The therapeutic landscape in multiple myeloma (MM) has changed dramatically over the last 2 decades. With the introduction of novel immunotherapies, patients with MM can expect deeper responses, longer remissions, and improved overall survival. Since its approval by the US Food and Drug Administration in 2015, the monoclonal antibody specific for CD38, daratumumab, has been incorporated into both frontline and relapsed treatment regimens. Its role as a maintenance therapy is currently being explored. Subsequently, a variety of novel antibody therapeutics have evolved from the success of daratumumab, using similar concepts to target the malignant plasma cell clone. Noteworthy naked monoclonal antibodies include isatuximab, another agent directed against CD38, and elotuzumab, an agent directed against SLAM family member 7. Antibody-drug conjugates, complex molecules composed of an antibody tethered to a cytotoxic drug, target malignant cells and deliver a lethal payload. The first to market is belantamab mafodotin, which targets B-cell maturation antigen (BCMA) on malignant plasma cells and delivers a potent microtubule inhibitor, monomethyl auristatin F. Additionally, bispecific T-cell antibodies are in development that engage the immune system directly by simultaneously binding CD3 on T cells and a target epitope—such as BCMA, G-protein coupled receptor family C group 5 member D (GPRC5d), and Fc receptor homologue 5 (FcRH5)—on malignant cells. Currently, teclistamab, an anti-BCMA bispecific, is closest to approval for commercial use. In this review, we explore the evolving landscape of antibodies in the treatment of MM, including their role in frontline and relapse settings.

Learning Objectives

  • Review the use of MoAbs in NDMM (transplant eligible and ineligible) and RRMM

  • Understand the evolving role of ADCs in RRMM

  • Explore the current landscape and future directions of BsAbs in RRMM

A 54-year-old woman is diagnosed with immunoglobulin G kappa (IgGκ) multiple myeloma (MM). She undergoes induction therapy with triplet combination, followed by autologous stem cell transplant (ASCT) and lenalidomide maintenance. She experiences several relapses and is cycled through various lines of therapy. She has now had 4 lines of therapy and is considered triple-class refractory (TCR), having become refractory to a proteosome inhibitor, an immunomodulatory drug, and an anti-CD38 monoclonal antibody (MoAb). Her treating physician offers to send her to an academic center for a clinical trial, but she opts to stay close to home and is started on belantamab mafodotin.

Despite decades of scientific advancement, MM remains incurable in the vast majority of patients.1  Currently, the primary goal of treatment is to increase survival and maintain a reasonable quality of life. This is accomplished through therapeutic suppression of the malignant plasma cell (PC) clone, which subsequently mitigates disease-related complications.1 

Since their approval, MoAbs have been widely incorporated into both frontline and relapsed settings. Still, patients who become TCR remain challenging to treat and require therapies with novel mechanisms of action. In the recent LocoMMotion study, TCR MM patients who prospectively received widely available standard of care (SOC) therapies demonstrated an overall response rate (ORR) of 25%, a median duration of response (DOR) of 4.5 months, and overall survival (OS) of 11.1 months.2  To address this area of unmet need, the focus has shifted toward new approaches, such as chimeric antigen receptor (CAR) T-cell therapies, antibody-drug conjugates (ADCs), and bispecific antibodies (BsAbs).3  Although CAR T-cell therapy has shown remarkable overall efficacy of greater than 70% across various early-phase studies—leading to the approvals of idecabtagene vicleucel and ciltacabtagene autoleucel—delays in drug administration due to manufacturing time and grade 3/4 adverse events (AEs) from cytokine release syndrome (CRS), neurotoxicity, and cytopenias remain major concerns.3  The desire for safe “off-the-shelf” immunotherapies has strengthened interest in ADCs and BsAbs, which themselves have demonstrated promising efficacy in relapsed/refractory MM (RRMM).3 

In this review we present the state of development of each class of antibody-directed therapy in MM, with an emphasis on the rapidly advancing ADC and BsAb therapeutic armamentarium.

In the last decade, three MoAbs were approved for the treatment of MM. Daratumumab (anti-CD38) and elotuzumab (anti-SLAM family member 7 [SLAMF7]) were approved for commercial use in 2015 while isatuximab (anti-CD38) was approved in 2020.

Daratumumab is a humanized IgG1κ MoAb that binds to CD38 expressed on malignant PCs.4  It effectively eliminates CD38- expressing PCs through several mechanisms: antibody-dependent T-cellular cytotoxicity, antibody-dependent T-cellular phagocytosis, complement-dependent cytotoxicity, induction of apoptosis via Fcγ receptor–mediated cross-linking, and by various immunomodulatory effects.4  Several randomized controlled trials have observed the clinical benefits of adding daratumamab to immunomodulator drugs and proteosome inhibitors in RRMM, establishing its use as an SOC agent in this setting (Table 1).58 

Table 1.

