August 26, 2021
Although the myeloma community has benefited substantially from regulatory approval of several new therapies, including Xpovio, Blenrep and, most recently, the anti-BCMA CAR T-cell product Abecma, there is still a substantial unmet need for treatments that can achieve deep and sustained responses when the disease is no longer responsive to standard treatment. It is therefore very encouraging to see the promising early results achieved with the bispecific antibody teclistamab.
How bispecific antibodies work
Bispecific monoclonal antibodies harness the activity of the patient’s own T cells in the bone marrow microenvironment surrounding the myeloma. One of the two arms of the antibody attaches via the CD3 receptor to the T cells. The second arm attaches via the BCMA (B-cell maturation antigen, a protein involved in myeloma cell growth and survival) or other receptors in some products, to the nearby myeloma cells. This activity significantly increases the anti-myeloma treatment effects.
Several bispecific antibodies to treat myeloma are currently under evaluation. But teclistamab is the farthest along in the early development and clinical trial process, in large part because preliminary information indicated both significant efficacy (response in refractory patients) and acceptable tolerability.
Early results with teclistamab
Teclistamab is an anti-BCMA and CD3 bispecific antibody. Dr. Saad Usmani from the Levine Cancer Institute in Charlotte, North Carolina is the lead author of the recently published Lancet manuscript. Dr. Usmani’s study offers data on 157 patients treated with teclistamab, which was administered either intravenously every two weeks or by subcutaneous (beneath the skin) injection weekly.
The first goals of this phase I trial were to assess both toxicities and the different routes of administration and dosages. Important toxicities included infections, cytokine release syndrome (an immune reaction), and neurotoxicity. Reduced blood-count levels were frequent, especially reduced white cells (neutropenia) in 48% of patients, anemia in 33% and reduced platelet levels in 23%.
Recommended phase II dose
Forty patients were treated with the recommended phase II dose of 1,500ug /Kg subcutaneously weekly and were followed for approximately 6 months. Among the 33 triple-refractory (unmet need) group of patients in the study, the response rate was 61%. Ongoing treatment was feasible, and responses deepened over time. The 6-month progression-free survival was 67%, meaning that responses were sustained.
The study’s authors note that the teclistamab was well-tolerated and adverse events were generally mild and manageable. The teclistamab IGg4 monoclonal antibody has a prolonged blood half-life and the weekly dosing resulted in satisfactory treatment levels in the bloodstream.
The bottom line
Teclistamab is an important and promising new bispecific antibody therapy. Further data from the phase II trial are needed to assess the therapy’s full impact. The weekly subcutaneous schedule should be manageable for patients.
The exact “ideal niche” or optimal initial and sequential treatment situation for use of a bispecific such as teclistamab, as opposed to, for example, the BCMA-targeted monoclonal antibody-drug conjugate Blenrep and anti-BCMA CAR T-cell products (such as Abecma) will be established in the real-world setting. One advantage of teclistamab is that it is an off-the-shelf product that can be administered in the clinic, without the need for bridging therapy. Nor is it subject to delay in the manufacturing of a cellular product like CAR T-cells.
The International Myeloma Working Group has established an Immune Therapy Registry, led by Dr. Thomas Martin (University of California, San Francisco) and Dr. Yi Lin (Mayo Clinic, Rochester, Minnesota), that will greatly assist in this real-world evaluation of the treatment’s benefit, quality of life issues, and toxicities.
The potential future availability of another active immune therapy option is clearly a very positive development.
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