In the Journals

Dual CAR T-cell combination a ‘promising treatment option’ for multiple myeloma

A combination of humanized anti-CD19 and anti-B-cell maturation antigen chimeric antigen receptor T-cells has shown activity in patients with relapsed or refractory multiple myeloma, according to results of a single-center, single-arm phase 2 clinical trial published in The Lancet Haematology.

The dual CAR T-cell combination resulted in a 95% response rate, with 43% of patients achieving a complete response to therapy.

“To our knowledge, this is the first study using humanized anti-CD19 CAR T cells combined with anti-BCMA CAR T cells for the treatment of relapsed or refractory multiple myeloma,” Kailin Xu, MD, PhD, professor in the department of hematology at the Affiliated Hospital of Xuzhou Medical University told Cell Therapy Next.

BCMA is an ideal target for CAR T-cell therapy, and promising results have been obtained in relapsed or refractory multiple myeloma. Several studies have shown that a small component of multiple myeloma clones is believed to express CD19, and these cells are considered to be less differentiated multiple myeloma cells, or myeloma-like stem cells,” Xu said.

By expanding the coverage of multiple myeloma cell targets and eliminating less-differentiated multiple myeloma cells, the strategy may improve the duration of response of CAR T-cell activity in patients with relapsed or refractory multiple myeloma, he added.

“This dual CAR-T cell combination might be a promising treatment option for relapsed or refractory multiple myeloma,” Xu and colleagues wrote in their analysis.

Dual CAR strategy

The study comprised patients aged 18 to 69 years who had histologically confirmed multiple myeloma at the Affiliated Hospital of Xuzjou Medical University in China between May 1, 2017, and Jan. 20, 2019. Patients who had an autologous hemopoietic stem cell transplant less than 100 days before study enrollment were not eligible.

Study patients underwent lymphodepletion with fludarabine (30 mg/m² per day for 3 days) and cyclophosphamide (750 mg/m² per day) before infusion of autologous anti-CD19 CAR T cells (1 × 10 cells/kg) and murine anti-BCMA CAR T cells (1 × 10 cells/kg).

The primary end point was overall response, with a secondary end point of safety that included incidence of cytokine release syndrome (CRS).

Twenty-one patients (median age 58 years; interquartile range = 49.5-61 years; 52% women) received the dual CAR T-cell therapy. The study population underwent a median of six lines of previous therapies (range, 4-17).

Twenty of twenty-one patients (95%) who received dual anti-CD19/anti-BCMA CAR T-cell therapy had an overall response to treatment at a median follow-up of 179 days (IQR = 72-295 days). Nine patients (43%) had a stringent complete response, three patients (14%) had a complete response, five patients (24%) had a very good partial response, and three patients (14%) had a partial response to treatment. Eighty-one percent of patients were minimal residual disease (MRD)-negative, with 94% achieving MRD-negative status within one month of CAR T-cell infusion.

Xu told Cell Therapy Next that he was surprised by the MRD results in the study.

“Of all the patients who had minimal residual disease negativity, only one relapsed during follow-up, indicating that the combination of humanized anti-CD19 and anti-BCMA CAR T cells might allow patients to have a better prognosis in the future,” Xu added.

The most common treatment-related toxicity was CRS, which occurred in 19 of 21 patients (90%). Eighteen patients (86%) had grade 1 or 2 CRS, and one patient (5%) had grade 3 CRS. There were no cases of grade 4 or 5 CRS in the study population. CRS occurred a median of 9 days (range, 1-15 days) after treatment with a median duration of 4 days (range, 1-14 days).

Nearly all patients (95%) experienced adverse hematological toxicities, including grade 3 or higher neutropenia (86%), anemia (62%) and thrombocytopenia (62%). Two patients died during the study’s follow-up period, but neither death was determined to be treatment-related.

