Gene therapy for multiple myeloma

Prognosis of multiple myeloma (MM) remains insufficient despite the intervention of high dose chemotherapy with auto- or allo- hematopoietic stem cell transplantation and the advent of molecular target drugs such as thalidomide, lenalidomide, and bortezomib. Further development or new concepts of therapeutic approaches are still required for MM treatment. Current standard protocol for MM treatment does not include gene delivery method or oncolytic virus approaches. Since MM is a disorder originated from B cell lineage, it involves immunological aspects in both pathogenesis and clinical manifestations. Therefore, the comprehension of immunology as well as oncology is essential to exploit new therapeutic approaches. Recently, novel therapeutic concepts for MM have been emerging. In this review, we present current progress of gene therapy related to MM treatments as well as the overview of MM treatment history.     

Intensive therapy in multiple myeloma

During the past 10 years, high-dose therapy (HDT) has been widely explored in multiple myeloma. The first randomized study comparing conventional chemotherapy and HDT followed by autologous bone marrow transplantation has been completed by the Intergroupe Fran?ais du Myelome. This trial designed for patients under 65 years of age with newly diagnosed myeloma has shown that HDT is superior to CC in terms of response rate, event free survival and survival. However a number of issues remain to be addressed regarding autologous transplantation: feasibility and survival impact in patients over 60 years of age, conditioning regimen, source of stem cells, impact of tandem transplants, maintenance therapy. The place of allogeneic bone marrow transplantation in the management of younger patients remains controversial due to a high toxic death rate.     

Pulmonary fibrosis following therapy with Melphalan for multiple myeloma

A patient suffering from multiple myeloma developed pulmonary fibrosis, of a type known to be associated wtih busulphan, whilst being treated with Melphalan.     

基于运动矢量追踪的多手术器械光学定位算法

目的 光学定位手术导航系统因其具有较高的定位精度、对患者无电磁辐射等特点,成为手术导航系统中空间定位的主要发展方向之一。其难点在于对多个带光学标记物的手术器械如何快速识别和实时跟踪。本文提出基于运动矢量追踪的多手术器械定位算法,以解决多手术器械的识别和跟踪问题。方法利用手术器械固定几何形状和运动矢量,实现对手术器械的识别和跟踪。首先基于不同手术器械的不同边长比对各个手术器械注册识别,其次根据识别出的结果利用前后帧的运动矢量实现对各个手术器械的实时跟踪。本文实时跟踪了两个器械的运动轨迹,并测量了使用本文算法时手术器械距离上的精度。结果 借助光栅尺进行距离测试,本文所提算法测得大手术器械的距离测量平均绝对误差为0.031 mm,小手术器械的距离测量平均绝对误差为0.065 mm。结论 基于几何形状识别和运动矢量跟踪的光学定位算法的精度满足手术导航系统的需求。     

Bcl-2 antisense therapy in multiple myeloma

Multiple myeloma is a plasma cell tumor localised in the bone marrow. During chemotherapy drug resistance develops in almost all patients. We have indications that the anti-apoptopic protein Bcl-2 is a key element in multi drug resistance in myeloma. Reduction of Bcl-2 renders the tumor cell susceptible to drug induced apoptosis. This suggests that therapies directed at lowering Bcl-2 levels in myeloma cells in vivo, like Bcl-2 antisense treatment, might chemosensitize the tumor cells and therefore might be applicable for therapeutic use.     

Combined therapy of multiple myeloma: cytostatics and plasmapheresis

In 11 patients with III A stage multiple myeloma in every week before new course of cytostatics started, three times plasmapheresis therapy had been performed. There was no difference in reducing of plasma cell mass, plasma immunoglobulins concentration and proteinuria or disappearance of osteolytic bone lesions between the group of patients treated with combination chemotherapy and plasmapheresis and chemotherapy alone. However there was visible disparity in the disappearance of bony pains: rapidly in the plasmapheresis group. One serious complication after plasmapheresis therapy was notified: gastric haemorrhage. The remaining plasmapheresis complications: tetany, nausea, vomiting, chills and bradycardia were related to citrate toxicity.     

