The New England Journal of Medicine AUGUST 11, 2022

Teclistamab in Relapsed or Refractory Multiple Myeloma

Philippe Moreau, Saad Z. Usmani, Adam D. Cohen, et al.

Bottom Line

In patients with heavily pretreated relapsed or refractory multiple myeloma, the BCMA-directed bispecific antibody teclistamab demonstrated significant and durable clinical activity with a manageable safety profile.

Key Findings

1. The primary endpoint was met, with an overall response rate (ORR) of 63.0% (95% CI, 55.2 to 70.4) among the 165 enrolled patients.

2. Deep clinical responses were observed, with 58.8% of patients achieving a very good partial response or better and 39.4% achieving a complete response or better.

3. Responses were durable, with a median duration of response of 18.4 months (95% CI, 14.9 to not estimable) at a median follow-up of 14.1 months.

4. Progression-free survival (PFS) was 11.3 months (95% CI, 8.8 to 17.1), indicating sustained disease control in a heavily pretreated population with a median of 5 prior lines of therapy.

5. The safety profile included high frequencies of cytokine release syndrome (72.1%, mostly grade 1 or 2) and neutropenia (70.9%), with infections occurring in 76.4% of patients.

Study Design

Design

Phase 1/2 Clinical Trial

Open-Label

Sample

165

Patients

Duration

14.1 mo

Median

Setting

Multicenter, 9 countries

Population Adults with relapsed or refractory multiple myeloma who received at least three prior lines of therapy, including a proteasome inhibitor, an immunomodulatory drug, and an anti-CD38 antibody, and were not previously exposed to BCMA-targeted therapy.

Intervention Subcutaneous teclistamab (1.5 mg/kg weekly) following step-up dosing (0.06 mg/kg and 0.3 mg/kg).

Comparator None (single-arm study).

Outcome Overall response rate (ORR), defined as a partial response or better, per International Myeloma Working Group (IMWG) 2016 criteria.

Study Limitations

• The study was a single-arm, open-label trial, lacking a randomized control group for direct comparison to standard-of-care treatments.

• The study population was limited to patients who had not previously received BCMA-targeted therapies, potentially limiting generalizability to patients with prior BCMA exposure.

• The relatively small sample size and specific inclusion criteria necessitate caution when extrapolating these results to the broader, more heterogeneous population of patients with relapsed or refractory myeloma.

• Long-term toxicity, particularly regarding the risk of severe infections, requires ongoing monitoring.

Clinical Significance

Teclistamab represents a major advancement in the treatment landscape for triple-class exposed relapsed or refractory multiple myeloma, providing an effective, off-the-shelf, T-cell redirecting therapeutic option for patients with limited alternatives.

Historical Context

Prior to the development of BCMA-directed bispecific antibodies like teclistamab, patients with relapsed or refractory multiple myeloma who had exhausted proteasome inhibitors, immunomodulatory drugs, and anti-CD38 antibodies faced poor outcomes. The success of MajesTEC-1 established the efficacy of redirecting T-cells to BCMA-expressing myeloma cells, leading to FDA approval as the first BCMA-directed bispecific antibody for this patient population.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What is the specific mechanism of action by which teclistamab facilitates the destruction of malignant plasma cells in multiple myeloma?

Key Response

Teclistamab is a bispecific T-cell engager (BiTE) that simultaneously binds to the B-cell maturation antigen (BCMA) expressed on the surface of myeloma cells and the CD3 receptor on the surface of T cells. This dual binding brings cytotoxic T cells into direct proximity with the cancer cells, inducing T-cell activation and subsequent lysis of the plasma cells, independent of the major histocompatibility complex (MHC) presentation.

Resident

A patient with relapsed/refractory myeloma is starting teclistamab. What are the key elements of the 'step-up' dosing schedule and the most important toxicity to monitor for during the first week?

Key Response

To mitigate the risk and severity of cytokine release syndrome (CRS), teclistamab is administered using a step-up dosing schedule (typically two smaller doses followed by the first full treatment dose). Residents must monitor closely for CRS (fever, hypotension, hypoxia) and ICANS (neurotoxicity), often requiring inpatient observation for 48 hours after each step-up dose as mandated by the REMS program.

