = 87), with a median time to response of 1.7 months [67], supporting the case for further development of elranatamab in patients relapsing after receiving BCMA-directed therapies.

The use of elranatamab on earlier phases of the disease is yet to be elucidated, and the ongoing phase III trials MagnetisMM-7 (NCT05317416) and MagnetisMM-6 (NCT05623020, Part 2) are recruiting NDMM patients to evaluate whether elranatamab monotherapy can provide clinical benefit compared to lenalidomide monotherapy after ASCT [68], or the combination of elranatamab plus daratumumab and lenalidomide in NDMM patients not eligible for transplant (TNE) due to comorbidities, respectively [69,70].

Overall, the toxicity profile of elranatamab is comparable to that of other BsAbs, even slightly better than its main comparator teclistamab. CRS was observed at low grade in 87% of patients in the MagnetisMM-1. Notably, premedication and step-up priming regimen appeared to mitigate the risk for CRS, with a drop of incidence from 87% to 67% with the 44-mg step-up dose in MagnetisMM-1 trial and 56% and 50% (all graded 1 or 2) with a 12/32-mg step-up dose in MagnetisMM-3 and MagnetisMM-5, respectively. No cases of ICANS were reported in the MagnetisMM-1 and MagnetisMM-5, while low-grade occurred in 3.4% of patients in the MagnetisMM-3, with a rapid resolution and no necessity for treatment discontinuation. By contrast, neutropenia emerged significantly (75% grade 3 or 4), though managed adequately with supportive care, and infections were reported in 67% of patients in MagenetisMM-3 (35% grade 3 or 4), in some cases leading to permanent discontinuation of elranatamab [71], highlighting the importance of considering appropriate prophylaxis when administering BsAbs.

2.2.3. Other anti-BCMA BsAbs under development or investigation in MM

Several other anti-BCMA BsAbs are also in clinical development, with some differences in terms of construct, binding affinity, administration route, schedule, and step-up dosing requirements.

Among these, linvoseltanmab (REGN 5458, Regeneron) is a human BCMA x CD3 bispecific antibody produced by Regeneron, able to bind and bridging BCMA expressed on a target plasma cell (high affinity, KD = 1 nM) and to CD3 on the surface of the effector T cell. Linvoseltamab has previously been studied as a single agent and is now under investigation (NCT05137054) in combination strategies with other anticancer therapies (either daratumumab, carfilzomib, bortezomib, pomalidomide, isatuximab, cemiplimab, fianlimab, or nirogacestat) to assess efficacy, safety, and dose to be used in each combination. The phase I/II trial LINKER-MM1 (NCT03761108) in 167 RRMM patients receiving a dose escalation of linvoseltamab, ≥200 mg dose levels turned into higher ORR, independently of cytogenetics risk, R-ISS stage, or prior therapies [72], recently confirmed as 64% in the 200 mg cohort, including in pts with high disease burden [73]. This recommended dose of linvoseltamab will be further explored in the phase III LINKER-MM3 (NCT05730036) trial in comparison with EloPd, upon 1 to 4 prior lines of therapy, or as single agent in NDMM, in the phase 1/2 LINKER-MM4 (NCT05828511) trial.

Pacanalotamab (AMG 420) is the first in class bispecific T-cell engager, evaluated in a phase I dose escalation (0.2 up to 800 μg/die, infused continuously for 4 weeks every 6 weeks) trial in RRMM patients, demonstrating a high degree of clinical activity in patients with heavily pretreated multiple myeloma, irrespective of cytogenetic risk [74]. Although AMG 420, as well as later products with extended half-life (i.e. AMG 701, Pavuratamab, Amgen), showed substantial activity, the development of these compounds was subsequently discontinued by the company.

