Efficacy of Humanized Anti-BCMA CAR T Cell Therapy in Relapsed/Refractory Multiple Myeloma Patients With and Without Extramedullary Disease

Abstract

In recent years, many new treatments for relapsed/refractory (R/R) multiple myeloma (MM) have improved patient prognosis, but the prognosis of patients with extramedullary MM is still particularly poor. Therefore, more efficacious therapies and novel strategies are urgently needed for these patients. The aim of this study was to observe and compare the efficacy and safety of humanized anti-B cell maturation antigen (anti-BCMA) chimeric antigen receptor (CAR) T cell therapy in R/R MM patients with and without extramedullary disease. Seven R/R MM patients with extramedullary disease and 13 without extramedullary disease received humanized anti-BCMA CAR T cell therapy. The overall response rate was not different between patients with and without extramedullary disease. There was no difference in the progression-free survival (PFS) or overall survival (OS) rates between the two groups at 180 days, but the PFS and OS rates in patients with extramedullary disease were lower at 360 days than those in patients without extramedullary disease. Although some patients with extramedullary disease experienced further disease progression, their M protein level did not increase. We did not see this change trend of M protein in patients without extramedullary disease. However, this was not observed in patients without extramedullary disease. Among patients who responded to CAR T cell therapy, the grades of cytokine release syndrome (CRS) and immune effector cell-associated neurotoxic syndrome (ICANS) were much higher among patients with extramedullary disease. In summary, R/R MM patients with extramedullary disease could benefit from humanized anti-BCMA CAR T cell therapy in the short term, although the CRS and ICANS grades were much higher in patients with extramedullary disease. Therefore, anti-BCMA CAR T cell therapy allows for a remission time for R/R MM patients with extramedullary disease, which could be maintained by bridging hematopoietic stem cell transplantation, radiotherapy, and other therapies.

Clinical trial registration: http://www.chictr.org.cn/index.aspx, identifiers ChiCTR1800017051 and ChiCTR2000033925.

Keywords: anti-B cell maturation antigen chimeric antigen receptor T; efficacy; extramedullary disease; multiple myeloma; refractory; relapsed.

Figure 1

Clinical responses of the humanized anti-BCMA CAR-T cell therapy. (A) Pt_with 1,2,5,6,7 (5/7, 71.4%) and Pt_without 4,6,8 (3/13, 23.1%) developed disease progression again and died of their primary disease. (B) There was no difference in ORR between patients with and without extramedullary disease when they achieved the best effect (P=0.876). (C) M protein levels increased again in Pt_with 5,7 when their disease progressed again, but it did not increase when the disease of Pt_with 1,2,6 progressed again. (D) All the patients with disease progression were accompanied by an increase of M protein level.

Figure 2

The survival observation of the humanized anti-BCMA CAR-T cell therapy. (A) The PFS in patients with extramedullary disease was lower than that of the patients without extramedullary disease at 360 days (P=0.037). There was no difference of the PFS in the two groups at 180 days (P=0.068). (B) The OS in patients with extramedullary disease was lower than that of the patients without extramedullary disease at 360 days (P=0.030). There was no difference of the OS in the two groups at 180 days (P=0.220).

Figure 3

The efficacy to the extramedullary disease. The skin lesion far from bone of Pt_with 4 disappeared after anti-BCMA CAR-T cell therapy. Myeloma cells in cerebrospinal fluid of Pt_with 7 disappeared after therapy. Soft tissue masses disappeared after this therapy.

Figure 4

The proportions of the anti-BCMA CAR-T cells in the therapy. (A, B). The proportions of anti-BCMA-CAR T cells in CD3+ T cells in peripheral blood in the two group of patients. (C, D). There was no difference in the median expansion peak of the anti-BCMA CAR-T cells in CD3+ T cells in peripheral blood in the two group of patients (P= 0.438). (E). In Pt_with 7, the highest anti-BCMA CAR-T cell expression in peripheral blood was 62.4%, the level of anti-BCMA CAR-T cells in her pleural effusion was 24.03%.

Figure 5

AEs and the serum levels in the anti-BCMA-CAR T cell therapy. (A, B) The grades of CRS and ICANS had no different in patients with and without extramedullary disease (P ^CRS = 0.050 and P ^ICANS = 0.050). (C, D) In patients obtained an ORR reaction, the grades of CRS and ICANS in patients with extramedullary disease was higher than that of in patients without extramedullary disease (P ^CRS =0.006 and P ^ICANS = 0.033). (E–G) The serum levels of IL-6, IL-2R, and TNF-a peaked 4 to 7 days after the infusion of anti-BCMA CAR T cells and declined 12 to 21 days. (H, I) IL-6 and IL-2R levels were higher in patients with extramedullary disease group than that of in patients without extramedullary disease group (P ^IL-6 = 0.030 and P ^IL-2R = 0.038). (J) There was no different in the TNF-a level between the two groups (P ^TNF-a = 0.241).