Pivotal randomized phase 3 trials of monoclonal antibody treatment for MM

Clinical trialPatient populationArm (n = number of patients)Overall response (%)Median progression-free survival (months)Hazard ratio (P value)
ALCYONE12  Transplant-ineligible NDMM D-VMP (n = 350) 91 36.4 0.42 (P < .001) 
VMP (n = 356) 74 19.3 
MAIA11  Transplant-ineligible NDMM D-Rd (n = 368) 92.9 NR 0.53 (P < .001) 
Rd (n = 369) 81.6 34.4 
ELOQUENT 124  Transplant-ineligible NDMM E-Rd (n = 374) 83 31.4 0.93 (P  = .44) 
Rd (n = 374) 79 29.5 
CASSIOPEIA9  Transplant-eligible NDMM D-VTd (n = 543) 93 NR 0.47 (P < .001) 
VTd (n = 542) 90 NR 
GRIFFIN10,a Transplant-eligible NDMM D-RVd (n = 99) 99 NR Not available 
RVd (n = 97) 92 NR 
GMMG-HD623  Transplant-eligible NDMM E-RVd (n = 555) B1 81.5%; B2 80.7% (≥VGPR) B1 66.2%; B2 67.2% (3 y PFS) Not available (P  = .86; no significant difference) 
RVd (n = 559) A1 78.9%; A2 78.2% (≥VGPR) A1 68.8%; A2 68.5% (3 y PFS) 
GMMG-HD719  Transplant-eligible NDMM I-RVd (n = 329) MRD 50.1% NR Not available (OR = 1.82; P < .001) 
RVd (n = 331) MRD 35.6% NR 
POLLUX6  RRMM, at least 1 prior line D-Rd (n = 286) 93 44.5 0.44 (P < .001) 
Rd (n = 283) 76 17.5 
ELOQUENT 220  RRMM, 1-3 prior lines E-Rd (n = 321) 79 19.4 0.71 (P < .001) 
Rd (n = 325) 66 14.9 
CANDOR8  RRMM, 1-3 prior lines D-Kd (n = 312) 84 NR 0.62 (P  = .003) 
Kd (n = 154) 75 15.8 
IKEMA18  RRMM, 1-3 prior lines I-Kd (n = 179) 87 NR 0.53 (P < .001) 
Kd (n = 123) 83 19.2 
CASTOR5  RRMM, at least 1 prior line D-Vd (n = 251) 83 16.7 0.31 (P < .001) 
Vd (n = 247) 63 7.1 
ELOQUENT 321  RRMM, at least 2 prior lines E-Pd (n = 60) 53 10.3 0.54 (P = .008) 
Pd (n = 57) 26 4.7 
APOLLO7  RRMM, at least 1 prior line D-Pd (n = 151) 69 12.4 0.63 (P = .0018) 
Pd (n = 153) 46 6.9 
ICARIA-MM17  RRMM, at least 2 prior lines I-Pd (n = 154) 63 11.5 0.6 (P = .001) 
Pd (n = 153) 32 6.5 
Clinical trialPatient populationArm (n = number of patients)Overall response (%)Median progression-free survival (months)Hazard ratio (P value)
ALCYONE12  Transplant-ineligible NDMM D-VMP (n = 350) 91 36.4 0.42 (P < .001) 
VMP (n = 356) 74 19.3 
MAIA11  Transplant-ineligible NDMM D-Rd (n = 368) 92.9 NR 0.53 (P < .001) 
Rd (n = 369) 81.6 34.4 
ELOQUENT 124  Transplant-ineligible NDMM E-Rd (n = 374) 83 31.4 0.93 (P  = .44) 
Rd (n = 374) 79 29.5 
CASSIOPEIA9  Transplant-eligible NDMM D-VTd (n = 543) 93 NR 0.47 (P < .001) 
VTd (n = 542) 90 NR 
GRIFFIN10,a Transplant-eligible NDMM D-RVd (n = 99) 99 NR Not available 
RVd (n = 97) 92 NR 
GMMG-HD623  Transplant-eligible NDMM E-RVd (n = 555) B1 81.5%; B2 80.7% (≥VGPR) B1 66.2%; B2 67.2% (3 y PFS) Not available (P  = .86; no significant difference) 
RVd (n = 559) A1 78.9%; A2 78.2% (≥VGPR) A1 68.8%; A2 68.5% (3 y PFS) 
GMMG-HD719  Transplant-eligible NDMM I-RVd (n = 329) MRD 50.1% NR Not available (OR = 1.82; P < .001) 
RVd (n = 331) MRD 35.6% NR 
POLLUX6  RRMM, at least 1 prior line D-Rd (n = 286) 93 44.5 0.44 (P < .001) 
Rd (n = 283) 76 17.5 
ELOQUENT 220  RRMM, 1-3 prior lines E-Rd (n = 321) 79 19.4 0.71 (P < .001) 
Rd (n = 325) 66 14.9 
CANDOR8  RRMM, 1-3 prior lines D-Kd (n = 312) 84 NR 0.62 (P  = .003) 
Kd (n = 154) 75 15.8 
IKEMA18  RRMM, 1-3 prior lines I-Kd (n = 179) 87 NR 0.53 (P < .001) 
Kd (n = 123) 83 19.2 
CASTOR5  RRMM, at least 1 prior line D-Vd (n = 251) 83 16.7 0.31 (P < .001) 
Vd (n = 247) 63 7.1 
ELOQUENT 321  RRMM, at least 2 prior lines E-Pd (n = 60) 53 10.3 0.54 (P = .008) 
Pd (n = 57) 26 4.7 
APOLLO7  RRMM, at least 1 prior line D-Pd (n = 151) 69 12.4 0.63 (P = .0018) 
Pd (n = 153) 46 6.9 
ICARIA-MM17  RRMM, at least 2 prior lines I-Pd (n = 154) 63 11.5 0.6 (P = .001) 
Pd (n = 153) 32 6.5 
a

Randomized phase 2 study

Note: This list is not exhaustive for all randomized trials including monoclonal antibodies.

D, daratumumab; d, dexamethasone; E, elotuzumab; I, isatuximab; K, carfilzomib; M, melphalan; OR, odds ratio; P, pomalidomide; p, prednisone; R, lenalidomide; T, thalidomide; V, bortezomib.

In transplant-eligible patients, the addition of daratumamab to bortezomib-thalidomide-dexamethasone (phase 3 CASSIOPEIA trial) improved depth of response and led to a significant progression-free survival (PFS) benefit.9  Similarly, the addition of daratumumab to lenalidomide-bortezomib-dexamethasone (RVd; phase 2 GRIFFIN trial) in transplant-eligible patients improved depth of response, including stringent complete remission and minimal residual disease (MRD) (10−5), and showed PFS benefit (HR 0.45; p  = 0.324), while median OS was not reached in either group with limited follow-up.10  In both CASSIOPEIA and GRIFFIN, there was a benefit to adding daratumumab across all subgroups except those with high-risk cytogenetics or International Scoring System stage III disease.

A PFS benefit is also seen for frontline daratumamab in combination with bortezomib-melphalan-prednisone (VMP; phase 3 ALCYONE trial) or lenalidomide-dexamethasone (Rd; phase 3 MAIA trial) in transplant-ineligible patients.11,12  Further, daratumumab has been combined with carfilzomib/Rd (KRd) as an induction therapy, with or without ASCT, in the phase 2 MASTER and MANHATTAN studies. Early results show impressive MRD-negative (10−5) remissions; 80% in the MASTER trial and 71% in the MANHATTAN trial.13,14 

The question of daratumumab maintenance was first addressed in the second randomization of the CASSIOPEIA trial, in which patients were further randomized after ASCT/consolidation to daratumumab for up to 2 years or active surveillance. The median PFS was not reached (NR) in the daratumumab maintenance arm and was 46.7 months in the observation arm (hazard ratio [HR], 0.53; 95% CI, 0.42–0.68; P < .0001).15  Unexpectedly, those patients who had received daratumumab during induction and consolidation derived no incremental benefit from daratumumab maintenance alone vs observation alone (HR, 1.02; 95% CI, 0.71–1.47; P = .91), suggesting that depth of response, rather than continuous therapy, may have been the determining factor.15  Ongoing trials such as GRIFFIN (NCT02874742), DRAMMATIC (NCT04071457), PERSEUS (NCT03710603), and AURIGA (NCT03901963) will help elucidate the optimal use of daratumumab or daratumamab plus lenalidomide as maintenance therapy.