Alnuctamab (CC-93269, BMS) is a T-cell engager with bivalent binding to BCMA and its clinical activity has been demonstrated in the phase I, dose escalation (Part A and C) and expansion (Parts B and D), first-in-human clinical study (NCT03486067), in which alnuctamab was administered intravenously (Part A, 0.15–10 mg), or subcutaneously (Part C), to 70 and 73 RRMM patients previously exposed to at least 3 lines of therapy, respectively. Preliminary results showed an ORR of 39% for IV administration, with a mDOR of 33.6 months and a mPFS of 3,1 months. CRS was reported in about three-fourths of patients (76%), of which 7% grade ≥3. As for SC administration, ORR was 51% across all doses and 77% for doses ≥30 mg, with a median time to response of 1 month and 80% of evaluable patients achieving MRD negativity (flow cytometry, sensitivity 10⁻⁵) [75]. Safety was improved, with 56% of patients having low-grade (G1–2) and short-lived CRS events in 53% of patients. Other treatment-emergent adverse events (TEAEs) reported were neutropenia (49%), infections (47%), anemia (41%), and thrombocytopenia (33%) [76].

A phase I dose-escalation and expansion study (NCT03933735) was aimed at evaluating the safety, clinical pharmacology and clinical activity of ABBV-383 (formerly known as TNB-383B), a fully human, monoclonal, IgG4 bispecific antibody targeting BCMA and incorporating a low-activating CD3, to potentially minimizing off-target toxicity and cytokine release while maximizing anti-MM cell activity [77]. Preliminary results on 103 RRMM patients who have received at least 3 prior lines of therapy, not including anti-BCMA therapies, treated IV with ABBV-383 (dose escalation [0.025–120 mg], n = 73; dose expansion [60 mg], n = 30) showed an ORR of 79% at doses ≥40 mg, and similar trend (64% ORR) at ≤40 mg [78,79]. Updated results on 124 patients (dose escalation, n = 73; dose expansion, n = 51) confirmed these data, showing ABBV-383 to have a similar efficacy as compared with other anti-BCMA agents in terms of ORR (59%, [39% ≥VGPR] in the 60 mg expansion and 68% [54% ≥VGPR] in the ≥40 mg escalation plus expansion cohorts). MRD-negativity was found in 8 out 11 MRD-evaluable patients with CR or sCR. mPFS on the overall population was 10.4 months, not reached in the ≥40 mg escalation plus expansion and in the 60 mg expansion cohorts, as well as for mDOR [80]. Overall, ABBV-383 was well tolerated at all doses administered, with a low incidence of grade ≥3 hematologic and non-hematologic TEAEs, most commonly neutropenia (all grades: 37%), anemia (29%), CRS (57%), infections (41%), and fatigue (30%). A phase Ib study (NCT05650632) to assess adverse events and step-up dose optimization of IV infused ABBV-383 on 120 RRMM is also planned.

RO7297089 is a bispecific, tetravalent antibody targeting BCMA and CD16a, determining an immunological synapse to mediate killing of BCMA-positive cells by NK cells and macrophages (CD16a-positive). In the phase I, dose-escalation study (NCT04434469) RO7297089 was administered as a single agent to patients with RRMM who had progressed on or following prior therapy. Overall, RO7297089 showed a moderate clinical activity (7% of patients reached a PR, 7% MR and 52% had a stable disease as their best response), along with an acceptable safety profile, most common AEs being anemia, infusion-related reaction, and thrombocytopenia. A possible reason for the moderate clinical activity of this agent may be found in its relatively long half-life, but further data on dose or drug modification are needed to understand the potential role of this agent [81].

WVT078 is an anti-BCMA × anti-CD3 BsAb that binds to BCMA with sub-nanomolar-affinity, and preliminary data from the first-in-human phase I dose-escalation study (NCT04123418) on 33 patients receiving IV WVT078 once weekly at escalated dosing of 48–250 µg/kg support a favorable efficacy and safety profile of WVT078 in RRMM patients. Preliminary evidence of clinical activity reported an ORR of 38.5% at the active doses (75% at the highest dose level tested), with a CRR (CR + sCR) of 11%. Clinical responses appeared to occur shortly after treatment and deepening over time in the time considered [82]. As for safety, CRS was reported in 60.6% of patients and additional administration schedules are being considered to maximize the exposure of WVT078 while mitigating the risk of CRS, but further characterization of an active dose and longer follow-up are required to better define the potential activity of WVT078 and its safety profile.

