CAR T-Cell Immunotherapy Makes Strides in Multiple Myeloma, with Durable RemissionMultiple Myeloma, Web Exclusives
Chicago, IL—The era of immunotherapy in multiple myeloma is near. Two presentations at ASCO 2017 demonstrated that cellular therapy can steer immune reconstitution against multiple myeloma.
Edward A. Stadtmauer, MD, Chief, Hematologic Malignancies Section, Abramson Cancer Center, University of Pennsylvania, Philadelphia, reviewed cellular strategies, from vaccine-primed T-cell transfer after autologous stem-cell transplantation (ASCT) to chimeric antigen receptor (CAR) T-cell therapy and the many promising targets in multiple myeloma.
Candidate antigen targets in the use of CAR T-cell therapies include CD138, CD38, CD56, CD19, kappa light chain, and B-cell maturation antigen (BCMA). The rationale for using anti-CD19 therapy in multiple myeloma is that malignant precursor cells are likely CD19-positive, even if the majority of plasma cells are CD19-negative, as assessed by conventional flow cytometry, Dr Stadtmauer said.
“Specifically targeting B-cells may improve durability of response to plasma cell-directed therapies,” said Dr Stadtmauer.
A 2015 study of CTL019 administration after ASCT in 10 patients with multiple myeloma who had disease progression within 1 year of the initial stem-cell transplant, despite a median of 6 previous lines of therapy, showed very good partial responses and 2 partial responses by day 100. The median progression-free survival after ASCT plus CTL019 was 185 days.
BCMA is a member of the tumor necrosis factor receptor superfamily that is expressed on mature B-cell subsets, plasma cells, and plasmacytoid dendritic cells.
Cytokine Release Syndrome
Cytokine release syndrome is a life-threatening toxicity of CAR T-cell therapy, characterized by persistent high fevers, rigors, myalgias, hypoxia, and neurologic dysfunction. Although this syndrome responds to steroid administration, steroids can compromise the efficacy of CAR T-cell therapy. A more benign treatment for cytokine release syndrome is tocilizumab (Actemra), said Dr Stadtmauer.
Durable Remission with LCAR-B38M
New data released at the meeting indicated that 2 new CAR T-cell therapies targeting BCMA showed impressive early response rates, with equally impressive safety profiles. BCMA-specific CAR-modified T-cells (LCAR-B38M) led to durable remissions in a study of 35 patients with relapsed or refractory multiple myeloma.
Overall, 33 of 35 (94%) patients achieved clinical remission, defined as complete or very good partial response within 2 months of receiving CAR T-cell therapy, which was given as 3 split doses over the course of 1 week, reported Wanhong Zhao, MD, PhD, Associate Director of Hematology, Second Affiliated Hospital of Xi’an Jiaotong University, China.
Eligible patients had clear BCMA expression on >50% of malignant plasma cells and must have been resistant to ≥3 previous regimens. The majority of the patients had 2 or 3 previous lines of therapy. Of the 19 patients who were followed for >4 months, 14 achieved stringent complete response criteria, and none relapsed. The 5 patients who were followed for ≥1 years maintained their stringent complete response status.
“It appears that with this novel immunotherapy there may be a chance for cure in multiple myeloma, but we will need to follow patients much longer to confirm that,” Dr Zhao said.
Transient cytokine release syndrome was reported in 85% of patients, but it was mostly mild. No neurologic side effects were reported. A similar study is expected to launch in the United States in 2018.
Durable Remission with bb2121
Jesus G. Berdeja, MD, Director, Myeloma Research, Sarah Cannon Research Institute, Nashville, TN, provided an update from a phase 1 study of the BCMA-targeted CAR T-cell therapy (bb2121).
The results showed deep and durable responses in 15 evaluable patients with heavily pretreated multiple myeloma in the active-dose cohorts. No grade 3 or 4 neurotoxicity was reported.
The objective response rate was 100% in the 15 patients who received bb2121 at doses >50 × 106 cells, and the objective response rate was 89% across all 21 patients who received bb2121. Patients received a median of 7 lines of therapy. No disease progression was reported in the active-dose cohorts, with a follow-up of 8 to 54 weeks.
The 4 patients who were evaluable for minimal residual disease (MRD) were negative for MRD, indicating a low risk for relapse. Overall, 2 patients had grade 3 cytokine release syndrome that resolved within 24 hours.
Pivotal phase 3 data demonstrated treatment with luspatercept resulted in statistically significant increased red blood cell transfusion independence compared with placebo.
The clinical application of assays that utilize next-generation sequencing (NGS) technology is accelerating rapidly in the field of oncology.