Top advances of the year: Bispecific antibodies in early lines of therapy in multiple myeloma

Short abstract

After their introduction as therapy for highly refractory multiple myeloma, bispecific T‐cell engagers have recently yielded exceptionally deep and durable responses in earlier lines of therapy, including early data in newly diagnosed disease. Multiple challenges remains, including optimal setting and combination, mitigation of toxicities, and refinement of optimal duration of therapy.

INTRODUCTION

Bispecific antibodies (BsAbs) are engineered molecules designed to simultaneously bind CD3 on T cells and a tumor‐/tissue‐associated antigen on malignant cells—most commonly B‐cell maturation antigen (BCMA), G‐protein coupled receptor class C group 5 member D (GPRC5D), Fc receptor homolog 5 (FCRH5), or CD38 in multiple myeloma (MM). Upon dual binding, BsAbs facilitate formation of an immunologic synapse between the T cell and the myeloma cell. Crosslinking of the CD3ε subunit and CD45 phosphatase spatial exclusion triggers T‐cell activation independent of native T‐cell receptor specificity and without reliance on major histocompatibility complex–mediated antigen presentation. Activated T cells then undergo degranulation, releasing perforin and granzymes into the synapse, while also secreting proinflammatory cytokines such as interferon‐γ and tumor necrosis factor‐α. Perforin‐mediated pore formation allows granzymes to enter the tumor cell and initiate apoptotic signaling pathways, resulting in targeted myeloma cell lysis.

BsAbs have become part of the anti‐MM armamentarium primarily for patients with relapsed and refractory multiple myeloma (RRMM) and multiple lines of therapy (LOT), owing to single‐arm trials in patients previously exposed to an immunomodulatory agent (IMiD), a proteasome inhibitor (PI), and an anti‐CD38 mAb (Table 1). ¹ , ² , ³ , ⁴ , ⁵ , ⁶ Most patients will experience a deep and enduring response. Yet, in advanced disease, BsAbs do not produce objective response in 30% to 40% of patients, presumably because of disease burden, poor T‐cell fitness, or antigen loss/modification. ¹⁰ , ¹¹ , ¹² , ¹³ Additionally, attrition rates and decreased patient fitness worsen with each LOT underscoring the importance of deploying effective therapies earlier in the disease course to maximize patient benefit.

TABLE 1.

Trials reporting outcome of bispecific T‐cell engagers in late lines and early lines in relapsed/refractory multiple myeloma.

	Late line: RRMM				Early line: RRMM
	MajesTEC‐1 1 , 2	MagnetisMM‐3 3 , 4	Linker‐MM1 5	MonumenTAL‐1 6 , 7	MajesTEC‐3 8	MajesTEC‐9 9
Treatment	Teclistamab	Elranatamab	Linvoseltamab	Talquetamab a	Tec‐Dara	Teclistamab
N	165	123	117	143–154	291	299
Active comparator	NA	NA	NA	NA	DPd/DVd	PVd/Kd
Median age	64	68	70	67–67	64	70
Cytogenetic high risk	26%	25%	39%	31%–30%	37%	36%
Median prior LOT	5	5	5	5–4.5	2	2
Lenalidomide exposed	100%	100%	100%	100%	100%	100%
Lenalidomide refractory	92%	NA	NA	80%–71%	83%	79%
Anti‐CD38 mAb exposed	100%	100%	100%	100%	5%	100%
Anti‐CD38 mAb refractory	90%	NA	NA	94%–92%	0%	86%
Prior PI	100%	100%	100%	100%	100%	87%
≥CR	46%	37%	52%	33%–40%	82%	66%
MRD negativity (10–5 threshold)	29%	23%	27%	NR–NR	58%	39%
Median follow‐up (mo)	30.4	28.4	21.3	35.6–19.4	34.5	17.3
Median PFS (mo)	11.4	17.2	NR	7.5–11.2	NR	NR
Milestone PFS	NA	NA	60% at 18 months	NA	83% at 36 months	70% at 18 months
PFS HR (95% CI)	NA	NA	NA	NA	0.17 (0.12–0.23)	0.29 (0.23–0.38)
Median OS (mo)	22.2	24.6	31.4	34.0–NR	NR	NR
Milestone OS	NA	NA	NA	49%–61% at 36 months	83% at 36 months	79% at 18 months
OS HR (95% CI)	NA	NA	NA	NA	0.46 (0.32–0.65)	0.60 (0.43–0.83)

Abbreviations: DPd, daratumumab, pomalidomide, dexamethasone; DVd, daratumumab, bortezomib, dexamethasone; HR, hazard ratio; Kd, carfilzomib, dexamethasone; NA, not applicable; NR, not reached/not reported; OS, overall survival; PFS, progression‐free survival; PI, proteasome inhibitor; PVd, pomalidomide, bortezomib, dexamethasone; RRMM, relapsed and refractory multiple myeloma.

