Can A Second Type of BCMA Multiple Myeloma Therapy Be Used After the First Fails?

Patient 1

In June of 2016, a 59-year-old woman with IgG myeloma was placed on the Phase I UPENN study using the Novartis BCMA CAR T cell treatment in June of 2016. She had 90% of plasma cells in her bone marrow. She was resistant to bortezomib, lenalidomide, carfilzomib, pomalidomide, and daratumumab, with 10 prior lines of therapy. Her myeloma genetics included a gain of 1q, the t(4;14) and deletion of 17p, tested by FISH. 

She received 5 × 10⁸ CAR T cells without lymphodepleting chemotherapy, achieving a minimal response with reduction of marrow plasma cells to 20% at day 28. By month 2, her disease started to progress with rising light chains. Testing of her BCMA levels after treatment showed a modest decrease in BCMA at day 28 compared with her baseline, but the BCMA remained on the majority of her myeloma cells. 

She then joined the Phase I GSK BCMA antibody drug conjugate trial. Antibody drug conjugates use the T cells to deliver a toxic payload to the cancer cells. She received 2 doses at 3.4 mg/kg IV every 3 weeks, again achieving an minimal response for her M-spike but with more substantial reduction in serum free lambda light chains  as well as a decrease in bone marrow plasma cells from 38% pretreatment to <5% on day 125. Therapy was held for 6 weeks because of corneal toxicity, and then restarted at 2.55 mg/kg for 2 additional doses.

Her blood M-spike continued to decrease but she again had light chain progression and came off therapy in January 2017. A February 2017 biopsy of a focal bone lesion demonstrated continued BCMA expression on myeloma cells.  She subsequently received several additional therapies, including salvage autologous stem cell transplant, but ultimately died in September 2018.

Patient 2

A 49-year-old man with IgG kappa myeloma was treated on the GSK2857916 phase 1 trial starting in August 2016. At enrollment, he had received 5 prior lines and was refractory to carfilzomib, lenalidomide, daratumumab, elotuzumab, and pomalidomide. Baseline bone marrow had 70% plasma cells with normal cytogenetics. He received 3 doses of GSK2857916 at 3.4 mg/kg every 3 weeks, with continued progression on therapy. Myeloma cell BCMA expression pre- and post-GSK2857916 is not available.

He then started pembrolizumab (a checkpoint inhibitor), lenalidomide, and dexamethasone in late October 2016, achieving a durable marginal response that was ongoing when he opted to enroll on the Poseida BCMA CAR T-cell phase I trial.

In April 2018, he received 1.64 × 10⁸ CAR T cells following cyclophosphamide and fludarabine conditioning and achieved a partial response that is ongoing 12 months post-CAR T-cell infusion, without any subsequent therapy. Bone marrow myeloma cell percentage decreased from 65% pre-infusion to 15% on day 79. Assessment of BCMA expression by flow cytometry demonstrated BCMA expression on most of the myeloma cells pre-CAR T-cell infusion, with ongoing BCMA expression on residual cells post-treatment. 

The investigators stated: 

To our knowledge, these are the first reported cases of patients who progressed on a prior BCMA-targeted therapy (both of which were given at clinically active doses) and subsequently tolerated and responded to a different BCMA-targeted modality, including patient 1, who received these therapies sequentially without intervening therapy. These were patients with limited remaining treatment options who benefited because they had trial options that did not exclude prior BCMA-directed therapy. This is especially important in the heavily relapsed/refractory setting, in which BCMA CAR T cells, despite their high response rates, do not lead to long-term durable remissions in the majority of cases. The long-term response durability of anti-BCMA ADCs and bi-specific antibodies remains unknown at this time.