P44 detection of soluble bcma in tears of mm patients treated with belantamab mafodotin

Belantamab mafodotin (Belamaf) is the first BCMA targeted therapy approved for the treatment of Multiple Myeloma patients with relapsed or refractory disease who have received at least four prior therapies, including an anti-CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent. This antibody-drug conjugate containing monomethyl auristatin F (MMAF) provides deep and durable remissions in this hard-to-treat MM population, but also induces significant ocular toxicity. This includes microcytic-like epithelial changes leading to transient blurred vision, dry eyes symptoms and loss of visual acuity. The underlying mechanisms are not yet fully understood, but clinical evidence from other ADC studies suggests that the cytotoxic payload MMAF is associated with the ocular toxicity observed. Of note, the cornea itself is not vascularized and does not express BCMA, thus, it remains an open question how toxic effects are transmitted to the cornea. It has been hypothesized that ADC may be transported via the vessels of the corneal limbus, but also transportation via the tear fluid is possible. To date, dose reduction of Belantamab Mafodotin is the only way to efficiently reduce ocular side effects of the treatment and no other mitigation strategies have been successfully established. We screened for soluble BCMA (sBCMA) in peripheral blood and tear fluid in seven healthy young volunteers and in 10 randomly selected MM patients from our institution. Tear fluid was collected using polyvinyl sponges and later eluted via high speed centrifugation. A commercially available human BCMA ELISA kit was used for BCMA quantification. Plasma samples were diluted within range of 1:40 to 1:500 and tear fluid was diluted 1:50 using dilution buffers provided according to manufacturer’s instruction. In our healthy cohort, peripheral blood sBCMA (PBsBCMA) levels ranged from 10-20ng/ml with no difference between plasma and serum. Strikingly, we detected sBCMA in the tear fluid, but quantities were 10-fold reduced (0,5 to 3ng/ml). This, to the best of our knowledge, is the first report of sBCMA in human tear fluids (TFsBCMA), providing a novel potential transport mechanism of MMAF or of the ADC to the cornea epithelium. We next measured PBsBCMA and TFsBCMA levels in 10 MM patients from our institution and, likely reflecting their active and variable tumor burden, we found an increase not only in PBsBCMA (50-3500ng/ml) but also TFsBCMA load (3ng to 772ng/ml) compared to our healthy individuals. Interestingly, three patients with the highest TFsBCMA levels were treated with Belantamab Mafodotin at the timepoint of sampling, with a 50- to 100-fold increase compared to MM patients not treated with anti-BCMA therapy. The ongoing DREAMM-5 trial interrogates the addition of the gamma-secretase inhibitor Nirogacestat to minimize sBCMA levels in patients treated with Belantamab Mafodotin. Our novel finding of TFsBCMA suggests that it may be of additional value to also track TFsBCMA levels in these patients, and that such a strategy, lowering sBCMA levels, may not only increase treatment efficiency but may also hold potential to reduce ocular side effects under Belantamab Mafodotin therapy.