^acohort receiving 400 mcg/kg weekly or 800 mcg/kg every 2 weeks, respectively.

It is expected that lower disease burden, improved immune fitness, and less genomic heterogeneity and instability would result in better efficacy of BsAbs in earlier lines. Indeed, clinical data consistently demonstrate that bispecific antibodies achieve longer progression‐free survival when used earlier in the disease course. The MajesTEC‐1 study with the BCMA‐directed BsAb teclistamab, median progression‐free survival (PFS) was 21.7 months for patients with ≤3 prior lines compared to 9.7 months for those with >3 prior lines. ¹⁴ Similarly, the GPRC5D‐directed BsAb talquetamab showed median PFS of 17.8 months in patients with ≤4 prior lines versus 8.5 months in those with >4 prior lines, are reported in the MonumenTAL‐1 trial. ⁷ , ¹⁵

Here, we summarize recent information on the outcomes of BsAbs in earlier LOT, discuss implication to clinical practice, and summarize important ongoing trials that are likely to shape BsAb use, and consequently the MM therapeutic landscape, in the upcoming years.

BISPECIFIC ANTIBODIES FOR RRMM IN EARLIER LINES

MajesTEC‐ 3 trial

This trial is the first phase 3 trial with a BsAb in MM. ¹⁴ Patients with RRMM, one to three prior LOTs, with prior exposure to lenalidomide and a PI, and without refractoriness to anti‐CD38 monoclonal antibody were randomized to either a combination of teclistamab and daratumumab (Tec‐Dara) or an investigator’s choice of daratumumab containing triplet, either daratumumab, pomalidomide and dexamethasone (DPd), or daratumumab, bortezomib, and dexamethasone. After median follow‐up of 34.5 months, and at first interim analysis, patients on Tec‐Dara had improvement in the primary endpoint of PFS over DPd/DVd (hazard ratio [HR] = 0.17; 95% CI, 0.12–0.23). The 3‐year PFS rate was 83.4% for Tec‐Dara and 29.7% for DPd/DVd.

The percentage of patients who had a complete response or better was significantly higher in Tec‐Dara (81.8% vs. 32.1%), as well as the proportion of patients achieving minimal residual disease (MRD) negativity by next‐generation sequencing (58.4% vs. 17.1%, when analyzed by intention to treat). Remarkably, overall survival (OS) was also improved with Tec‐Dara (HR = 0.46; 95% CI, 0.32–0.65) with 3‐year OS rates of 83.3% vs. 65.0% (Table 1).

Cytokine release syndrome (CRS) occurred in 60.1% of Tec‐Dara patients, all grades 1 or 2. Immune‐effector cells‐associated neurotoxicity syndrome was seen in 1.1%, all reversible. There was similar rate of grade 3 and 4 adverse events (95.1% vs. 96.6%). Serious adverse events occurred in 70.7% vs. 62.2% and deaths from treatment emergent adverse events in 7.1% vs. 5.9%, notwithstanding the much longer duration of treatment in Tec‐Dara (32.4 vs 16.1 months). Infections emerged as the most important toxicity associated with Tec‐Dara. Grade 3 and 4 infections occurred in 54.1% of patients in Tec‐Dara versus 43.3% in DPd/DVd. There were 13 deaths (4.6%) from infection in Tec‐Dara, nine being in patients not under intravenous immunoglobulin replacement, and 12 being in the first 6 months of treatment. With the introduction of an infection mitigation strategy, including universal Pneumocystis jirovecii pneumonia and herpes simplex virus prophylaxis and immunoglobulin replacement therapy (IgRT), there was only one subsequent infection‐related death. Remarkably, although high‐grade infections were more frequent with Tec‐Dara in the first 6 months of treatment, the rate was similar in the two groups beyond month 6. These findings support IgRT as a major supportive care advancement to reduce infectious risks and is now part of routine supportive care protocols. Most recently, experts are advising primary IgRT prophylaxis in all BsAb‐treated patients regardless of immunoglobulin G levels. ¹⁶ This trial also incorporated reduction in frequency of administration of teclistamab (from weekly to every 2 weeks to every 4 weeks), potentially affecting safety profile without compromising efficacy. The outstanding results of this combination fueled the interest in limited duration therapy. In fact, the LimiTEC trial, in more heavily pretreated patient population, suggests that patient sustaining deep response on teclistamab do not seem to have increase in risk of progression with treatment discontinuation, ¹⁷ a finding that needs to be further confirmed in comparative trials.