3. Discussion

T-cells play a crucial role in the adaptive immune response to tumor cells and harnessing their abilities as a weapon against myeloma appears to be a viable strategy. Nonetheless, the best treatment choice is yet to be determined.

So far, CAR-T-based therapies have ensured impressive and most promising results in terms of efficacy and deep of responses (34.9 months mPFS, 83% ≥CR and 92% of MRD-negativity reported with cilta-cel) (Table 3), despite limitations of cross-trial comparison. In addition, recent data on health-related quality of life (HRQoL) indicate that CAR-T-based therapies (ide-cel) led to significant and meaningful improvements in relevant symptoms, physical functioning, fatigue, and overall health status of TCE RRMM patients [83]. Noteworthy, these remarkable results were achieved through single-infusions of CAR-T and this aspect may be fundamental in the perspective of patients, who after the necessary time for CAR-T administration – inpatient or outpatient- and recovery, in which proximity to the hospital is still recommended up to 30 days, can benefit from a treatment-free period. Conversely, BsAbs need continuous therapy, often with weekly infusion schedules, and albeit hospitalization is limited to step up dosing phases, or to handle major complications, this type of treatment forces patients to remain anchored in proximity of the hospital, both physically and mentally, or otherwise tied to a constant treatment regimen, instead of a ‘one-shot’ dosing. BsAbs should be therefore considered for those patients living at a reasonable distance from the hospital, or having the ability to travel frequently and, where necessary, to be accompanied by caregivers.

Table 3. Anti-BCMA comparing therapies: pros and cons of each treatment.

	CAR-T	BsAbs
Efficacy	ORR >80% (98% cilta-cel)	ORR 55–75%
Deep of response	≥CR 83% 92% MRD-negativity	≥CR < 40% Up to 90% MRD-negativity (elranatamab)
Disease-free and survival outcomes	mPFS 34.9 mos (cilta-cel) mOS 24.8 to NR	mPFS 12 mos mOS 18.3 mos (teclistamab)
Dosing frequency	One dose	Treat to progression
Health-related quality of life	Meaningful improvements in symptoms, physical functioning, overall health status, and HRQoL	Improved pain and overall HRQoL
Availability	Limited slots, cell therapy facility	Wider availability
Waiting time for the product	4–6 week turn-around time*	Off the shelf
Toxicity	Higher rates of CRS, ICANS Hypogamma lasting average 6 mos	CRS (mostly grade 1–2), very low ICANS Hypogamma long-lasting
Prolonged cytopenias	More common	Limited to neutropenia, usually decreasing with bi-weekly/monthly dosing
Infection risk	High (shorter duration)	High and prolonged (long-lasting)
Time off therapy	Yes, one time treatment	Continuous therapy
Hospitalization	Inpatient or outpatient Hospital proximity up to 30 days	Limited to step up dosing phase
Treatment logistics	Complex, only in specialized center Long time for production	Simple infusion, but frequent Requires hospital stay
Best Candidates	Fit, good PS, No rapid progression	Can travel frequently
Costs	> $400K One time, upfront	>$30k/month Pay as you go
Patient place in therapy	Later line, salvage fit, >3 LOT	Later line salvage unfit, >3 LOT

*Newer constructs require shorter time of manufacturing (down to 2 days manufacturing process).

Abbreviations: CR: complete remission; CRS: cytokines release syndrome; ICANS: immune effector cell-associated neurotoxicity syndrome; LOT: lines of therapy; mos: months; MRD: minimal residual disease; PS: performance status.

