All content on this site is intended for healthcare professionals only. By acknowledging this message and accessing the information on this website you are confirming that you are a Healthcare Professional. If you are a patient or carer, please visit the International Myeloma Foundation or HealthTree for Multiple Myeloma.

The Multiple Myeloma Hub uses cookies on this website. They help us give you the best online experience. By continuing to use our website without changing your cookie settings, you agree to our use of cookies in accordance with our updated Cookie Policy

Introducing

Now you can personalise
your Multiple Myeloma Hub experience!

Bookmark content to read later

Select your specific areas of interest

View content recommended for you

Find out more
  TRANSLATE

The Multiple Myeloma Hub website uses a third-party service provided by Google that dynamically translates web content. Translations are machine generated, so may not be an exact or complete translation, and the Multiple Myeloma Hub cannot guarantee the accuracy of translated content. The Multiple Myeloma Hub and its employees will not be liable for any direct, indirect, or consequential damages (even if foreseeable) resulting from use of the Google Translate feature. For further support with Google Translate, visit Google Translate Help.

Steering CommitteeAbout UsNewsletterContact
LOADING
You're logged in! Click here any time to manage your account or log out.
LOADING
You're logged in! Click here any time to manage your account or log out.

The Multiple Myeloma Hub is an independent medical education platform, sponsored by Bristol Myers Squibb, GSK, Pfizer, Roche and Sanofi. The levels of sponsorship listed are reflective of the amount of funding given. Digital educational resources delivered on the Multiple Myeloma Hub are supported by an educational grant from Janssen Biotech, Inc. View funders.

2024-11-29T14:58:26.000Z

Symposium | BCMA-directed ADCs for the treatment of MM

Nov 29, 2024
Share:
Learning objective: After reading this article, learners will be able to describe novel therapeutic targets in MM and explain mechanisms of action for agents, alone or combined, as well as how they might overcome mechanisms of resistance to previous agents.

Bookmark this article

Test your knowledge! Take our quick quiz before and after you read this article to find out if you improved your knowledge. Results help us to improve content and continually provide open-access education.

At the ESH 7th Translational Research Conference on Multiple Myeloma in 2024, the Multiple Myeloma Hub held a symposium titled: How to sequence B-cell maturation antigen (BCMA)-directed therapies in early relapsed/refractory multiple myeloma (RRMM). During the symposium, Martin Kaiser, The Royal Marsden Hospital, London, UK, delivered a presentation on BCMA-directed antibodydrug conjugates (ADCs) for the treatment of MM.

In this presentation, Professor Kaiser focuses on the potential and evolving role of ADCs in the treatment of multiple myeloma, particularly in comparison to other BCMA-targeting therapies such as bispecific antibodies and chimeric antigen receptor (CAR) T-cell therapies. The discussion includes mechanisms of action (Figure 1), recent clinical trial data, toxicity profiles, resistance mechanisms (Figure 2), and future directions for optimizing ADC use. The efficacy of belantamab mafodotin in triplet regimens and its potential role in therapy sequencing are also covered.

Figure 1. BCMA-directed ADCs: Mechanism of action* 

ADC, antibody–drug conjugate; BCMA, B-cell maturation antigen; DNA, deoxyribonucleic acid.
*Khattak et al.1

 

Figure 2. Impact of ADCs on mechanisms of resistance: T-cell independence*

ADC, antibody–drug conjugate; BCMA, B-cell maturation antigen; CAR, chimeric antigen receptor.
*Su and Ye.2

Key points

Mechanism of action

  • ADCs selectively target cells by binding to specific antigens, such as BCMA, expressed on the surface of myeloma cells; this specificity minimizes damage to surrounding tissues.
  • ADCs deliver a cytotoxic payload directly to myeloma cells without engaging T cells.
  • Several ADCs are currently under investigation for the treatment of MM; among these, belantamab mafodotin is the most advanced BCMA-targeted ADC, with data available from phase III clinical trials.