MajesTEC‐3 provides evidence to support Tec‐Dara as mainstream myeloma therapy as early as in second line, marking the transition of BsAbs from a niche late‐line therapy to a transformative, mainstream, off‐the‐shelf therapy with remarkable activity. This trial supported the approval in the United States of Tec‐Dara for patients with RRMM and one or more prior LOTs, and approval is expected to follow in other parts of the world.

MajesTEC‐9 trial

This randomized phase 3 trial is comparing teclistamab monotherapy versus standard‐of‐care regimens, either pomalidomide, bortezomib, and dexamethasone (PVd) or carfilzomib and dexamethasone (Kd) in patients with RRMM who have received one to three prior lines of therapy, including both an anti‐CD38 monoclonal antibody and lenalidomide. At median follow‐up of 17.3 months, patients randomized to teclistamab experienced a significant reduction in the hazard of disease progression or death (HR = 0.29; 95% CI, 0.23–0.38) and death from any cause (HR = 0.60; 95% CI, 0.43–0.83). ⁹ The estimated 18‐month PFS rate was 69.8% for teclistamab versus 26.9% for PVd/Kd. Patients receiving teclistamab underwent similar treatment deescalation and infection prophylaxis as in MajesTEC‐3. Grade 3 and 4 adverse events occurred in 84.9% of patients receiving teclistamab and 76.3% of those receiving PVd/Kd. Fatal adverse events occurred in 6.5% of patients on teclistamab and 3.5% in those on PVd/Kd. Most deaths in both groups were caused by infection.

Ongoing trials

MagnestisMM‐5 (NCT05020236) randomizes patients with RRMM, one to three prior LOTs, and prior exposure to lenalidomide and a PI, to treatment with either, the BCMA‐directed BsAb elranatamab as monotherapy or elranatamab plus daratumumab versus DPd. The eligibility and the expected patient population is similar to MajesTEC‐3, as such this study should help us discern the added benefit and potential risk of an anti‐CD38 mAb in combination with a BCMA‐directed BsAb. MagnetisMM‐32 (NCT06152575) randomizes patients with RRMM, one to four prior LOTs, prior therapy with anti‐CD38 mAb and lenalidomide, to treatment with elranatamab versus a standard combination regimen, either elotuzumab, pomalidomide, and dexamethasone (EPd) or PVd or Kd. Other randomized trials are ongoing testing the BCMA‐directed BsAb linvoseltamab (NCT05730036, NCT07222761) in earlier LOTs. The Cervino trial (NCT06158841) randomizes patients with RRMM and one or more prior LOT and exposure to PI, IMiD, and anti‐CD38 mAb to treatment with the BCMA‐directed BsAb etentamig or a standard combination regimen, either EPd, Kd or selinexor, bortezomib, and dexamethasone.

MonumenTAL‐3 (NCT05455320) randomized patients with RRMM, ≥1 prior LOT and prior exposure to lenalidomide and a PI to treatment with either talquetamab plus daratumumab, or talquetamab, pomalidomide, and daratumumab or DPd. This is expected to be the first phase 3 trial with a non–BCMA‐directed BsAb, and among other things will test clinically the impact of the synergistic addition of an IMiD to BsAb. MonumenTAL‐6 (NCT06208150) randomized patients with RRMM, one to four prior LOTs, prior exposure to lenalidomide, and an anti‐CD38 mAb to treatment with talquetamab plus pomalidomide, talquetamab plus teclistamab or a standard triplet, either EPd or PVd. One of the innovations of this trial is the combination of two BsAbs with different targets, a regimen previously shown to be highly active, particularly among patients with extramedullary disease, yet with important toxicity, in the single‐arm RedirecTT‐1 trial. ¹⁸

Contextualization with other therapies

The therapeutic options for patients with RRMM and one to three prior LOTs have been dominated by anti‐CD38 mAb‐based triplets and, in patients with anti‐CD38 mAb‐refractory disease, other carfilzomib‐based and pomalidomide‐based combinations. Recently, the BCMA‐directed chimeric antigen receptor T‐cells (CAR T‐cell) ide‐cel ¹⁹ , ²⁰ and cilta‐cel ²¹ , ²² have proven superiority over conventional regimens. In the case of cilta‐cel, that superiority was demonstrated even in patients with one prior LOT, and anti‐CD38 naïve, including with OS benefit. Another innovation in this space is the introduction of anti‐BCMA antibody‐drug conjugate belantamab mafodotin (belamaf) in combination with conventional agents. Belamaf, bortezomib, and dexamethasone yielded improved PFS and OS over DVd in patients with RRMM, 1+ prior LOT, and no refractoriness to anti‐CD38 mAb. ²³ Belamaf, pomalidomide and dexamethasone showed improved PFS over PVd in a population with lenalidomide‐exposed RRMM, including 23% of patients with anti‐CD38 refractory disease. ²⁴

Although BsAb, CAR T cells, and antibody‐drug conjugate–based triplets appear to deliver improved efficacy over legacy regimens, they have unique challenges regarding toxicity, access and affordability. These highly active therapies have not been directly compared to one another, and treatment choice is informed mostly by availability, perception of efficacy and toxicity, and patient preference.