Also, the safety profile and toxicities related to both CAR-T and BsAbs is an important matter. As seen in clinical trials, the two most common toxicities observed acutely after CAR-T infusion include CRS and ICANS and prompt intervention is crucial. Though both BsAbs and CAR-T may cause CRS, it appears to be generally less frequent and with a shorter duration when occurring post BsAbs administration. In parallel, or commonly after CRS has subsided, ICANS may occur, as a toxic encephalopathy with word-finding difficulty, aphasia, and confusion, till coma, seizures, motor weakness, and cerebral edema in severe cases. However, the ICANS rate observed with BsAbs seem to be noticeably lower with respect to ide-cel and cilta-cel administration. Additionally, CAR-T cells can induce cytopenia and hypogammaglobulinemia persisting form months, and severe grade hematologic toxicities, with different time for recovery: older, or more heavily pretreated patients, may be at higher risk for the onset of prolonged cytopenia and this aspect should be considered. On the other hand, the high risk for infections represents the major hurdle with BsAbs [56,64,84,85]. Importantly, anti-BCMA BsAbs are associated with major and prolonged infectious risk, even months later the beginning of therapy, therefore, IVIG supplementation therapy is strongly recommended. On the contrary, CAR-Ts or BsAbs directed against other targets, like the G protein-coupled receptor class C group 5 member D (GPRC5D) have an inferior, or time-limited, infectious risk, likely due to a different expression of the target on normal versus malignant plasma cells [86,87]. However, GPRC5D-targeting BsAbs are associated with specific ‘on target/off tumor’ toxicities including rash, nail disorders, and dysgeusia. Nevertheless, patients receiving BsAbs thus far were heavily pretreated while the use of BsAbs in earlier stages of the treatment paradigm may likely reduce infectious complications, in patients with less pronounced disease- and treatment-related immunosuppression, but further trial- and real-world data are eagerly awaited.

Overall, it is thus far not possible to determine whether one of these anti-BCMA treatments may outweigh the other: likely, a greater amount of data in real-life settings will provide more precise elements in this sense, but there is still a long way to go. However, the two therapies are not mutually exclusive, and patients already exposed to an anti-BCMA therapy may benefit from other kind of approaches, but there is no definitive data to determine which sequencing may be more suitable to maximize efficacy. Available data on cilta-cel therapy after exposure to BCMA-targeted agents, was shown feasible and quite effective, with no new or unexpected toxicity [30,88], and preliminary data from pooled analyses confirm that BCMA retreatment can maintain effectiveness, albeit with reduced ORR. Other possibilities may include dual-targeting approaches, in combination strategies, or sequential targeting by switching the target, but again but the use of two BsAbs with different targets seems to correlate with a reduced ORR, and wash-out time in case of BsAbs before other BsAb or CAR-T is an aspect to be considered [49,67,89]. Also, the reasons underlying resistance to anti-BCMA antibodies, including defective host immune functions and BCMA antigen escape or loss of expression, are not fully elucidated and better knowledge is therefore necessary to improve proper management of the disease.

4. Conclusion

CAR-T and BsAbs anti-BCMA strategies represent a breakthrough in the treatment of RRMM and, despite limitations, some of which have been addressed here, may effectively represent the future in the treatment of MM. In the meantime, intense research is underway to identify better candidates, manage toxicities, and proper sequencing of anti-BCMA agents, in order to best harness the potency of these innovative BCMA-targeting immunotherapies. Further data are urgently awaited to move in the direction of more tailored and individualized anti-myeloma therapies.

5. Expert opinion

Important improvements in diagnosis and prognostication of MM have granted unprecedent results in the treatment landscape, as evidenced by the recent incorporation of novel agents in the anti-myeloma armamentarium. Notably, a sizable slice of new agents is directed against BCMA, representing one of the most promising targets in MM, due to its abundant expression on the surface of malignant cells and its role in sustaining the onset and development of the disease. As a result, currently available immune approaches, either approved or under active investigation, represent the most exciting area for new therapies against myeloma.