Isatuximab is another IgG1κ MoAb that binds to CD38. One notable difference from daratumumab is that isatuximab can induce direct cytotoxicity via caspase-dependent apoptosis and lysosome-mediated nonapoptotic cell killing.16  Isatuximab has been successfully combined with pomalidomide- dexamethasone (Pd; phase 3 ICARIA-MM trial) and Kd (phase 3 IKEMA trial) in RRMM, with superior PFS demonstrated in the isatuximab arms (Table 1).17,18  In the GMMG-HD7 phase 3 study in newly diagnosed multiple myeloma (NDMM), isatuximab added to RVd improved MRD (10−5) negativity rates (50.1% vs 35.6%) prior to ASCT, further supporting the incorporation of an anti-CD38 MoAb in frontline treatment.19 

Elotuzumab, a humanized IgG1 MoAb directed against SLAMF7, has shown improved PFS and OS in combination with Rd (phase 3 ELOQUENT-2 trial) and Pd (phase 3 ELOQUENT-3 trial) in RRMM.20,21  Disappointingly, when added to frontline RVd in transplant-eligible NDMM patients (phase 2 SWOG-1211 and phase 3 GMMG-HD6 trials) or to Rd (phase 3 ELOQUENT-1 trial) in transplant-ineligible patients, no improvements in outcomes were demonstrated.2224 

Despite the success of naked MoAbs, the vast majority of MM patients ultimately relapse and require novel interventions. Consequently, researchers have cleverly combined the specificity of MoAbs with a cytotoxic drug, creating a sophisticated delivery system that transports a lethal payload directly to the antigen-expressing cell (Figure 1). This technology has already shown success in other hematologic malignancies, including lymphoma (brentuximab vedotin) and acute myeloid leukemia (gemtuzumab ozogamicin).25 

Figure 1.

Characteristics of ADCs. The components of the ADC and its target antigen influence the efficacy and safety profile. Preferably, target antigens should only be found on malignant cells, be abundantly expressed, be capable of internalization, and not be shed from the cellular membrane. The cytotoxic drug (payload or warhead) is the ultimate effector component, inducing direct cell killing either by inhibiting microtubule formation or directly damaging cellular DNA. It should be highly potent in the subnanomolar range and preferably nonpermeable to avoid damage to surrounding tissues. The linker connects the warhead to the antibody. These should be stable in circulation and cleavable upon lysosomal degradation. The conjugation chemistry of the linker determines the drug:antibody ratio, which critically influences the ADC potency. ADCC, antibody-dependent T-cellular cytotoxicity, Fab, fragment antigen-binding region.

Figure 1.

Characteristics of ADCs. The components of the ADC and its target antigen influence the efficacy and safety profile. Preferably, target antigens should only be found on malignant cells, be abundantly expressed, be capable of internalization, and not be shed from the cellular membrane. The cytotoxic drug (payload or warhead) is the ultimate effector component, inducing direct cell killing either by inhibiting microtubule formation or directly damaging cellular DNA. It should be highly potent in the subnanomolar range and preferably nonpermeable to avoid damage to surrounding tissues. The linker connects the warhead to the antibody. These should be stable in circulation and cleavable upon lysosomal degradation. The conjugation chemistry of the linker determines the drug:antibody ratio, which critically influences the ADC potency. ADCC, antibody-dependent T-cellular cytotoxicity, Fab, fragment antigen-binding region.

Close modal

Several ADCs have been evaluated in clinical trials in RRMM (Table 2), the most promising of which target B-cell maturation antigen (BCMA). BCMA has emerged as an attractive target, as it is expressed at high levels on PCs and plasmablasts but not on other tissues.26  This selectivity, in addition to the fact that BCMA undergoes internalization, makes it an ideal target for ADCs.26 

Table 2.

