Combining CAR-T with standard therapy improves response duration in multiple myeloma patients

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UPENN scientists provide clinical evidence for combining CD19 CAR-T therapy with melphalan and autologous stem cell transplantation for prolonging progression-free survival in advanced multiple myeloma patients.

Multiple myeloma is a hematological cancer that develops in the plasma cells of bone marrow. Although survival rate has improved with the development of modern therapies, response durability remains inadequate. Nearly all patients, even those who achieve complete responses, eventually relapse and develop treatment-refractory, fatal disease.

The relapse could be due to these cells’ myeloma-propagating potential (ability to give rise to clinical relapses) and individual multiple myeloma cells may differ in their myeloma-propagating potential. Therefore, developing therapies to specifically target cells with high myeloma-propagating capability could be a potential strategy to prevent or delay relapses. CD19 is absent on most multiple myeloma cell population but there have been studies showing its presence on minor subsets of myeloma cells with unique myeloma-propagating properties.

To test whether targeting CD19 in multiple myeloma cells would delay tumor relapse, Dr Carl June and team at the Perelman School of Medicine at the University of Pennsylvania conducted a pilot clinical trial in 10 advanced multiple myeloma patients. Autologous T cells were transduced with an anti-CD19 chimeric antigen receptor (CAR) (CTL019) and was combined with high-dose melphalan and autologous stem cell transplantation (ASCT), a standard multiple myeloma therapy. To differentiate the clinical effects of ASCT from those of CTL019, results were compared with patients who had previously undergone ASCT and with poor response, defined as progression-free survival (PFS) of less than 1 year. The study assessed whether ASCT + CTL019 resulted in longer PFS compared to ASCT alone (control group).

Results published in JCI Insight showed that PFS after ASCT + CTL019 significantly exceeded in 2 of 10 subjects. This prolonged PFS was not likely due to ASCT alone as there was no improvement in PFS in the control group. In addition, the patient with the most prolonged PFS exhibited new anti-myeloma immunity and unusually durable response to subsequent therapy. ASCT + CTL019 was also safe and feasible, with most toxicity attributable to ASCT and no severe cytokine release syndrome.

Findings from the study suggest that CTL019, despite absent on most neoplastic plasma cell population, has the ability to favorably alter the clinical disease trajectory in multiple myeloma patients.

Source: Garfall Al et al., Anti-CD19 CAR T cells with high-dose melphalan and autologous stem cell transplantation for refractory multiple myeloma. JCI Insight, April 2018.