Anti-BCMA CAR-T Cell Therapy in Relapsed or Refractory Multiple Myeloma Patients with Impaired Renal Function

Anti-B cell maturation antigen(BCMA)chimeric antigen receptor(CAR)T-cell therapyis effective and well-tolerated for refractory or relapsed multiple myeloma(RRMM).The purposcof the present study was to analyze efficacy in RRMM patients with renal impairment treated byanti-BCMA CAR-T cell therapy.A total of 59 RRMM patients were selected,and divided intoimpaired renal function(lRF)group[basclinc cstimated giomerular filtration rate(eSFR)<90 m/min/1.73 m^2(n=18)]and normal renal function(NRF)group(baseline eGFR≥90 mL/min/1.73 m,n=41).For patients with IRF,eGFR at the 6th month post-CAR-T cells infusion was significantlyhigher than the baseline(P<0.05).The multivariate analysis showed that light chain type and beta-2 micro-globulin(bcta-2M)were associated factors with the decrease of serum creatinine.Medianprogression-free survival(PFS)in the NRF group and IRF group was 266 days and 181 daysrespectively.Overall survival(OS)in the NRF group and lRF group was 877 days and 238 daysrespectively.There was no significant difference in the objective response rate(ORR)between thelRF group and the NRF group.It is suggested that CAR-T cells therapy could improve the renalfunction during the treatment of RRMM.The renal function could be more significantly improvedin RRMM patients with light chain type than with other types.

Megakaryocyte aplastic thrombocytopeniaafter CAR T-cell therapy in a patient withmultiple myeloma:A case report

Chimeric antigen receptor(CAR)T-cell therapy is an effective new treatment strategy for hematologic malignancies.The success of CAR T-cell therapy in treating leukemia and lymphoma has promoted its development for multiple myeloma(MM),and the initial results of CAR T cell therapy have been encouraging.CAR T-cell therapy target antigens that have been clinically evaluated in MM;these antigens include CD19,B cell maturation antigen(BCMA),CD38,and CD138.A barrier to the widespread use of CAR T-cell therapy is its toxicity,primarily cytokine release syndrome(CRS),and neurologic toxicity.This study reports a patient with refractory MM who also developed megakaryocyte aplastic thrombocytopenia after receiving CAR T-cell therapy;such a case or the unusual side effects involving medications are yet unreported.There are risks in using cyclosporine and other immunosuppressants that may lead to MM recurrence as the use of such substances is contradictory to previous treatments;therefore,we temporarily administered platelet infusion as supportive care.Thus far,the condition of the patient has been steady and the patient regularly takes blood test in the hospital.

Successful Treatment of Low-Dose Lenalidomide Maintenance Therapy Followed by Second Autologous Peripheral Blood Stem Cell Transplantation in Heavily Treated Multiple Myeloma

Recently, the prognosis of multiple myeloma has been improved by using high-dose chemotherapy followed by autologous peripheral blood stem cell transplantation (ASCT), bortezomib, and immunomodulatory drugs including thalidomide and lenalidomide. On the other hand, treatment strategy remains difficult for refractory and relapse cases. Here, we report the successful treatment of low-dose lenalidomide maintenance therapy followed by salvage ASCT in a heavily treated patient with multiple myeloma. This 58-year-old woman with IgG-λ multiple myeloma had a 5th recurrence in June, 2011. It was 7 years post-diagnosis, and she had received conventional therapies such as VAD, MP therapy. Furthermore, the patient had already been treated with ASCT, bortezomib, and thalidomide therapy. At the 5th recurrence, she had extramedullary plasmacytoma in the left orbit. She initially received bortezomib and dexamethasone therapy as induction therapy. After peripheral blood stem cell collection, radiation therapy was performed. The patient then received a second ASCT. Three months later, the response was very good partial response. Finally, the patient was treated with 5 mg/day lenalidomide orally as a maintenance therapy, and she achieved stringent complete response after 2 months according to International Myeloma Working Group response criteria. Low-dose lenalidomide maintenance therapy might be also useful for ASCT as salvage therapy, although further studies are warranted.

Progress in Drug Therapy for Multiple Myeloma

Multiple myeloma remains incurable with conventional treatments.However,new active drugs,including the immunomodulatory agents,thalidomide and lenalidomide, and the proteasome inhibitors bortezomib and NPI-0052,and other targeted therapies,have shown promising anti-myeloma activity.These agents represent a new generation of treatments for multiple myeloma that affect both specific intracellular signaling pathways and the tumor microenvironment.This review therefore focuses on the extensive clinical data available from studies of these drugs in the treatment of newly diagnosed,refractory and relapsed multiple myeloma.

An Evolutionary Approach for Personalized Therapy in Multiple Myeloma

Most patients with multiple myeloma (MM) respond well to initial therapy, but invariably relapse due to evolution of resistant phenotypes. Here we examine the evolutionary dynamics of proliferation of resistant MM phenotypes during therapy. By applying computational models to data from three clinical trials for newly diagnosed MM patients, we have quantified the size and level of chemoresistance of subpopulations within the tumor burden in 124 patients, prior to and during therapy. Subsequently, we used the computational models to explore an alternative strategy of “adaptive therapy” (AT), which includes defined treatment holidays, to improve the duration of “controlled disease” (CD). Simulations showed that AT could prolong CD in all three trials: 50.0% vs. 11.1% 50-month CD for a single agent approach in older adults (P = 0.0123), 80.4% vs. 58.8% 60-month CD for a multi-agent bortezomib based therapy (P = 0.0082), and 54.0% vs. 24.0% 60-month CD for a multi-agent lenalidomide based therapy (P < 0.0001). Increases in duration of CD resulted from the stabilization of tumor burden, which in turn would delay the growth of chemoresistant sub-populations in patients with partial (PR), or very good partial response (VGPR). These computational algorithms suggest that AT may provide an alternative and feasible therapeutic management strategy in MM.