Fellow

In the MajesTEC-1 trial, what were the implications of BCMA expression levels on treatment response, and how does this inform the potential for antigen escape as a resistance mechanism?

Key Response

The study found that teclistamab was effective across varying levels of BCMA expression, suggesting that even low density is sufficient for T-cell engagement. However, emerging data post-trial indicate that biallelic loss of the TNFRSF17 gene (encoding BCMA) or extracellular domain mutations can lead to antigen escape, which is a critical consideration when sequencing BCMA-targeted therapies versus alternative targets like GPRC5D or FcRH5.

Attending

Considering the high rate of Grade 3/4 infections observed in the MajesTEC-1 trial, how should the clinical management of hypogammaglobulinemia be optimized for patients on long-term teclistamab therapy?

Key Response

The trial reported a high incidence of infections (over 70% total), partly due to profound B-cell aplasia. Practice-changing management involves aggressive primary prophylaxis, including the use of intravenous or subcutaneous immunoglobulin (IVIG/SCIG) to maintain IgG levels above 400 mg/dL and vigilance for opportunistic infections (e.g., PJP, HSV/VZV), which are now standard supportive care considerations for bispecific antibodies.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

MajesTEC-1 utilized a single-arm design for its pivotal data; critique the limitations of using the MAMMOTH study or other retrospective cohorts as historical controls for determining the relative efficacy of teclistamab.

Key Response

Historical controls often suffer from selection bias and differences in the 'standard of care' era. Specifically, patients enrolled in prospective trials like MajesTEC-1 often have better performance status and organ function than the 'real-world' triple-class refractory populations in retrospective studies, which can lead to an overestimation of the hazard ratio benefit if not adjusted via propensity score matching or similar rigorous statistical methods.

Journal Editor

What potential 'threats to validity' regarding the durability of response (DOR) would a peer reviewer flag in a single-arm study like MajesTEC-1 where the median follow-up is relatively short at the time of initial publication?

Key Response

A reviewer would flag the 'immortal time bias' in responders and the potential for censored data to inflate DOR estimates if follow-up is insufficient. Editors would look for a sensitivity analysis regarding the timing of responses and require a mature Kaplan-Meier estimate for the duration of response to ensure the 'durable' claim is supported by more than just early-responding outliers.

Guideline Committee

Based on the MajesTEC-1 results, how should teclistamab be positioned relative to BCMA-directed CAR-T cell therapies in the treatment algorithm for triple-class exposed myeloma, according to current NCCN or IMWG guidelines?

Key Response

Current guidelines (like NCCN) list both as options for patients who have received at least 4 prior lines. Teclistamab is favored for patients with rapidly progressive disease who cannot wait for CAR-T manufacturing ('off-the-shelf' advantage) or those lacking access to specialized CAR-T centers. However, the committee must balance this against the burden of continuous administration for teclistamab versus the one-time infusion of CAR-T.

Clinical Landscape

Noteworthy Related Trials

2019

OPTIMISMM Trial

n = 559 · Lancet Oncol

Tested

Pomalidomide plus bortezomib and dexamethasone

Population

Relapsed or refractory multiple myeloma

Comparator

Bortezomib plus dexamethasone

Endpoint

Progression-free survival

Key result: The addition of pomalidomide significantly improved progression-free survival compared to standard bortezomib-based therapy.

2020

DREAMM-2 Trial

n = 196 · Lancet Oncol

Tested

Belantamab mafodotin

Population

Relapsed or refractory multiple myeloma

Comparator

None (single-arm study)

Endpoint

Overall response rate

Key result: Belantamab mafodotin showed clinically meaningful activity as a BCMA-targeting antibody-drug conjugate in patients with limited treatment options.

2021

CARTITUDE-1 Trial

n = 97 · NEJM

Tested

Ciltacabtagene autoleucel (CAR-T therapy targeting BCMA)

Population

Relapsed or refractory multiple myeloma

Comparator

None (single-arm study)

Endpoint

Overall response rate

Key result: The trial demonstrated a deep and durable response with an overall response rate of 97%.

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