multiple myeloma
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CHICAGO—Early phase 1 results suggest a chimeric antigen receptor (CAR) T-cell therapy can induce tumor regression in heavily pretreated patients with multiple myeloma (MM).
The therapy, P-BCMA-101, has only been tested in 3 patients in the lowest dose cohort.
However, signs of efficacy have been seen in all 3 patients, including a lasting partial response in 1 patient.
There have been no dose-limiting toxicities, and none of the patients have developed cytokine release syndrome (CRS).
“The results from the first cohort of the phase 1 P-BCMA-101 study have surpassed historical benchmarks of safety and efficacy in multiple myeloma at this dose level and give us confidence to move ahead into additional dose cohorts,” said Eric Ostertag, MD, PhD, chief executive officer of Poseida Therapeutics, Inc.
Dr Ostertag and his colleagues presented these results at the AACR Annual Meeting 2018 (abstract CT130). The trial is sponsored by Poseida Therapeutics, Inc.
The trial is enrolling patients with relapsed/refractory MM who have received a proteasome inhibitor and immunomodulatory agent.
Conditioning consists of standard cyclophosphamide (300 mg/m2) and fludarabine (30 mg/m2) on days -5 to -3. Patients then receive a single dose of P-BCMA-101 on day 0.
The trial has a 3+3 dose-escalation design, with up to 6 dose levels. The first dose level is 0.75 x 106 P-BCMA-101 cells/kg.
The 3 patients who have received this dose had 6 to 9 prior therapies.
Patient 1
The first patient was a 54-year-old female with lambda light chain MM. She had t(11;14), del13q14, and 11q23(x3).
Before she received P-BCMA-101, the patient had an increase in free light chains (FLCs) to 3290 mg/L, which caused renal failure. She was treated with cyclophosphamide/prednisone and plasmapheresis bridging therapy before proceeding to P-BCMA-101.
The patient achieved a partial response 2 weeks after receiving P-BCMA-101, and this has persisted through week 12. She had a maximal reduction in urine M-protein of 92% and a reduction in plasma FLCs of 79%.
The patient did not experience any adverse events (AEs) considered related to P-BCMA-101.
Patient 2
The second patient was a 50-year-old female with oligosecretory kappa light chain MM and plasmacytomas. She had del17p (TP53) and 11q13(x3).
Due to enlarging plasmacytomas, the patient was treated with DT-PACE (dexamethasone plus thalidomide with cisplatin, doxorubicin, cyclophosphamide, and etoposide) before receiving P-BCMA-101.
Her bone plasmacytomas resolved to below background within 4 to 8 weeks of P-BCMA-101 administration, but 1 new non-bone lesion appeared months later.
AEs considered at least possibly related to treatment in this patient included grade 2-4 neutropenia as well as grade 3-4 thrombocytopenia.
Patient 3
The third patient was a 65-year-old female with lambda light chain MM and del13q14.
Her urine M-protein and FLCs briefly dipped and rose after she received bridging therapy with lenalidomide and dexamethasone, but they decreased at 4 weeks after P-BCMA-101 administration, which corresponded with P-BCMA-101 expansion in the peripheral blood.
AEs considered at least possibly related to treatment included easy bruising (grade 1), fatigue (grade 2), febrile neutropenia (grade 3), hypogammaglobinemia (grade 2), neutropenia (grade 2-3), and thrombocytopenia (grade 3-4).
“The lack of cytokine release syndrome in any of the 3 patients, in spite of marked efficacy, is unprecedented at this dose, which we believe is attributable to multiple differentiated aspects of our technology, resulting in a highly purified CAR T product with a high percentage of cells with a T stem cell memory phenotype,” Dr Ostertag said.
In addition to a lack of CRS, there were no dose-limiting toxicities. Therefore, the dose has been escalated to 2 x 106 P-BCMA-101+ CAR T cells/kg for the next patient cohort. The first patient has been treated at this dose level, with no CRS yet reported.
About P-BCMA-101
P-BCMA-101 employs a B-cell maturation antigen-specific Centyrin™ fused to a second-generation CAR scaffold (a CARTyrin) rather than a single-chain variable fragment (scFv).
Centyrins have similar binding affinities as scFvs but are said to be potentially less immunogenic than scFvs, more stable at the cell surface, and resistant to antigen/ligand-independent tonic signaling.
P-BCMA-101 is engineered using PiggyBac™, a transposon-based system requiring only mRNA and plasmid DNA (no virus).
The increased cargo capacity of PiggyBac allows for the incorporation of a safety switch and a selectable gene. The safety switch can be activated to enable depletion in case AEs occur. And the selectable gene allows for enrichment of CAR+ cells.