Summary of antibody-drug conjugates for MM

NameTargetPayloadCombinationTrial phase: number of patients (n)Response/activityCurrent status (ClinicalTrials.gov)
Belantamab mafodotin (belamaf) BCMA MMAF Monotherapy28  Phase 1: n = 35 ORR 60% DREAMM-1 (completed) NCT02064387 
Phase 2: n = 196 ORR 31% DREAMM-2 (completed) NCT03525678 
B (Q3W) vs Pd Phase 3: n = 380 (E) N/A DREAMM-3 (recruiting) NCT04162210 
B (Q3W) + Pemb30  Phase 1/2: n = 41 ORR 47% DREAMM-4 (active, not recruiting) NCT03848845 
B + novel agent31  Phase 1/2: n = 464 (E) ORR 53% with feladilimab DREAMM-5 (recruiting) NCT04126200 
B-Vd OR Rd32  Phase 1/2: n = 152 (E) ORR 78% in BVd arm DREAMM-6 (active, not recruiting) NCT03544281 
B-Pd34  Phase 1/2: n = 96 (E) ORR 88.9% ALGONQUIN (recruiting) NCT03715478 
B-Rd (transplant-ineligible NDMM) Phase 1/2: n = 66 (E) N/A NCT04808037 (recruiting) 
B-Vd vs D-Vd Phase 3: n = 575 (E) N/A DREAMM-7 (active, not recruiting) NCT04246047 
B-Pd vs V-Pd Phase 3: n = 450 (E) N/A DREAMM-8 (recruiting) NCT04484623 
B-VRd (transplant-ineligible NDMM33  Phase 1: n = 144 (E) ORR 100%
(n = 12) 
DREAMM-9 (recruiting) NCT04091126 
Monotherapy in renal impairment Phase 1: n = 36 (E) N/A DREAMM-12 (recruiting) NCT04398745 
Monotherapy in liver impairment Phase 1: n = 28 (E) N/A DREAMM-13 (recruiting)
NCT04398680 
   Monotherapy
(varying doses and schedules) 
Phase 2: n = 180 (E) N/A DREAMM-14 (recruiting) NCT05064358 
AMG 224 BCMA Mertansine Monotherapy36  Phase 1: n = 42 (E) ORR 27%
(3  mg/kg) 
NCT02561962 (active, not recruiting) 
CC 99712 BCMA Maytansinoid-like Monotherapy Phase 1: n = 160 (E) N/A NCT04036461 (recruiting) 
MEDI2228 BCMA PBD Monotherapy37  Phase 1: n = 82 ORR 66% at 0.14  mg/kg NCT03489525 (completed) 
Indatuximab ravtansine CD138 Maytansinoid
DM4 
In combination with R or P Phase 1/2: n = 64 ORR 71.7% with R and 70.6% with P NCT01001442 (completed) 
Lorvotuzumab mertansine CD56 Mertansine Monotherapy Phase 1: n = 37 ORR 5.7% NCT00346255 (completed) 
Milatuzumab CD74 Doxorubicin Monotherapy Phase 1: n = 25 26% SD NCT00421525 (completed) 
STRO-001 CD74 MMAF Monotherapy Phase 1: n = N/A N/A NCT03424603 (recruiting) 
DFRF4539A FcRH5 MMAE Monotherapy Phase 1: n = 39 ORR 5%; 49% SD NCT01432353 (completed) 
SGN-CD48A CD48 MMAE Monotherapy Phase 1: n = 14 N/A NCT03379584 (terminated) 
ABBV-838 SLAMF7 MMAE Monotherapy Phase 1/1b: n = 75 ORR 10.7% NCT02462525 (terminated) 
NameTargetPayloadCombinationTrial phase: number of patients (n)Response/activityCurrent status (ClinicalTrials.gov)
Belantamab mafodotin (belamaf) BCMA MMAF Monotherapy28  Phase 1: n = 35 ORR 60% DREAMM-1 (completed) NCT02064387 
Phase 2: n = 196 ORR 31% DREAMM-2 (completed) NCT03525678 
B (Q3W) vs Pd Phase 3: n = 380 (E) N/A DREAMM-3 (recruiting) NCT04162210 
B (Q3W) + Pemb30  Phase 1/2: n = 41 ORR 47% DREAMM-4 (active, not recruiting) NCT03848845 
B + novel agent31  Phase 1/2: n = 464 (E) ORR 53% with feladilimab DREAMM-5 (recruiting) NCT04126200 
B-Vd OR Rd32  Phase 1/2: n = 152 (E) ORR 78% in BVd arm DREAMM-6 (active, not recruiting) NCT03544281 
B-Pd34  Phase 1/2: n = 96 (E) ORR 88.9% ALGONQUIN (recruiting) NCT03715478 
B-Rd (transplant-ineligible NDMM) Phase 1/2: n = 66 (E) N/A NCT04808037 (recruiting) 
B-Vd vs D-Vd Phase 3: n = 575 (E) N/A DREAMM-7 (active, not recruiting) NCT04246047 
B-Pd vs V-Pd Phase 3: n = 450 (E) N/A DREAMM-8 (recruiting) NCT04484623 
B-VRd (transplant-ineligible NDMM33  Phase 1: n = 144 (E) ORR 100%
(n = 12) 
DREAMM-9 (recruiting) NCT04091126 
Monotherapy in renal impairment Phase 1: n = 36 (E) N/A DREAMM-12 (recruiting) NCT04398745 
Monotherapy in liver impairment Phase 1: n = 28 (E) N/A DREAMM-13 (recruiting)
NCT04398680 
   Monotherapy
(varying doses and schedules) 
Phase 2: n = 180 (E) N/A DREAMM-14 (recruiting) NCT05064358 
AMG 224 BCMA Mertansine Monotherapy36  Phase 1: n = 42 (E) ORR 27%
(3  mg/kg) 
NCT02561962 (active, not recruiting) 
CC 99712 BCMA Maytansinoid-like Monotherapy Phase 1: n = 160 (E) N/A NCT04036461 (recruiting) 
MEDI2228 BCMA PBD Monotherapy37  Phase 1: n = 82 ORR 66% at 0.14  mg/kg NCT03489525 (completed) 
Indatuximab ravtansine CD138 Maytansinoid
DM4 
In combination with R or P Phase 1/2: n = 64 ORR 71.7% with R and 70.6% with P NCT01001442 (completed) 
Lorvotuzumab mertansine CD56 Mertansine Monotherapy Phase 1: n = 37 ORR 5.7% NCT00346255 (completed) 
Milatuzumab CD74 Doxorubicin Monotherapy Phase 1: n = 25 26% SD NCT00421525 (completed) 
STRO-001 CD74 MMAF Monotherapy Phase 1: n = N/A N/A NCT03424603 (recruiting) 
DFRF4539A FcRH5 MMAE Monotherapy Phase 1: n = 39 ORR 5%; 49% SD NCT01432353 (completed) 
SGN-CD48A CD48 MMAE Monotherapy Phase 1: n = 14 N/A NCT03379584 (terminated) 
ABBV-838 SLAMF7 MMAE Monotherapy Phase 1/1b: n = 75 ORR 10.7% NCT02462525 (terminated) 

Note: This list is not exhaustive for all ADCs developed for MM.

B, belantamab; belamaf, belantamab mafodotin; D, daratumumab; d, dexamethasone; E, estimate; MMAE, monomethyl auristatin E; N/A, not available; Pemb, pembrolizumab; P, pomalidomide; Q3W, once every 3 weeks; R, lenalidomide; SD, stable disease; V, bortezomib.

Belantamab mafodotin (GSK2857916), a first-in-class humanized IgG1, afucosylated ADC conjugated to monomethyl auristatin-F (MMAF), was the first ADC to demonstrate significant therapeutic benefit in MM. Preclinical studies demonstrate that belantamab mafodotin eliminates myeloma cells through several mechanisms of action: direct cell killing via the inhibition of microtubule polymerization, classical IgG effector functions through an enhanced fragment crystallizable region (Fc) domain, and immunogenic cell death, a process in which dying cells elicit an adaptive immune response.27 

Belantamab mafodotin was evaluated in the pivotal DREAMM-2 study.28  This phase 2 study explored doses of 2.5  mg/kg or 3.4  mg/kg administered intravenously every 3 weeks until progression. In patients receiving the US Food and Drug Administration–approved 2.5-mg/kg dose (n = 97), all were TCR and had a median of 7 (3-12) prior lines of therapy. The ORR was 31% (97.5% CI, 20.8–42.6), and the median PFS and OS were 2.8 (95% CI, 1.6–3.6) and 13.7 months (95% CI, 9.9-not reached), respectively. For responding patients, the DOR was 11 months (95% CI, 4.2-not reached). Post hoc analyses demonstrated similar response and OS in patients with high-risk cytogenetics and those with impaired renal function, although patients with extramedullary disease did not appear to derive the same benefit.28  Consistent with MMAF-containing ADCs, the most common AEs (any grade/grade ≥3) were keratopathy (72%/46%), change in best corrected visual acuity (54%/31%), thrombocytopenia (38%/22%), anemia (27%/21%), and blurred vision (25%/4%). Dose reductions and delays due to toxicity occurred in 54% and 35%, respectively, and were less common in the 2.5-mg/kg arm of the study.

