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No Evidence That BCMA Expression Is Completely Lost Following Belamaf Treatment in Patients With RRMM
The first-in-class humanized antibody-drug conjugate belantamab mafodotin (belamaf) demonstrated significant responses in the DREAMM-2 trial comprised of patients with relapsed/refractory multiple myeloma (RRMM). Daniel E Lowther, PhD, spoke about whether immune impairment and complete target loss were observed in those who received belamaf in the DREAMM-1 and DREAMM-2 trials.
In their presentation at the 64th American Society of Hematology Annual Meeting and Exposition, “No evidence of BCMA expression loss or systemic immune impairment after treatment with the BCMA-targeted antibody-drug conjugate belantamab mafodotin in the DREAMM-1 and DREAMM-2 trials of patients with relapsed/refractory multiple myeloma,” Lowther and colleagues looked at the two trials, which enrolled adult patients with RRMM who received at least three prior lines of therapy including an immunomodulatory drug, a proteasome inhibitor, and in DREAMM-2 only, an anti-CD38 monoclonal antibody.
“Targeted therapies and those utilizing the immune system provide significant clinical benefit to patients with multiple myeloma and other diseases,” Dr Lowther said. “However, understanding the mechanisms and how to sequence these therapies remains incompletely understood. Target loss itself is thought to be the most likely resistance mechanism. In our study, we sought to understand how the sequence and whether target loss was actually seen in response to belamaf.”
Free sBCMA—a shed form of BCMA that circulates in the blood after being cleaved from the cell membrane—was measured using an electrochemiluminescence assay. The researchers measured the absolute concentration of sBCMA at baseline, with absolute concentration and fold-change from baseline assessed at best achieved response and latest progression. After the first post-infusion timepoint, samples were taken >4 days after infusion in order to minimize the interference of belamaf. As part of this post-hoc analysis, they modeled association of sBCMA with time-on-study, and adjusted for longitudinal categorical response using a linear mixed model.
“Belamaf monotherapy has demonstrated rapid, deep, and durable responses in DREAMM-1 and DREAMM-2 studies in patients with relapsed/refractory multiple myeloma,” Dr Lowther said. “And in these patients, serum BCMA levels are elevated and associated with clinical status including correlation with M-protein, serum-free light change, degree of plasma cell/bone marrow interaction, and lack of response to therapy.
“Soluble BCMA itself is a shed form of the membrane-bound target, so by measuring this level during belamaf treatment, we’re going to present evidence that complete target loss is not seen after progression on therapy. And in addition, immune system impairments at the systemic level doesn’t appear to be there either after 1 year of treatment.”
Lowther and colleagues detected sBCMA levels in 98% (50/51) and 98.9% (181/183) of eligible patients in DREAMM-1 and DREAMM-2, respectively, at progression regardless of belamaf response status. Measured against predose levels, decreased sBCMA was immediately observed in all response groups postinfusion. In nonresponders, predose levels of sBCMA had returned within 1 cycle. Those with at least partial response showed lower but measurable sBCMA levels, which the authors believe suggests BCMA loss is not commonly observed in patients receiving belamaf.
Of patients who responded but later progressed in the DREAMM-2 trial, sBCMA levels in 97% (64/66) showed a significant drop during response but returned to near baseline levels upon progression.
“Through this longitudinal monitoring of patients’ immune cell populations, we saw no change in immune cell ratios or major cell populations regardless of response status throughout the treatment course,” Dr Lowther said. “Therefore, our conclusion is that belamaf treatment does not negatively impact the systemic immune system, and depletion of immune cell subsets is not likely a mechanism for resistance to therapy in this setting.”
Lowther D, Houseman E, Han G, et al. No evidence of BCMA expression loss or systemic immune impairment after treatment with the BCMA-targeted antibody-drug conjugate belantamab mafodotin in the DREAMM-1 and DREAMM-2 trials of patients with relapsed/refractory multiple myeloma. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022. Abstract 652. Funded by GlaxoSmithKline.
Lowther D, Houseman E, Han G, et al. No evidence of BCMA expression loss or systemic immune impairment after treatment with the BCMA-targeted antibody-drug conjugate belantamab mafodotin in the DREAMM-1 and DREAMM-2 trials of patients with relapsed/refractory multiple myeloma. Presented at: 64th ASH Annual Meeting and Exposition; December 10-13, 2022. Abstract 652. Funded by GlaxoSmithKline.