Clinical implications

“In comparison to the long-term responses and potential for cure seen with anti-CD19 CAR T cells in B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia, the responses to CAR T-cell therapy for patients with multiple myeloma have not been as durable,” Sandra Susanibar Adaniya, MD, a fellow in the division of hematology and oncology at the University of Pennsylvania Perelman School of Medicine, and Alfred L. Garfall, MD, assistant professor of medicine at the University of Pennsylvania Perelman School of Medicine wrote in an accompanying editorial.

Adaniya and Garfall acknowledged that many patients have achieved disease control of their multiple myeloma in previous trials of anti-BCMA CAR T-cell therapy, but that longer-term responses to treatment of greater than 2 years were rare.

They called results of the study by Xu and colleagues “encouraging,” because of the 81% of patients who had an ongoing response to treatment at 6 months of follow-up.

“Although this durability of responses is impressive and supports further study of this approach, caution is warranted in attributing these favorable outcomes to the additional targeting of CD19. In this trial, there was no comparator group receiving the anti-BCMA CAR-T cells alone, and the anti-BCMA CAR T cells used had not previously been reported as monotherapy,” Adaniya and Garfall wrote.

“Our results confirm that combined infusion of humanized anti-CD19 and anti-BCMA CAR T cells is feasible in patients with relapsed or refractory multiple myeloma, and the preliminary activity warrants further investigation in randomized trials,” Xu told Cell Therapy Next.

“However, longer follow-up is needed to assess the extent of the activity with this dual CAR T-cell therapy and randomized studies are warranted to elucidate the potential value and mechanism of the combination of anti-BCMA and anti-CD19 CAR T cells.” – by Drew Amorosi

For more information:

Kailin Xu, MD, PhD, can be reached at Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China; email: lihmd@163.com.

Disclosures: Garfall reports research funding from Amgen, Janssen, Novartis and Tmunity; personal fees from Kite Pharma and Surface Oncology; and is an inventor on patents in the field of CAR T-cell therapy for multiple myeloma. Guangjun is an employee of iCARTAB Biomedical Co. Ltd. The remaining authors report no relevant financial disclosures.

A combination of humanized anti-CD19 and anti-B-cell maturation antigen chimeric antigen receptor T-cells has shown activity in patients with relapsed or refractory multiple myeloma, according to results of a single-center, single-arm phase 2 clinical trial published in The Lancet Haematology.

The dual CAR T-cell combination resulted in a 95% response rate, with 43% of patients achieving a complete response to therapy.

“To our knowledge, this is the first study using humanized anti-CD19 CAR T cells combined with anti-BCMA CAR T cells for the treatment of relapsed or refractory multiple myeloma,” Kailin Xu, MD, PhD, professor in the department of hematology at the Affiliated Hospital of Xuzhou Medical University told Cell Therapy Next.

BCMA is an ideal target for CAR T-cell therapy, and promising results have been obtained in relapsed or refractory multiple myeloma. Several studies have shown that a small component of multiple myeloma clones is believed to express CD19, and these cells are considered to be less differentiated multiple myeloma cells, or myeloma-like stem cells,” Xu said.

By expanding the coverage of multiple myeloma cell targets and eliminating less-differentiated multiple myeloma cells, the strategy may improve the duration of response of CAR T-cell activity in patients with relapsed or refractory multiple myeloma, he added.

“This dual CAR-T cell combination might be a promising treatment option for relapsed or refractory multiple myeloma,” Xu and colleagues wrote in their analysis.

Dual CAR strategy

The study comprised patients aged 18 to 69 years who had histologically confirmed multiple myeloma at the Affiliated Hospital of Xuzjou Medical University in China between May 1, 2017, and Jan. 20, 2019. Patients who had an autologous hemopoietic stem cell transplant less than 100 days before study enrollment were not eligible.

Study patients underwent lymphodepletion with fludarabine (30 mg/m² per day for 3 days) and cyclophosphamide (750 mg/m² per day) before infusion of autologous anti-CD19 CAR T cells (1 × 10 cells/kg) and murine anti-BCMA CAR T cells (1 × 10 cells/kg).

The primary end point was overall response, with a secondary end point of safety that included incidence of cytokine release syndrome (CRS).