Belantamab mafodotin is US Food and Drug Administration approved for use in RRMM patients who have received 4 or more lines of therapy. The approval came with a boxed warning, indicating that toxicity to the cornea may result in vision loss, corneal ulcers, or dry eyes. Although the mechanism is yet unclear, preclinical data suggest that ocular toxicity is related to the receptor- independent uptake of the intact ADC into the epithelial limbal stem cells of the cornea.29  In DREAMM-2, 72% of patients in the 2.5-mg/kg cohort demonstrated keratopathy on ophthalmologic exam; however, only 56% experienced symptoms (most commonly blurred vision and/or dry eyes), and only 3 patients (3%) discontinued therapy for corneal AEs.28  Importantly, experience from DREAMM-2 indicates that patients recover from corneal toxicity with dose holds for grade 2 events or higher, with the majority of patients (88%) maintaining responses despite prolonged dose delays. Based on this experience, the recommendations for management of corneal events include the frequent use of preservative-free lubricant eye drops, eye care professional assessments before each dose, and timely dose holds and modifications.

Numerous studies are now evaluating belantamab mafodotin in different drug combinations, dosing schedules, and treatment settings (Table 2). This includes studies combining belantamab mafodotin with pembrolizumab (DREAMM-4),30  with novel agents (DREAMM-5),31  with lenalidomide or bortezomib (DREAMM-6),32  and with RVd in NDMM (DREAMM-9).33  Notably, in the Algonquin study, belantamab mafodotin was combined with Pd to identify the optimal dose and schedule in pomalidomide-naive patients.34  Across cohorts of patients receiving belantamab mafodotin, 1.92  mg/kg every 4 weeks or 2.5  mg/kg every 4, 8, or 12 weeks (n = 56), the ORR was 88.9% (≥ very good partial response [VGPR], 72%) and PFS, 17 months (14.5-not reached); notably, 48% of patients were TCR.34  Additionally, studies exploring lower doses and extended schedules of belantamab mafodotin as a strategy to reduce the incidence and severity of corneal toxicity are ongoing (DREAMM-9, DREAMM-14, and NCT04808037). Emerging data from these studies are encouraging, demonstrating a reduction in the incidence and severity of corneal toxicity with good clinical efficacy.34,35 

Several other ADCs targeting BCMA have been developed. AMG 224 is a humanized IgG1 anti-BCMA mertansine-conjugated ADC. In a phase 1 study, at the expansion dose of 3  mg/kg (n = 11) the ORR was 27%.36  Mild ocular events were observed in 30% of patients with no reports of keratopathy. MEDI2228 is another humanized pyrrolobenzodiazepine (PBD)-conjugated anti-BCMA ADC. In a first-in-human study, an ORR of 65.9% was reported at the maximum tolerated dose (MTD) of 0.14  mg/kg (n = 41).37  The safety profile was consistent with PBD-containing ADCs and included rash (31.7%), thrombocytopenia (31.7%), pleural effusions (24.4%), and increased gamma- glutamyl transferase (24.4%). Unexpectedly, ocular AEs in the form of photophobia were reported in 58.5% of patients. Phase 1 studies of CC-99712, an anti-BCMA ADC conjugated to 4 maytansinoid molecules, and HDP-101, an anti-BCMA ADC conjugated to an amanitin derivative, are recruiting (NCT04036461 and NCT04879043, respectively).

ADCs targeting antigens other than BCMA have shown less promising efficacy in MM. Table 2 summarizes the current state of development of indatuximab ravtansine (anti-CD138), lorvotuzumab mertansine (anti-CD56), STRO-001 (anti-CD74), and several other ADCs with novel targets, most having had their development halted due to disappointing efficacy.

BsAbs are unique antibody constructs that simultaneously bind 2 antigens. In cancer therapeutics, this usually involves targeting an antigen on the tumor and a molecule on an immune cell, resulting in immune effector cell activation and tumor lysis (Figure 2). Similar to the ADCs, BCMA has been the selected antigen target for the development of BsAbs, although others have emerged (Table 3).

Figure 2.

Characteristics of BsAbs. IgG-like BsAbs include an Fc region, while non–IgG-like BsAbs consist of only Fab (fragment antigen-binding) variable regions and linkers. Since the Fc portion provides stability and longevity to the molecule in circulation, most non–IgG-like BsAbs require more frequent dosing to maintain therapeutic plasma levels; they also lack the Fc-mediated effector functions such as antibody-dependent T-cellular cytotoxicity and complement-dependent cytotoxicity. Several BsAbs, both IgG-like and non–IgG-like, are under development for the treatment of MM. BiAb, bispecific antibodies.

Figure 2.

Characteristics of BsAbs. IgG-like BsAbs include an Fc region, while non–IgG-like BsAbs consist of only Fab (fragment antigen-binding) variable regions and linkers. Since the Fc portion provides stability and longevity to the molecule in circulation, most non–IgG-like BsAbs require more frequent dosing to maintain therapeutic plasma levels; they also lack the Fc-mediated effector functions such as antibody-dependent T-cellular cytotoxicity and complement-dependent cytotoxicity. Several BsAbs, both IgG-like and non–IgG-like, are under development for the treatment of MM. BiAb, bispecific antibodies.

Close modal
Table 3.