In this context, great attention has been given to BCMA-targeting CAR-T cells and BsAbs, suitable candidates to form the basic skeleton of future anti-myeloma therapies. The inclusion of these products in clinical practice is rather expected, although almost feared. Data from clinical trials are robust; however, the integration into the clinic remains a challenge, due to the heavy burden associated with these cutting-edge therapies, and these limitations may hinder their effective entry into real-life contexts.

As an instance, FDA and EMA approved the first two cellular products for RRMM heavily pretreated patients (ABECMA, BMS, and CARVYKTI, Janssen Biotech) almost 2 years ago, and yet the treatment is far from being effectively and widely used in clinical practice. First and foremost, limitations with CAR-T-based therapies rely on the feasibility of the entire process, given the complexity of product manufacturing, waiting time to receive the final product, and functioning network between cell factories and product-distributors, but also between clinical centers across the country. Indeed, CAR-T products delivery requires 4–6 weeks turn-around time, and patients at risk of rapid progression do not have the luxury of being off treatment for so long periods. Within clinical trials, a number of patients who underwent leukapheresis procedures were unable to receive the therapy, due to the longtime wait (29 and 33 days for cilta-cel and ide-cel, respectively) [17,25,90,91]. Also, the allocation of CAR-T slots among centers was low (median of 1%er monthly, with an average waiting list of about 20 patients, or more), due to the shortage of cell factories across the countries, and similar numbers were found in real-world experiences [92,93]. Albeit the ability to promptly deliver CAR T for lymphoma and acute lymphoblastic leukemia proves that individualized patient manufacturing may not be an insurmountable barrier, especially considering newer constructs requiring a reduced time for manufacturing, the limited availability of accredited transplant centers across the national territory will certainly be the first bottleneck to respond to an ever-increasing demand for administration of CAR-T in MM. Indeed, authorized centers to infuse CAR-T-based therapies are limited and this barrier is far from being improved in the short term.

In this view, it could be argued that BsAbs ‘off the shelf’ products may be a valid alternative as promptly and widely available products for patients in need of short-term control of the disease. Nonetheless, data on their use are emerging and practical management of these agents is not to be underestimated, in terms of hospitalization requirements both for administration and, more importantly, to manage the onset of major and prolonged toxicities. Though prophylaxis with IVIG as supportive therapy might help, to some extent, product supply could be an issue and the overload for the facility would still be remarkable. Even from the patient’s perspective, the commitment is sizable, and the quality of life may be severely affected by the burden of continuous therapy and the associated logistics. Moving into the perspective of a future entry of these therapies in clinical practice, both options will have a major impact on clinical centers. Importantly, even the costs for the national health care system are high. Apart from manufacturing and delivery of the final product, CAR-T management undoubtedly requires elevated costs for the entire process, including patient hospitalization and tight monitoring during and after infusion. However, this is a one-time expense, whereas continuous and prolonged BsAbs therapies are paid as you go, and costs are deferred over time, but still high (Table 3).

Meanwhile, all the efforts should be focused on individualizing and choosing the most suitable candidates for each treatment. Though clinical trials have undoubtedly aided in identifying optimal products and regimens for specific patient groups, information on a broader use are lacking. In fact, the stringent eligibility criteria imposed by clinical studies might ultimately have led to efficacy and safety outcomes not reflective of those observed in a real-life context, where treated patients could be affected by more aggressive disease, and/or comorbidities that would have these patients excluded from the trials. On the contrary, real-world administration of CAR-T and BsAbs will include patients with different backgrounds in terms previous number and types of therapies, efficacy and safety outcomes, long-term toxicities, and treatment after relapse, among others. More data on the use outside clinical trials would therefore be of utmost importance, to channel these energy- and resource-intensive processes in favor of those patients who can best benefit from these approaches. Likely, age, comorbidities, or frailty score may be driven factors to select eligible patients for each treatment, but no definitive criteria have been so far determined in this sense.

