Combination with Cytotoxic Therapy and Checkpoint Blockade Overcomes Primary Resistance to BCMA Bispecific Antibody Therapy and Leads to Durable Remission of Vk*MYC Multiple Myeloma

Primary resistance to BCMA-directed bispecific antibodies (BCMA-BsAb) is a major clinical hurdle despite their outstanding efficacy for relapsed and refractory multiple myeloma (MM). Primary resistance has been linked clinically to patient characteristics including tumor burden. Our previous work in the immunocompetent Vk*MYC model of MM credentialed that tumor burden also correlates with resistance to a murine BCMA-BsAb, which we addressed through drug combinations with MM backbone agents. Pairing the BsAb with cyclophosphamide (Cy) was well-tolerated, reversed primary resistance, reshaped an immunosuppressive tumor microenvironment (TME) and led to durable responses with immunosurveillance in all but the most aggressive settings.

Here, we aimed to improve the BCMA-BsAb and Cy combination strategy with a goal of curing models representing clinically relevant Cy-refractory aggressive settings, by adding T cell checkpoint blockade. Despite a lack of single agent activity of checkpoint inhibitors in MM (and in our models), PD1 and TIGIT are relevant targets as their expression on T cells correlates with both primary and acquired resistance to BCMA-directed cell therapies. Our team hypothesized that blockade of either PD1 or TIGIT with concurrent BCMA-BsAb and Cy would deepen anti-MM responses and provide a more durable immunotherapy regimen by sustaining activation of the T cell repertoire.

Methods: We preclinically tested the ability of two weeks of concurrent dosing of BCMA-BsAb with Cy, checkpoint inhibitors targeting either PD1 or TIGIT, or the triple combination to overcome primary resistance and improve survival in a Cy-resistant transplantable Vk*MYC model of MM. We followed the response longitudinally in the blood, and in the bone marrow and spleen after complete responses were achieved at five weeks.

Results: The double combination of a checkpoint inhibitor to the BCMA-BsAb was well-tolerated and abolished primary resistance, yet, failed to provide curative responses. Whereas the triple combination with either PD1 or TIGIT blockade remained safe, provided robust initial responses that overcame primary resistance and resulted in durable complete and curative responses in the entire cohort. These survival benefits represent significant improvements over control combinations tested here but also over all historical preclinical anti-MM therapy tested in our models to date.

Both PD1 and TIGIT blockade with Cy/BCMA-BsAb triple combinations delivered a similar multiphasic potent anti-tumor response. This response was first characterized by highly effective T cell-mediated lysis of the tumor, as evidenced by deep reduction of M-spike after two weeks of treatment. As we previously published, the addition of Cy to BCMA-BsAb rapidly reshapes the TME by depleting Tregs and exhausted T cells and brings naive T cells to the tumor. However, we observed elevated T cell checkpoint expression at times of BsAb-relapse in aggressive models, suggesting that blockade of these pathways may help sustain T cell activation. Indeed, the ensuing T cell response in the triple combination gradually builds and encourages a pool of less terminally differentiated T cells to proliferate to allow for a more sustained response with repeat dosing. For the first time, we observe that the triple combination significantly engages the CD4 T cell compartment, which can be essential for a complete anti-tumor response. At the time of complete response, single cell analysis displays that T cells retained in the BM were less exhausted and defined by elevated CCR2 expression, a known marker of activated memory T cells, suggestive of ongoing immunosurveillance.

Conclusions: Here we demonstrated through controlled in vivo experimentation how the addition of Cy reverts primary resistance to BCMA-BsAb by reshaping the TME in our Cy-insensitive preclinical model. Adding checkpoint inhibitors targeting TIGIT or PD1 further improves the durability of BsAb and Cy combination to cure all mice in these cohorts, by critically lysing the tumor, resetting the suppressive TME, and instigating a gradual, multiphasic, and sustained anti-MM T cell response. The concurrently delivered triple combination is well tolerated and provides optimal temporal control of MM especially in a preclinical model reflecting primary resistance mediated by high tumor burden and may have translational benefit to MM patients.