Autologous BCMA-CART successfully treats refractory relapsed multiple myeloma with TP53 gene mutation and central nervous system infiltration


The patient, male, 66 years old, diagnosed multiple myeloma for more than 4 years, and the second recurrence came to our hospital in March.
The patient had no obvious cause of fatigue in October 2014, accompanied by increased foam in the urine. Visit a famous blood disease research institute in the country to check blood white blood cells (WBC) 15.36 × 10 ^ 9 / L, hemoglobin (HGB) 70g / L, platelets (PLT) 40 × 10 ^ 9 / L; bone marrow cell morphology found abnormal plasma cells 43%, flow cytometry showed that abnormal plasma cells expressed CD138, CD56, CD38, cKappa; serum and urine immunofixation electrophoresis showed IgG-κ monoclonal immunoglobulin; diagnosis of multiple myeloma (IgG-κ type) . PDD (bortezomib 3.5mg d1, 4, 8, 11, doxorubicin liposome, dexamethasone 20mg d1-4, d8-11) reached complete remission (CR) after 1 course of treatment, but lung appeared Department of infection; adjusted for VD (vincristine, doxorubicin liposome) chemotherapy for 1 course of treatment. After infection control, the PDD regimen was treated with 13 courses of chemotherapy, and thalidomide was maintained for half a year.

2, after entering our hospital for diagnosis and treatment The hospital admission rate was 107 beats/min, and other vital signs were normal. Check blood WBC2.34×10^9/L, HGB70g/L, PLT57×10^9/L; blood globulin 81.2g/L; blood β2 microglobulin 6.81mg/L; bone marrow abnormal plasma cells 60%, flow Cellular analysis of abnormal plasma cells completely expressed CD269 (BCMA), CD38, CD138, CD56, CD81dim and cytosolic Igκ; 339 blood tumor genes were detected by second-generation sequencing technology (NGS), and TP53 gene function loss mutation was found, and KRAS , DNMT3A, PRDM1 gene variation. The number of cerebrospinal fluid cells was 2×10^6/L, and 8.51% by flow cytometry was abnormal plasma cells. Pulmonary CT showed two lung infections.
The morphology of bone marrow cells into our hospital is as follows:

Due to the patient's medical history for more than 4 years, the disease recurred repeatedly during repeated chemotherapy, and the new protease inhibitor esamizomib combined with chemotherapy was still ineffective after the last relapse. It is estimated that the tumor cells are resistant and the prognosis is poor. Chemotherapy alone is unlikely to achieve complete remission. Family members expressed knowledge and requested treatment with BCMA-CART cells.
Central nervous system tumors are the main cause of neurotoxicity after CART treatment. In order to reduce central nervous system toxicity after CART treatment, intermittent intrathoracic injection of chemotherapy drugs to cerebrospinal fluid leukocytes 4×10^6/L, flow cytometry analysis 1.65 % is an abnormal phenotypic plasma cell. Then start CART cell therapy. Because the patient is older and the basal heart rate is faster, cyclophosphamide is more toxic to the heart. Therefore, only fludarabine 50 mg×3/day is given for three days before returning CART. After stopping chemotherapy, BCMA-CART cells are returned 5.2×10. ^5/kg body weight.
On the 4th day after the BCMA-CART cells were returned, the heart rate of the patient was slightly increased compared with the previous one. The heart rate was as fast as 140 beats/min on the 7th day. On the 8th day, the patient developed repeated fever and the body temperature was above 38 °C. Oral administration of the ibuprofen suspension can be temporarily reduced to normal. On the 9th day, there was continuous high fever and the highest body temperature reached 40 °C. The antipyretic drugs could not be reduced to normal. The maximum heart rate could reach 170 beats/min, and the wheezing and urination were obviously reduced. The examination showed that the abdominal distension and the lungs could be Smell dry and wet voices. Consider the aforementioned cytokine release syndrome (CRS), which is produced by CART cell proliferation and killing tumor cells. Considering the patient's age, the previous chemotherapy time is long, worry about the fatal complications caused by CRS, and the high-dose hormone combined with plasma exchange 3 times, symptomatic supportive treatment. After the patient's body temperature is normal, other vital signs are stable.
On the 15th day after the CART cells were returned, the morphology and flow pattern of the bone marrow were not observed, and the serum IgG was significantly decreased. On the 27th day, blood routine: WBC 2.93×10^9/L, NEU 0.25×10^9/L↓, HGB 88g/L, PLT 28×10^9/L, and serum creatinine was discharged normally. After the patient was discharged from hospital, the blood cells gradually reached normal levels
Because patients with MM cells have TP53 gene mutations, even if they reach remission, they are prone to recurrence. Therefore, oral Venetok (BCL2 inhibitor) is combined with olaparib targeted therapy. On day 92, patients were assessed for complete remission (CR) according to the International Myeloma Working Group (IMWG) criteria. On the 43rd day after CART, there was hypothermia, cough, and cough. The lungs could smell wet rales. The chest CT showed multiple flaky shadows in the lungs. Considering lung infection, gamma globulin, Shupushen, Linai Zolconazole and oral voriconazole were discharged from the hospital one week after infection. So far, patients have been treated with CART for 4 months. Currently, patients are generally in good condition and have a good quality of life.