DREAMM-7

  • The phase III DREAMM-7 (NCT04246047) clinical trial evaluated belantamab mafodotin in combination with bortezomib and dexamethasone (BVd) compared with standard daratumumab, bortezomib, and dexamethasone (DVd) therapy.
  • The overall response rate increased numerically from 71% in the DVd group to 83% in the BVd group.
  • The complete response measurable residual disease negativity rate significantly improved, rising from 9.6% in the DVd group to 24.7% in the BVd group.
  • Median progression-free survival was substantially longer with the BVd regimen, at 36.6 months compared with 13.4 months with the DVd regimen.
  • The efficacy rates observed with the BVd regimen were maintained even after bortezomib discontinuation, demonstrating promising durability.

DREAMM-8

  • The phase III DREAMM-8 (NCT04484623) clinical trial evaluated belantamab mafodotin in combination with pomalidomide and dexamethasone (BPd) vs daratumumab, pomalidomide, and dexamethasone (DPd).
  • Overall response rate was higher in the BPd group at 77% compared with 72% in the PVd group.
  • Complete response measurable residual disease negativity rate was significantly increased with BPd, at 24% compared with 5% in the PVd arm.
  • At the time of analysis, median progression-free survival was not reached in the BPd group, compared with 12.7 months in the PVd group, indicating sustained benefits with BPd therapy.
  • These results align closely with those from DREAMM-7, reinforcing the potential of belantamab mafodotin combination therapies in MM.

Ocular toxicities

  • The most common ocular events noted with belantamab mafodotin included corneal changes and mild visual impairments, such as dry eyes and visual disturbances.
  • Severe visual impairment, defined as bilateral worsening of best-corrected visual acuity to 20/200 or worse, was rare, occurring in 2% of DREAMM-7 patients and 1% of DREAMM-8 patients who received belantamab mafodotin.
  • As the corneal epithelium regenerates regularly, recovery can occur after treatment pauses or dose adjustments of belantamab mafodotin.
  • Most patients, including those with higher-grade toxicity, experienced full recovery or substantial improvement following dose adjustment.
  • Although ocular toxicity requires monitoring and management, it does not significantly impact patients’ quality of life or long-term treatment outcomes.

Dosing strategies

  • Emerging data supports less frequent dosing schedules to optimize efficacy and minimize toxicity.
  • Lower doses or reduced dosing frequencies helped to manage toxicities, without sacrificing the efficacy of belantamab mafodotin.
  • Extended dosing regimens could enhance the tolerability and accessibility of ADC therapies.

Resistance mechanisms and sequencing

  • T-cell engagers require functional T cells, which can lead to T-cell exhaustion and limit their effectiveness.
  • Unlike CAR T-cell therapies and bispecific antibodies, ADCs do not rely on T-cell activity.
  • ADCs demonstrate sustained efficacy when used after other BCMA-targeted therapies, such as CAR T-cell therapies or bispecific antibodies.
  • Additional studies are needed to establish optimal sequencing of ADCs with other therapies and explore the benefits of treatment-free intervals.

Clinical implications and future directions

  • Belantamab mafodotin has shown efficacy and manageable toxicity, supporting its use in the early relapse setting and offering a promising option for patients in early relapse, particularly in cases where CAR T-cell or bispecific therapies are unavailable.

I will change my clinical practice as a result of this symposium
12 votes - 67 days left

This independent educational activity was supported by GSK. All content was developed independently by the faculty. The funder was allowed no influence on the content of this activity.

  1. Khattek ZE, Hashmi H, Kahn SI, et al. Dawn of a new era of antibody-drug conjugates and bispecific T-cell engagers for treatment of multiple myeloma: a systematic review of literature. Ann Hematol. 2021;100(9):2155-2172. DOI: 1007/s00277-021-04599-5
  2. Su CT, Ye JC. Emerging therapies for relapsed/refractory multiple myeloma: CAR-T and beyond. J Hematol Oncol. 2021;14(1):115. DOI: 1186/s13045-021-01109-y

Your opinion matters

HCPs, what is your preferred format for educational content on the Multiple Myeloma Hub?
79 votes - 32 days left ...

Newsletter

Subscribe to get the best content related to multiple myeloma delivered to your inbox