MCL1 gene co‐expression module stratifies multiple myeloma and predicts response to proteasome inhibitor‐based therapy

Multiple myeloma (MM) is the second most common hematologic cancer, characterized by abnormal accumulation of plasma cells in the bone marrow. The extensive biological and clinical heterogeneity of MM hinders effective treatment and etiology research. Several molecular classification systems of prognostic impact have been proposed, but they do not predict the response to treatment nor do they correlate to plasma cell development pathways. Here we describe the classification of MM into two distinct subtypes based on the expression levels of a gene module coexpressed with MCL1 (MCL1‐M), a regulator of plasma cell survival. The classification system enabled prediction of the prognosis and the response to bortezomib‐based therapy. Moreover, the two MM subtypes were associated with two different plasma cell differentiation pathways (enrichment of a preplasmablast signature versus aberrant expression of B cell genes). 1q gain, harboring 63 of the 87 MCL1‐M members including MCL1, was found in about 80% of the MM with upregulated MCL1‐M expression. Clonal analysis showed that 1q gain tended to occur as an early clonal event. Members of MCL1‐M captured both MM cell‐intrinsically acting signals and the signals regulating the interaction between MM cells with bone marrow microenvironment. MCL1‐M members were co‐expressed in mouse germinal center B cells. Together, these findings indicate that MCL1‐M may play previously inadequately recognized, initiating role in the pathogenesis of MM. Our findings suggest that MCL1‐M signature‐based molecular clustering of MM constitutes a solid framework toward understanding the etiology of this disease and establishing personalized care. Article Summary: A pathogenic mechanism‐guided molecular classification would facilitate treatment decision and etiology research of multiple myeloma. On the basis of the expression levels of a gene module coexpressed with MCL1, we have established a classification scheme assigning multiple myeloma into two subtypes with distinct prognosis, treatment responses and pathogenic backgrounds.     

Overview of anti-BCMA CAR-T immunotherapy for multiple myeloma and relapsed/refractory multiple myeloma

Multiple myeloma (MM) is a haematological malignancy caused by malignant proliferation of plasma cells in bone marrow. In recent years, MM patients are commonly treated with chemotherapy, autologous stem cell transplantation, protease inhibitors, immunomodulatory drugs and monoclonal antibodies, however most patients eventually relapse. Therefore, more effective therapies are highly needed. Anti-BCMA CAR-T therapy, a novel and efficacious method for treating MM and relapsed/refractory multiple myeloma (RRMM), has been designed and applied in clinics. The CAR-T can specifically recognize the targeted molecule B cell maturation antigen (BCMA) and kill MM cells expressing BCMA and several clinical trials have revealed high response rates in the therapy. Herein, we summarize the developments, the current design and clinical trials, the side effects of anti-BCMA CAR-T therapy and comparison of it with other CAR-T therapies.     