Summary of bispecific T-cell antibodies for MM

NameTargetAntibody constructTriple-class refractory (median LoT)Trial phaseSchedulePreliminary response/activitySafetyCurrent status (ClinicalTrials.gov)
AMG 42038  BCMA-CD3 BiTE® N/A (29% prior anti-CD38, median 5 LoT) Phase 1 Continuous infusion for 4 wk (out of 6) ORR = 31%
ORR MTD = 70% 
38% CRS (6.25% ≥ gr 3)
5% ≥ gr 3 polyneuropathy
24% ≥ gr 3 infection 
Active, not recruiting
NCT03836053 
AMG 70139  BCMA-CD3 HLE-BiTE® 68% (median 6 LoT) Phase 1/2 Weekly IV ORR = 36%
ORR = 83% at 9  mg 
75% CRS (10.5% ≥ gr 3)
8% neurotoxicity (gr 1-2)
13% ≥ gr 3 infection 
Recruiting
NCT03287908 
Elranatamab41  BCMA-CD3 Humanized IgG2a Fc 91% (median 6 LoT; 22% prior anti-BCMA) Phase 1 Weekly or every 2 wk Sc ORR = 64% for doses ≥215  µg/kg 67% CRS (gr 1-2) MagnetisMM-1 Recruiting
NCT03269136 
REGN545842  BCMA-CD3 Fc Fab arms 97.1% (median 5 LoT) Phase 1/2 Weekly IV ORR = 73.3% at 96-200-mg doses 38.2% CRS (gr 1-2)
4% neurotoxicity (gr 1-2)
23% pneumonia (11% ≥ gr 3) 
Recruiting
NCT03761108 
Teclistamab40  BCMA-CD3 Humanized IgG4 Fc 77.8% (median 5 LoT; prior anti-BCMA not permitted) Phase 1/2 Weekly Sc ORR = 63% 72.1% CRS (gr 3, 0.6%; no gr 4)
14.5% neurotoxicity (1 gr 4 event)
44.8% ≥ gr 3 infection 
MajestTEC-1 Recruiting
NCT03145181 
CC-9326944  BCMA-CD3 Asymmetric 2-arm IgG 66.7% (median 6 LoT) Phase 1 Weekly IV ORR = 83.3% in 10 pts with doses ≥6  mg 89.5% CRS (1 gr 5 event)
26.3% infection 
Recruiting
NCT03486067 
TNB-383B44  BCMA-CD3 IgG4 Fc CD3 activating T effector cells 62% (median 5 LoT) Phase 1 Q21d IV ORR = 79% at doses ≥40  mg 52% CRS (3% ≥ gr 3 at RP2D)
28% infection 
Recruiting
NCT03933735 
Cevostamab45  FcRH5-CD3 Humanized IgG1 Fc 85% (median 6 LoT; 33.5% prior anti-BCMA) Phase 1 Q21d IV ORR = 54.5% at 160-mg-dose level 80.7% CRS (1.3% ≥ gr 3)
18.8% ≥ gr 3 infection
14.3% neurotoxicity (0.3% ≥ gr 3) 
Recruiting
NCT03275103 
Talquetamab46  GPRC5D-CD3 Humanized IgG4 Fc Weekly: 77% (median 6 LoT; 30% prior anti-BCMA)
Biweekly: 65% (median 5 LoT; 17% prior anti-BCMA) 
Phase 1/2 Weekly or biweekly Sc Weekly: ORR = 70%
Biweekly: ORR = 71% 
Weekly: 73% CRS (1 gr 3)
Biweekly: 78% CRS (gr 1-2) 
MonumenTal-1
Recruiting
NCT03399799 
NameTargetAntibody constructTriple-class refractory (median LoT)Trial phaseSchedulePreliminary response/activitySafetyCurrent status (ClinicalTrials.gov)
AMG 42038  BCMA-CD3 BiTE® N/A (29% prior anti-CD38, median 5 LoT) Phase 1 Continuous infusion for 4 wk (out of 6) ORR = 31%
ORR MTD = 70% 
38% CRS (6.25% ≥ gr 3)
5% ≥ gr 3 polyneuropathy
24% ≥ gr 3 infection 
Active, not recruiting
NCT03836053 
AMG 70139  BCMA-CD3 HLE-BiTE® 68% (median 6 LoT) Phase 1/2 Weekly IV ORR = 36%
ORR = 83% at 9  mg 
75% CRS (10.5% ≥ gr 3)
8% neurotoxicity (gr 1-2)
13% ≥ gr 3 infection 
Recruiting
NCT03287908 
Elranatamab41  BCMA-CD3 Humanized IgG2a Fc 91% (median 6 LoT; 22% prior anti-BCMA) Phase 1 Weekly or every 2 wk Sc ORR = 64% for doses ≥215  µg/kg 67% CRS (gr 1-2) MagnetisMM-1 Recruiting
NCT03269136 
REGN545842  BCMA-CD3 Fc Fab arms 97.1% (median 5 LoT) Phase 1/2 Weekly IV ORR = 73.3% at 96-200-mg doses 38.2% CRS (gr 1-2)
4% neurotoxicity (gr 1-2)
23% pneumonia (11% ≥ gr 3) 
Recruiting
NCT03761108 
Teclistamab40  BCMA-CD3 Humanized IgG4 Fc 77.8% (median 5 LoT; prior anti-BCMA not permitted) Phase 1/2 Weekly Sc ORR = 63% 72.1% CRS (gr 3, 0.6%; no gr 4)
14.5% neurotoxicity (1 gr 4 event)
44.8% ≥ gr 3 infection 
MajestTEC-1 Recruiting
NCT03145181 
CC-9326944  BCMA-CD3 Asymmetric 2-arm IgG 66.7% (median 6 LoT) Phase 1 Weekly IV ORR = 83.3% in 10 pts with doses ≥6  mg 89.5% CRS (1 gr 5 event)
26.3% infection 
Recruiting
NCT03486067 
TNB-383B44  BCMA-CD3 IgG4 Fc CD3 activating T effector cells 62% (median 5 LoT) Phase 1 Q21d IV ORR = 79% at doses ≥40  mg 52% CRS (3% ≥ gr 3 at RP2D)
28% infection 
Recruiting
NCT03933735 
Cevostamab45  FcRH5-CD3 Humanized IgG1 Fc 85% (median 6 LoT; 33.5% prior anti-BCMA) Phase 1 Q21d IV ORR = 54.5% at 160-mg-dose level 80.7% CRS (1.3% ≥ gr 3)
18.8% ≥ gr 3 infection
14.3% neurotoxicity (0.3% ≥ gr 3) 
Recruiting
NCT03275103 
Talquetamab46  GPRC5D-CD3 Humanized IgG4 Fc Weekly: 77% (median 6 LoT; 30% prior anti-BCMA)
Biweekly: 65% (median 5 LoT; 17% prior anti-BCMA) 
Phase 1/2 Weekly or biweekly Sc Weekly: ORR = 70%
Biweekly: ORR = 71% 
Weekly: 73% CRS (1 gr 3)
Biweekly: 78% CRS (gr 1-2) 
MonumenTal-1
Recruiting
NCT03399799 

Note: This list is not exhaustive for all bispecific T-cell antibodies developed for MM.

Fab, fragment antigen-binding; gr, grade; HLE, half-life extended; IV, intravenous; LoT, lines of therapy; pts, patients; Q21d, every 21 days; RP2D, recommended phase 2 dose; Sc, subcutaneous; wk, week.