BISPECIFIC ANTIBODIES IN NEWLY DIAGNOSED MULTIPLE MYELOMA

The ongoing phase 3 MagnetisMM‐6 trial randomized patients with newly diagnosed MM (NDMM) not eligible for autologous stem cell transplantation (ASCT) to treatment with elranatamab in combination with daratumumab and lenalidomide versus the standard daratumumab, lenalidomide, and dexamethasone regimen. Early data from single arm part 1 demonstrated that the elranatamab triplet can be administered safely with objective response rates of 97.3%, with the vast majority being very good partial responses or better (NCT0562302). ²⁵

In the multicohort MajesTEC‐5 (GMMG‐HD10/DSMM‐XX) study, teclistamab was combined with lenalidomide, daratumumab, and ± bortezomib as induction therapy for patients with NDMM and eligible for ASCT. All patients responded and all evaluable patients had MRD negativity after only three cycles of treatment and all achieved MRD negativity (10^–6 threshold) at the end of cycle 6. ²⁶

The single arm IFM2021‐01 trial (TecLille) explored the PI‐free, IMiD‐free, dexamethasone‐free combination of teclistamab and daratumumab in elderly, ASCT‐ineligible patients with NDMM. Early report with 37 patients demonstrated favorable safety profile with all patients obtaining a deep response and MRD negativity with no disease progression or deaths after median follow‐up of 10.3 months. ²⁷

Another approach taken with BsAb in NDMM is its use as monotherapy induction. In the single‐arm LINKER‐MM4 trial linvoseltamab yield response in 86% of patients receiving the optimal dose. ²⁸ Linvoseltamab monotherapy has also been employed as postinduction consolidation in a role traditionally served by ASCT. In the IMMUNOPLANT phase 2 trial, 17/19 patients with NDMM who remained MRD‐positive after initial combination therapy achieved MRD negativity after four cycles of linvoseltamab. ²⁹ Additionally, prophylactic tocilizumab was used as a CRS mitigation strategy, and although disease burden was low, no CRS events were reported. This supports that use of prophylactic tocilizumab, an emerging advancement to allow greater outpatient feasibility. Real‐world data have demonstrated that after just one dose of prophylactic tocilizumab, a low overall rate of CRS was observed (10.1%; 95% CI, 5.3–17). For teclistamab, elranatamab, linvoseltamab, and talquetamab individually, the CRS rates were 8.9%, 12.5%, 0%, and 13%, respectively. ³⁰

Last, BsAbs are being explored as post‐ASCT maintenance. The MajesTEC‐4/EMN30 explores teclistamab either as monotherapy or in combination with lenalidomide as maintenance therapy after ASCT. Preliminary report of a safety lead in cohort demonstrated that all 28 patients treated with teclistamab achieved MRD‐negative CR after 12 months of treatment. ³¹

These trials in NDMM demonstrate feasibility, safety, and incredible activity derived from the deployment of BsAb in patients without prior progression. Potential roles are being refined by ongoing trials, including as post‐ASCT maintenance (including with fixed duration), replacement for ASCT, or as a component of induction therapy, with and without ASCT consolidation.

FUTURE DIRECTIONS

Over the upcoming year, we expect clinical data from multitarget T‐cell engagers ³² such as ramantamig (BCMAxGPRC5DXCD3), ³³ , ³⁴ ISB2001 (BCMAxCD38xCD3), ³⁵ and SAR442257(CD38xCD3xCD28) ³⁶ to be generated in earlier lines of therapy, including NDMM. The expectation is that they may surpass the already impressive activity of BCMA and GPRC5D‐directed therapies, enabling strategies with less intense and fixed duration therapy and positioning T‐cell engagers as a cornerstone of MM therapy.

AUTHOR CONTRIBUTIONS

Heidi A. Worth and Luciano J. Costa cowrote the manuscript and provided final approval.

CONFLICT OF INTEREST STATEMENT

Dr. Worth declares no conflict of interest. Dr. Costa received research funding from AbbVie, Amgen, Janssen, Bristol Myers Squibb, and Genentech and honoraria from Amgen, Janssen, Bristol Myers Squibb, Adaptive Biotechnologies, Sanofi, and Pfizer.

FUNDING INFORMATION

None.