Neurologic sequelae of bone changes in multiple myeloma and its therapy

Multiple myeloma (MM) is a plasma cell malignancy characterized by infiltration of bone marrow, bone destruction, infiltration of soft tissues with plasma cells, and suppression of normal hematopoiesis. The production of monoclonal immunoglobulins with or without light chains is a major feature of the disease. Full spectrum of plasma cell dyscrasias include monoclonal gammapathy of undetermined significance, smouldering myeloma, indolent multiple myeloma, and fully developed, symptomatic multiple myeloma. The usual presenting features of MM include bone pain, weakness, fatigue, fever and infection. Neurologic symptoms are less common but one must not forget that MM may present with a neurologic disease. Careful neurologic history and examination are mandatory in patients with MM. Neurologic symptoms may be a direct manifestation of MM or may be due to the immune effect of monoclonal proteins directed against different neural structures. Finally, metabolic consequences (uremia, hypercalcemia, hyperviscosity) of MM may produce a broad spectrum of different neurologic symptoms including headache, blurring of vision, drowsiness, precoma, coma, vertigo, ataxia, hemiparesis and epileptiform seizures. The most common location of bone changes in MM is the thoracic spine, where it causes osteolytic changes with consequent compressive fractures. The most disastrous sequel is paraplegia. Multiple vertebral involvement with the evidence of osteolytic changes in other bones is usual, but solitary vertebral myeloma may occur. Myeloma usually involves the bone of the vertebral body and then spreads into the extradural space. However, patients with solitary extradural myeloma have been reported. Skull myeloma is frequently asymptomatic. It may grow externally or, rarely, there is intracranial expansion. Involvement of the cranial nerves is not rare, with II, V, VI, VII and VIII cranial nerves being most often affected. Isolated intracerebral plasmacytomas are extremely rare. Diagnostic approach includes plain X-rays of the skeleton, which was found to be the method of choice for demonstration of osteolytic changes, whereas magnetic resonance with gadolinium enhancement most reliably displays the degree of vertebral involvement and demonstrates any associated soft tissue mass. Current treatment of osteolytic changes in multiple myeloma include chemotherapy, radiotherapy in combination with dexamethasone, monthly infusions of bisphosphonates, surgical decompression, and kyphoplasty. Therapeutic approach is dictated by the presenting symptoms. In case of pain as the predominant symptom, treatment with chemotherapy and radiotherapy may be appropriate. Compressive symptoms are relieved with dexamethasone followed by radiotherapy and chemotherapy. Surgical decompression is used in patients with vertebral collapse and vertebral instability. Kyphoplasty is a new method used in the treatment of osteolytic changes of vertebral bodies. A viscous cement is injected into the cavity by a balloon-like inflatable bone tampon. It has been successfully employed to improve the quality of life, to reduce pain, and to increase overall functioning in patients with vertebral compression fractures by restoring most of the original height of the vertebral body. Bisphosphonates reduce pain associated with osteolytic changes in multiple myeloma, but also significantly reduce skeletal events (pathologic fracture, spinal cord compression, surgery or irradiation of bone) via unknown mechanism. It seems that bisphosphonates, by inhibiting bone resorption, alter the microenvironment in which the MM cells grow.     

Abnormal cytokine production by bone marrow stromal cells of multiple myeloma patients in response to RPMI8226 myeloma cells

INTRODUCTION: Recent studies indicate that bone marrow stromal cells (BMSCs) derived from patients with multiple myeloma (MM) differ from those of healthy donors in their expression of extracellular matrix compounds and in cytokine production. It is not known whether these abnormalities are primary or are acquired by BMSCs on contact with MM cells. MATERIALS AND METHODS: Interleukin (IL)-6, IL-11, IL-10, and tumor necrosis factor (TNF)-alpha production by CD166+ mesenchymal BMSCs and the CD38+/CD138+ RPMI8226 myeloma cell line cultivated in vitro in monocultures or co-cultivated under cell-to-cell contact or non-contact conditions in the presence of a tissue culture insert were measured. Intracellular cytokines were measured by flow cytometry analysis as the percentage of cytokine-producing cells or by mean fluorescence intensity as the level of cytokine expression in cells. Additionally, ELISA was used to measure IL-6, soluble IL-6 receptor (sIL-6R), IL-11, IL-10, TNF-alpha, B-cell-activating factor of the TNF family (BAFF), hepatocyte growth factor (HGF), and osteopontin (OPN) production in the supernatants of the cultures and co-cultures. RESULTS: A higher ability of the BMSCs of MM patients than in controls was detected to produce IL-6, IL-10, TNF-alpha, OPN, and especially HGF and BAFF in response to the RPMI8226 cells. Moreover, the BMSCs of the MM patients significantly enhanced the production of sIL-6R by the RPMI8226 cells. DISCUSSION: Cytokines over-expressed by BMSCs of MM patients can function as growth factors for myeloma cells (IL-6, IL-10, HGF), migration stimulatory factors for tumor plasma cells (TNF-alpha, HGF), adhesion stimulatory factors (HGF, BAFF and OPN), stimulators of osteoclastogenesis (IL-6, TNF-alpha), and angiogenic factors (TNF-alpha). The results of this experiment strongly suggest that the BMSCs from MM patients differed in spontaneous and myeloma cell-induced production of cytokines, especially of HGF and BAFF, and these abnormalities were both primary and acquired by the BMSCs on contact with the MM cells. This in turn suggests the presence of an undefined, autocrine stimulation pathway resulting in a prolonged production of cytokines even in long-term cultures in vitro and in vivo. These abnormalities might provide optimal conditions for the proliferation and differentiation of residual tumor cells or their precursors in the affected bone marrow.