AMG 420, which targets BCMA on PCs and CD3 on T cells, was the first BsAb to show efficacy in human trials. Coined a BiTE® (bispecific T-cell engager) because it lacks an Fc region, AMG 420 justified the development of bispecifics in MM, demonstrating a 70% ORR at the MTD (400  µg/d; n = 10).38  The BiTE® format offers the advantage of better tissue penetrance and access to epitopes but with the caveat of a short half-life, necessitating a continuous intravenous infusion. This has been remedied by the development of an extended half-life version, AMG 701,39  and numerous Fc-containing BsAbs that can be administered every 1 to 3 weeks, with the majority moving to subcutaneous formulations (Table 3).4046  Fc-containing bispecifics are larger and therefore more stable in circulation, while the Fc function may or may not be silenced depending on the agent. Thus far, BsAbs have been evaluated in heavily pretreated patients, with the majority being TCR; a good number have also included older patients (>80 years). All have demonstrated encouraging clinical activity (Table 3), although data on durability of responses are still immature.

Teclistamab, an anti-BCMA/CD3 BsAb, is furthest along in clinical development, with an anticipated commercial approval in 2022. In the phase 1/2 MajesTEC-1 study, 165 patients received teclistamab (77.8% TCR) at the recommended target dose of 1.5  mg/kg.40  The ORR was 63% (≥complete remission, 39.4%), with 44 patients (26.7%) achieving MRD (10−5). Responses were maintained across different subgroups, including poor-risk groups, with the exception of those with extramedullary disease, those with stage III disease, or those with PC marrow involvement of 60% or greater. The median DOR was 18.4 months (95% CI, 14.9-not estimable), while the PFS was 11.3 months (95% CI, 8.8-17.1). CRS, neutropenia, infection, and neurotoxicity of any grade/grade higher than or equal to 3 occurred in 72.1%/0.6%, 70.9%/64.2%, 76.4%/44.8%, and 14.5%/0%, respectively; 19 patients died from AEs, including 12 deaths due to COVID-19.

In the phase 1 MagnetisMM-1 study, elranatamab (PF-06863135), another anti-BCMAxCD3 BsAb, demonstrated an ORR of 64% among 55 patients (91% TCR) receiving doses of 215  µg/kg or higher.41  Remarkably, 7 of 10 patients treated with prior BCMA-targeted therapy achieved a partial response or better.41  The incidence of CRS at the recommended dose (1000  µg/kg or 76  mg) was 67% (all grade 1/2).41  Studies of teclistamab and elranatamab in combination with immunomodulatory drugs and anti-CD38s and in earlier lines of treatment are ongoing (Table 4).

Table 4.

Summary of bispecific T-cell antibody combinations for MM

NamePatient populationTrial phaseCombination drugsCurrent status (ClinicalTrials.gov)
Elranatamab RRMM Phase 1b/2 Arm 1: elranatamab + nirogacestat (GSI) MagnetisMM-4 (recruiting) NCT05090566 
Arm 2: elranatamab + lenalidomide + dexamethasone 
Phase 3 Arm 1: elranatamab MagnetisMM-5 (recruiting) NCT05020236 
Arm 2: elranatamab + daratumumab 
Arm 3: earatumumab + pomalidomide + dexamethasone 
Teclistamab + talquetamab RRMM Phase 3 Arm 1: teclistamab + daratumumab MajestTEC-3 (recruiting) NCT05083169 
Arm 2: daratumumab + pomalidomide + dexamethasone 
Arm 3: daratumumab + bortezomib + dexamethasone 
Phase 1 Arm 1: teclistamab + talquetamab NCT04586426 (recruiting) 
Arm 2: teclistamab + talquetamab + daratumumab 
Phase 1b Arm 1: daratumumab + teclistamab TRIMM-2 (recruiting) NCT04108195 
Arm 2: daratumumab + talquetamab 
Arm 3: daratumumab + talquetamab + pomalidomide 
Arm 4: daratumumab + teclistamab + pomalidomide 
Cevostamab RRMM Phase 1 Arm 1: cevostamab Recruiting NCT04910568 
Arm 2: cevostamab + pomalidomide + dexamethasone 
Arm 3: cevostamab + daratumumab + dexamethasone 
NamePatient populationTrial phaseCombination drugsCurrent status (ClinicalTrials.gov)
Elranatamab RRMM Phase 1b/2 Arm 1: elranatamab + nirogacestat (GSI) MagnetisMM-4 (recruiting) NCT05090566 
Arm 2: elranatamab + lenalidomide + dexamethasone 
Phase 3 Arm 1: elranatamab MagnetisMM-5 (recruiting) NCT05020236 
Arm 2: elranatamab + daratumumab 
Arm 3: earatumumab + pomalidomide + dexamethasone 
Teclistamab + talquetamab RRMM Phase 3 Arm 1: teclistamab + daratumumab MajestTEC-3 (recruiting) NCT05083169 
Arm 2: daratumumab + pomalidomide + dexamethasone 
Arm 3: daratumumab + bortezomib + dexamethasone 
Phase 1 Arm 1: teclistamab + talquetamab NCT04586426 (recruiting) 
Arm 2: teclistamab + talquetamab + daratumumab 
Phase 1b Arm 1: daratumumab + teclistamab TRIMM-2 (recruiting) NCT04108195 
Arm 2: daratumumab + talquetamab 
Arm 3: daratumumab + talquetamab + pomalidomide 
Arm 4: daratumumab + teclistamab + pomalidomide 
Cevostamab RRMM Phase 1 Arm 1: cevostamab Recruiting NCT04910568 
Arm 2: cevostamab + pomalidomide + dexamethasone 
Arm 3: cevostamab + daratumumab + dexamethasone 

Note: This list is not exhaustive for all bispecific T-cell antibody combinations developed for MM.

GSI, gamma secretase inhibitor.