Twenty-one patients (median age 58 years; interquartile range = 49.5-61 years; 52% women) received the dual CAR T-cell therapy. The study population underwent a median of six lines of previous therapies (range, 4-17).

Twenty of twenty-one patients (95%) who received dual anti-CD19/anti-BCMA CAR T-cell therapy had an overall response to treatment at a median follow-up of 179 days (IQR = 72-295 days). Nine patients (43%) had a stringent complete response, three patients (14%) had a complete response, five patients (24%) had a very good partial response, and three patients (14%) had a partial response to treatment. Eighty-one percent of patients were minimal residual disease (MRD)-negative, with 94% achieving MRD-negative status within one month of CAR T-cell infusion.

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Xu told Cell Therapy Next that he was surprised by the MRD results in the study.

“Of all the patients who had minimal residual disease negativity, only one relapsed during follow-up, indicating that the combination of humanized anti-CD19 and anti-BCMA CAR T cells might allow patients to have a better prognosis in the future,” Xu added.

The most common treatment-related toxicity was CRS, which occurred in 19 of 21 patients (90%). Eighteen patients (86%) had grade 1 or 2 CRS, and one patient (5%) had grade 3 CRS. There were no cases of grade 4 or 5 CRS in the study population. CRS occurred a median of 9 days (range, 1-15 days) after treatment with a median duration of 4 days (range, 1-14 days).

Nearly all patients (95%) experienced adverse hematological toxicities, including grade 3 or higher neutropenia (86%), anemia (62%) and thrombocytopenia (62%). Two patients died during the study’s follow-up period, but neither death was determined to be treatment-related.

Clinical implications

“In comparison to the long-term responses and potential for cure seen with anti-CD19 CAR T cells in B-cell acute lymphoblastic leukemia, diffuse large B-cell lymphoma, and chronic lymphocytic leukemia, the responses to CAR T-cell therapy for patients with multiple myeloma have not been as durable,” Sandra Susanibar Adaniya, MD, a fellow in the division of hematology and oncology at the University of Pennsylvania Perelman School of Medicine, and Alfred L. Garfall, MD, assistant professor of medicine at the University of Pennsylvania Perelman School of Medicine wrote in an accompanying editorial.

Adaniya and Garfall acknowledged that many patients have achieved disease control of their multiple myeloma in previous trials of anti-BCMA CAR T-cell therapy, but that longer-term responses to treatment of greater than 2 years were rare.

They called results of the study by Xu and colleagues “encouraging,” because of the 81% of patients who had an ongoing response to treatment at 6 months of follow-up.

“Although this durability of responses is impressive and supports further study of this approach, caution is warranted in attributing these favorable outcomes to the additional targeting of CD19. In this trial, there was no comparator group receiving the anti-BCMA CAR-T cells alone, and the anti-BCMA CAR T cells used had not previously been reported as monotherapy,” Adaniya and Garfall wrote.

“Our results confirm that combined infusion of humanized anti-CD19 and anti-BCMA CAR T cells is feasible in patients with relapsed or refractory multiple myeloma, and the preliminary activity warrants further investigation in randomized trials,” Xu told Cell Therapy Next.

“However, longer follow-up is needed to assess the extent of the activity with this dual CAR T-cell therapy and randomized studies are warranted to elucidate the potential value and mechanism of the combination of anti-BCMA and anti-CD19 CAR T cells.” – by Drew Amorosi

For more information:

Kailin Xu, MD, PhD, can be reached at Department of Hematology, Affiliated Hospital of Xuzhou Medical University, Xuzhou 221002, Jiangsu, China; email: lihmd@163.com.

Disclosures: Garfall reports research funding from Amgen, Janssen, Novartis and Tmunity; personal fees from Kite Pharma and Surface Oncology; and is an inventor on patents in the field of CAR T-cell therapy for multiple myeloma. Guangjun is an employee of iCARTAB Biomedical Co. Ltd. The remaining authors report no relevant financial disclosures.

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