At present, it is difficult to determine how many patients will effectively have access to these therapies, or whether these kinds of options will remain out of reach for too many patients, especially in larger settings, should these treatments be approved in earlier lines of therapy. Meanwhile, how to combine, or sequence, these therapies, and a better understanding of the mechanisms of resistance are urgent matters to be addressed, especially for those patients with limited available treatment options.

Article highlights

• BCMA represents one of the most promising targets, due to its abundant expression on the surface of malignant cells and its role in sustaining the onset and development of the disease.

• CAR-T cell therapy and BsAbs have shown to significantly enhance the depth of response and survival outcomes in MM.

• Phase 2 (karMMa) or 1/2 (CARTITUDE-1) studies showed deep and durable responses of two anti-BCMA CAR-T cell therapies, ide-cel and cilta-cel, in triple-class-exposed (TCE) RRMM patients, resulting in U.S. accelerated approval for the treatment of adult RRMM after ≥ 4 prior lines of therapy (Food and Drug Administration, FDA) and conditional approval in the European Union after ≥ 3 and progressed on last therapy (European Medicinal Agency, EMA). The superiority of ide-cel and cilta-cel over standard regimens has been demonstrated in two prospective studies for the treatment of RRMM patients in earlier lines of therapy.

• Different phase 1/2 or 2 studies have demonstrated the efficacy of the BCMA-targeting BsAbs teclistamab and elranatamab, resulting in regulatory approval for TCE RRMM.

• Ongoing and future clinical trials will evaluate these products in combination with other agents and/or in earlier lines of therapy.

• Ongoing and future clinical trials will evaluate newer constructs, aiming at increasing efficacy, reducing toxicity, and improving products administration, including toxicities management and reduced manufacturing time of CAR-T products.

• Proper patient selection is of utmost importance to channel these energy- and resource-intensive processes in favor of those patients who can best benefit from these approaches, but no definitive criteria have been so far determined.

• How to combine, or sequence, these therapies, and a better understanding of the mechanisms of resistance are urgent matters to be addressed.

Declaration of interest

M Martino has received honoraria for lectures, presentations, speaker bureaus, and for advisory boards from Celgene-BMS, Janssen-Cilag, Novartis, for advisory boards from Takeda, GlaxoSmithKline, and Pfizer, for manuscript writing from Sandoz, and research funding from Medac. B Gamberi has participated in advisory board for Amgen, Bristol Myers Squibb, Janssen, GlaxoSmithKline, Sanofi, Takeda and received honoraria from Bristol Myers Squibb, Janssen, GlaxoSmithKline, and Sanofi. E Antonioli has participated in advisory board for Bristol Myers Squibb, Janssen, Takeda, Pfizer, Amgen, and GlaxoSmithKline. S Mangiacavalli has participated in advisory board and received honoraria from Amgen, Bristol Myers Squibb, Janssen, GlaxoSmithKline, Janssen, Sanofi, and Takeda. S Bringhen declares participation in speakers’ bureaus for Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen, Sanofi, and AbbVie, and participation in advisory boards for Bristol Myers Squibb, Janssen, Takeda, Pfizer, Stemline Therapeutics, and Oncopeptides, and consultancy fees from Sanofi. E Zamagni has served in a consulting/advisory role and received honoraria from Janssen, Bristol-Myers Squibb, Sanofi, Amgen, GlaxoSmithKline, Pfizer, Oncopeptides, and Menarini-Stemline. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Author contributions

S Bringhen and E Zamagni contributed equally to this manuscript.

Acknowledgments

Medical writing support and editorial assistance were provided by Mattioli 1885 (Simona Barbato).

Additional information

Funding

This paper was not funded.