Other notable anti-BCMA BsAbs include REGN5458, CC-93269, and TNB-383B (Table 3). In a phase 1/2 trial of REGN5458, the ORR was 73.3% among patients treated at the 96-mg- and 200-mg-dose levels; no patients experienced CRS of grade 3 or higher.42  Of the 12 patients treated with 6  mg or more of CC-93269, the ORR was 83.3%.43  CRS was reported in 89.5% of patients, mostly grade 1/2 (57.9%/26.3%); however, one patient died in the setting of CRS, with infection as a potential contributor.43  In the dose-escalation cohort of TNB-383B (doses ≥40  mg every 3 weeks), the ORR was 79% (n = 19/24) with CRS reported as mainly grade 1/2.44 

Fc receptor homolog 5 (FcRH5) is a cell surface antigen of unknown function whose expression is restricted to B cells, with the highest expression on PCs. BFCR4350A (cevostamab) is a humanized IgG Fc antibody targeting FcRH5 and CD3. In an ongoing phase 1 study, cevostamab was administered for a fixed duration of 17 cycles, unlike other BsAb trials that treat to progression.45  Among 160 patients (85% TCR), the ORR was 56.7% and 36.1% for those patients receiving doses of 132 to 198  mg (n = 60) or 20 to 90  mg (n = 83), respectively. The ORR among patients who had prior CAR T-cell or anti-BCMA therapy was 44.4% and 36.4%, respectively. CRS was observed in 80.7% (128/160) of patients (mainly grade 1/2; 2 cases grade 3). In the single step-up dose cohorts (n = 86), the median DOR was 11.5 months (95% CI, 6.0, 18.4) at a follow-up of 14.3 months. Thus, cevostamab appears to be a beneficial treatment option, with a unique therapeutic target, for RRMM patients.

Talquetamab is an IgG4 Fc-containing BsAb targeting G- protein–coupled receptor family C group 5 member D (GPRC5D).46  GPRC5D is highly expressed on PCs but also on keratinized tissues. In the MonumenTal-1 study, patients received subcutaneous talquetamab at doses of 405 µg/kg (n = 30) weekly or 800  µg/kg biweekly (n = 23).44  Unique AEs, owing to the expression of GPRC5D on keratinized tissues, include dysgeusia, palmar/plantar desquamation, nail dystrophy, and systemic rash, which were reported in 75% of patients (mostly grade 1/2; 7.5% grade 3).46  Mitigation strategies for these toxicities included the use of emollient creams and, for oral AEs, saliva-substitute sprays and rinses at the onset of symptoms. The ORR and CRS in patients receiving the 405-µg/kg or 800-µg/kg dose was 70% and 73% (1 grade 3) and 71% and 78% (all grade 1/2), respectively.46  Trials exploring talquetamab in combination with teclistamab, as well as with SOC antimyeloma agents, are actively recruiting (Table 4).

The patient responds to belantamab mafodotin; however, she experiences multiple dose interruptions for corneal AEs and progresses after 9 months. She is then referred to an academic center and is enrolled in a clinical trial evaluating talquetamab (anti-GPRC5D) monotherapy. In cycle 1 she experiences grade 1 CRS but no neurotoxicity. After 6 months of therapy, she continues to have an ongoing response with manageable grade 1 dysgeusia and dermatologic symptoms.

Alongside CAR T-cell therapy, antibody-based immunotherapies have emerged as important off-the-shelf therapeutic options for all patients with RRMM (Table 5). The sequencing and duration of these therapies remain ongoing clinical questions, although emerging data are encouraging. In a heavily pretreated RRMM population relapsing on a BsAb (n = 64), the ORR to subsequent treatment (second BsAb, n = 20; CAR T, n = 15) was 58%, with an OS of 17.6 months (95% CI, 21.6-not reached).47  Further, in the MagnetisMM-1 study, 7 of 13 patients previously treated with an anti-BCMA targeted therapy (5/7 for those treated with anti-BCMA ADCs) responded to the BCMAxCD3 BsAb, elranatamab.41  Meanwhile in the ongoing phase 1 study of cevostamab (FCRH5xCD3 BsAb) that limited treatment to 17 cycles, 6 patients continued to maintain responses for 6 months or longer after the cessation of treatment.45 

Table 5.

Comparison of novel immunotherapy approaches in multiple myeloma

Antibody drug conjugatesBispecific T-cell engagersCAR T-cell therapy
Advantages Off-the-shelf therapy Off-the-shelf therapy 
Immune and nonimmune mechanisms of action 
Infrequent dosing (every 3 wk-12 wk) One-time therapy 
Encouraging response rates Deep responses Deep responses 
No CRS/ICANS Mostly grade 1-2 CRS/ICANS 
Outpatient administration Only initial dosing as inpatient Vacation from continuous therapy 
Disadvantages Continuous therapy until progression Continuous therapy until progression 
Frequent dose interruptions Weekly or biweekly dosing Administration delays due to manufacturing time 
Ocular toxicity Significant immunosuppression Potential for severe CRS/ICANS; prolonged cytopenias 
Ophthalmic exams prior to dosing Specialized centers required Complex infrastructure required 
Cost ($$) Cost ($$) Cost ($$$) 
Antibody drug conjugatesBispecific T-cell engagersCAR T-cell therapy
Advantages Off-the-shelf therapy Off-the-shelf therapy 
Immune and nonimmune mechanisms of action 
Infrequent dosing (every 3 wk-12 wk) One-time therapy 
Encouraging response rates Deep responses Deep responses 
No CRS/ICANS Mostly grade 1-2 CRS/ICANS 
Outpatient administration Only initial dosing as inpatient Vacation from continuous therapy 
Disadvantages Continuous therapy until progression Continuous therapy until progression 
Frequent dose interruptions Weekly or biweekly dosing Administration delays due to manufacturing time 
Ocular toxicity Significant immunosuppression Potential for severe CRS/ICANS; prolonged cytopenias 
Ophthalmic exams prior to dosing Specialized centers required Complex infrastructure required 
Cost ($$) Cost ($$) Cost ($$$) 

ICANS, immune effector cell-associated neurotoxicity syndrome; wk, week.

While ADCs and BsAbs demonstrate promising efficacy, future efforts need to focus on the optimal timing and duration of therapy, on combinational strategies, on mitigation of the risk of immunosuppression/infection (BsAbs) and corneal toxicity (ADC), on the mechanisms of resistance, and on equitable access. Although much work is still to be done, these novel approaches offer new hope for a yet incurable disease.

Christopher Cipkar: no competing financial interests to declare.

Christine Chen: consultancy: Forus Therapeutics; advisory board: Amgen, Bristol Myers Squibb, Janssen Pharmaceuticals.

Suzanne Trudel: research funding: Amgen, Bristol Myers Squibb, Genentech, GlaxoSmithKline, Janssen Pharmaceuticals, Pfizer, Roche; consultancy: Bristol Myers Squibb, Forus, GlaxoSmithKline, K36 Therapeutics, Roche; advisory board: Amgen, Bristol Myers Squibb, GlaxoSmithKline, Janssen Pharmaceuticals, Pfizer, Sanofi.

Christopher Cipkar: nothing to disclose.

Christine Chen: nothing to disclose.

Suzanne Trudel: nothing to disclose.

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