Anti-BCMA CAR-T cells for treatment of plasma cell dyscrasia: case report on POEMS syndrome and multiple myeloma

A 49-year-old female presented to our hospital in September 2016 due to numbness and weakness in both lower extremities for 2 weeks. Because of progressive weakness involving both lower limbs, the patient became disabled with unstable gait, unable to walk independently. Physical examination showed 4-grade muscle strength of both lower legs. After admission, detailed examinations were performed. Electromyogram revealed findings consistent with an acquired demyelinating polyneuropathy with increased distal latencies, conduction blocks, prolonged F wave latencies, and reduced conduction velocity. The cerebrospinal fluid examination was normal. Ultrasonography detected splenomegaly, ascites, pericardial effusion, and pleural effusion. No signs of sclerotic or lytic lesions were noted in X-ray or CT scans. Blood cell count and clinical biochemistry examinations were normal. Serum monoclonal protein was detected by serum protein electrophoresis. A largely elevated serum vascular endothelial growth factor (VEGF) level (2350.0 pg/mL) was detected by enzyme-linked immunosorbent assay (ELISA). Decreased cortisol and thyroxine level was recorded. Bone marrow aspiration and biopsy identified monoclonal plasma cells. According to immunohistochemistry (IHC) analysis, plasma cells (CD138⁺) accounted for 3%, and BCMA and CD138 expression was highly concordant (Fig. 1a). 1.1% of cells were considered monoclonal plasma cells in flow cytometry (Fig. 1c). According to the latest diagnostic criteria for POEMS [14, 15], the diagnosis of POEMS syndrome, in this case, was established based on the following evidence: major items including polyneuropathy, monoclonal plasma cell neoplasm, and elevated serum VEGF and minor items including splenomegaly, endocrine abnormality, and extravascular volume overload.

We started treatment with lenalidomide (25 mg/day for 21 days of a 28-day cycle) and once-weekly dexamethasone (10 mg). Serum monoclonal protein drastically decreased and neuropathy relieved after treatment for two cycles; however, frequent episodes of treatment-related orthostatic hypotension resulted in dose reduction of lenalidomide (10 mg/day for 21 days of a 28-day cycle) for the next 3 months. The serum monoclonal protein was largely reduced, and walking difficulty alleviated. However, the serum monoclonal protein quickly re-augmented, and symptoms worsened as low-dose treatment continued (Fig. 2a). The patient refused recommended salvage treatment with the bortezomib-based regimen or autologous stem cell transplantation (ASCT). Considering the reported anti-myeloma effects of anti-BCMA CAR-T cells [7, 8] and abundant expression of BCMA on monoclonal plasma cells (98.6% as revealed by flow cytometry) (Fig. 1c) and elevated serum BCMA (Fig. 2b) in this patient, we encouraged her to participate in a clinical trial involving anti-BCMA CAR-T treatment, to which she agreed. Chemotherapy (fludarabine 25 mg/m² and cyclophosphamide 20 mg/kg) was administered 4, 3, and 2 days before the first infusion of CAR-T cells (June 25, 2017) which was followed by two infusions administered once daily for the next 2 days. The effective anti-BCMA CAR-T cells totaled /1 × 10⁷/kg (Fig. 3b).

The patient developed a fever (37.4 °C, peaked 39.2 °C on the next day, and lasted for 7 days) and tachycardia about 24 h after the first infusion. The peak of serum ferritin and IL-6 (17.5 times higher than baseline) was detected on the third-day post-infusion, which was just the time where toxicity culminated (Fig. 2c). Cytopenia was observed but not central nervous system (CNS) toxicities. White blood cells and neutrophils returned to normal on the tenth day after infusion. No infusion of red blood cells or platelets was required during the entire treatment period (Fig. 2d). All coagulation and biochemistry parameters remained normal over the treatment period. She experienced grade 1 cytokine release syndrome (CRS), which was graded as described [16, 17]. The CAR-T cells remained detectable, and B cells gradually returned to normal levels in the blood 10 months after infusion (Fig. 2e).

Her serum monoclonal protein started to decrease 15 days after CAR-T cells infusion and became undetectable 90 days after infusion (Fig. 2a). The soluble BCMA and VEGF levels also decreased in a short time after treatment (Fig. 2b). Sixty days post-infusion, no abnormal plasma cells were found by bone marrow aspiration or flow cytometry (Fig. 1b, d), and she was able to do some cooking and walk without difficulty. An electromyogram showed that the conduction velocity of bilateral tibial nerves, peroneal nerves, sural nerves, and superficial peroneal nerves recovered, and the sensory nerve action potential (SNAP) amplitude was in normal range. F waves from bilateral tibial nerves showed a normal latency of 26.7 ms.

The patient received a diagnosis of IgA lambda multiple myeloma in November 2012, at the age of 59 years, after presenting with anemia and multiple bone lesions. She received induction therapy with 4 cycles of cyclophosphamide, bortezomib, and dexamethasone (CyBorD) which resulted in complete remission and high-dose melphalan (200 mg/m² of body surface area) followed by ASCT as consolidation. Approximately 27 months later, the disease progressed, and 62% of her bone marrow cells were plasma cells. Subsequent treatment included regimens incorporating clarithromycin, lenalidomide, bortezomib, dexamethasone, and daratumumab. According to the International Myeloma Working Group (IMWG) response criteria [18], the response was poor, and the disease kept progressing. In August 2017, after the failure of six prior lines of treatment, the patient was enrolled in the aforementioned trial and received anti-BCMA CAR-T cells. A bone marrow biopsy showed a 25% myeloma involvement. CD138 and BCMA co-expression were revealed by IHC (Fig. 4a). Largely elevated serum soluble BCMA was detected by ELISA (Fig. 4c). Risk factors were noted, including a complex karyotype, t (4;14) translocation, and gain of 1q21. The treatment protocol was the same as case 1’s except that only two infusions of CAR-T cells were given and the effective cells totaled 5.6 × 10⁶/kg (Fig. 3c). The patient was febrile for 7 days with a maximum temperature of 38.6 °C (Fig. 4e). The serum ferritin and IL-6 peaked respectively on the seventh- and sixth-day post-infusion, which was also the time where toxicity culminated (Fig. 4e). Pancytopenia was observed, and there was no CNS toxicity. White blood cells and neutrophils returned to normal 12 days after infusion. The patient was platelet transfusion dependent from day 2 until day 21 after CAR-T cell infusion. All coagulation and biochemistry parameters were normal over the whole treatment period. She experienced grade 1 CRS. The CAR-T cells remained detectable, and B cells gradually returned to normal levels in the blood 10 months after infusion (Fig. 4d).

Serum monoclonal protein and free lambda (λ) light chain levels substantially decreased 15 days after treatment. Serum monoclonal protein became undetectable 90 days post-infusion and remained undetectable for the next 5 months (Fig. 4c). Soluble BCMA level in the serum also decreased sharply in a short time post-infusion (Fig. 4c). Bone marrow MM cells were not detected by bone marrow aspiration and CD138 staining 90 days after CAR-T cell infusion (Fig. 4b). The response to treatment was stringent CR. At the about 8th month, serum monoclonal IgA-λ recurred (Fig. 4c), which indicated MM relapse, but the patient was free of abnormal routine blood test findings and bone pain. Serum monoclonal protein and free λ light chain levels kept increasing as MM progressed and serum BCMA protein level as well (Fig. 4c). She had biochemical recurrence 7.6 months after treatment. However, the patient refused further bone marrow examination.