Follow-Up Study of a Multiple Myeloma Patient Successfully Treated with Clarithromycin (CAM), Low-Dose Lenalidomide and Low-Dose Dexamethasone: Significance and Possible Mechanism of Action of CAM as an Add-On Therapy

Background: Recently, high efficacy of the chemotherapeutic regimen combining clarithromycin (CAM) with lenalidomide (Len) and dexamethasone (Dex) (BiRD) in treating multiple myeloma (MM) patients has been reported. However, the exact mechanism of added CAM has not been fully elucidated. This case report will provide helpful information for understanding the significance and the mechanism of action of CAM as an add-on therapy. Patient: A 78-year-old female patient with IgA-λ type MM was treated with low-dose Len coupled with low-dose Dex (low Rd), and excellent response was achieved for long term, but she later became refractory to this treatment. Then, CAM was added to low Rd (low Rd-CAM, i.e., modified BiRD therapy). This add-on-therapy was found to be effective, but later suspended because of pneumonitis. Then, low-dose Len coupled with CAM (low R-CAM) treatment was applied;but effect of this Dex-free treatment was insufficient. Thus, low Rd-CAM was reapplied and satisfactory reduction of IgA was achieved. This fact suggests that low Rd-CAM is the favorable combination, Dex is requisite and CAM might have enhanced the effect of Dex. In this case, various serum cytokines were examined during the course of illness. Only interleukin-6 showed apparent increase, and tumor necrosis factor-α, transforming growth factor-β, soluble IL-2 receptors and C-reactive protein showed the slight increase during low Rd-CAM treatment. The results seem somewhat conflicting, but it seems that intricate cytokine response due to immune activation might have occurred during low Rd-CAM treatment.

Multiple myeloma mesenchymal stromal cells: Contribution to myeloma bone disease and therapeutics

Multiple myeloma is a hematological malignancy inwhich clonal plasma cells proliferate and accumulate within the bone marrow. The presence of osteolytic le-sions due to increased osteoclast(OC) activity and sup-pressed osteoblast(OB) function is characteristic of the disease. The bone marrow mesenchymal stromal cells(MSCs) play a critical role in multiple myeloma patho-physiology, greatly promoting the growth, survival, drug resistance and migration of myeloma cells. Here, we specifically discuss on the relative contribution of MSCs to the pathophysiology of osteolytic lesions in light of the current knowledge of the biology of my-eloma bone disease(MBD), together with the reported genomic, functional and gene expression differences between MSCs derived from myeloma patients(pMSCs) and their healthy counterparts(dMSCs). Being MSCs the progenitors of OBs, pMSCs primarily contribute to the pathogenesis of MBD because of their reduced osteogenic potential consequence of multiple OB inhibi-tory factors and direct interactions with myeloma cells in the bone marrow. Importantly, pMSCs also readily contribute to MBD by promoting OC formation and ac-tivity at various levels(i.e., increasing RANKL to OPG expression, augmenting secretion of activin A, uncou-pling ephrinB2-EphB4 signaling, and through augment-ed production of Wnt5a), thus further contributing to OB/OC uncoupling in osteolytic lesions. In this review, we also look over main signaling pathways involved in the osteogenic differentiation of MSCs and/or OB activity, highlighting amenable therapeutic targets; in parallel, the reported activity of bone-anabolic agents(at preclinical or clinical stage) targeting those signaling pathways is commented.

Novel agents and new therapeutic approaches for treatment of multiple myeloma

This review summarizes the therapeutic strategies and the drugs actually in development for the management of myeloma patients. Multiple myeloma is caused by the expansion of monoclonal plasma cells and secretion of M-protein(immunoglobulins, Bence Jones protein and free light chains). Multiple myeloma still remains an incurable disease with a high incidence rate in the elderly, despite the introduction of several new therapeutic agents(bortezomib, lenalidomide and thalidomide) which have changed its natural history. The high heterogeneity of this disease leads to large differences in clinical responses to treatments. Thus, the choice of the best treatment is a difficult issue. However, the introduction of new drugs has made it possible to achieve high response rates and good quality respons-es with long-term disease control. Interactions between tumor cells and their bone marrow microenvironment play a pivotal role in the development, maintenance, and progression of myeloma, inducing also drug resistance. These knowledges have improved treatment options, leading to the approval of new drugs which not only target the malignant cell itself, but also its microenvironment. These agents are in preclinical/early clinical evaluation and they appear to further improve disease control, but their use is still not approved outside of clinical trials.

Novel mechanism of drug resistance to proteasome inhibitors in multiple myeloma

Multiple myeloma(MM) is a cancer caused by uncontrolled proliferation of antibody-secreting plasma cells in bone marrow, which represents the second most common hematological malignancy. MM is a highly heterogeneous disease and can be classified into a spectrum of subgroups based on their molecular and cytogenetic abnormalities. In the past decade, novel therapies, especially, the first-in-class proteasome inhibitor bortezomib, have been revolutionary for the treatment of MM patients. Despite these remarkable achievements, myeloma remains incurable with a high frequency of patients suffering from a relapse, due to drug resistance. Mutation in the proteasome β5-subunit(PSMB5) was found in a bortezomib-resistant cell line generated via long-term coculture with increasing concentrations of bortezomib in 2008, but their actual implication in drug resistance in the clinic has not been reported until recently. A recent study discovered four resistance-inducing PSMB5 mutations from a relapsed MM patient receiving prolonged bortezomib treatment. Analysis of the dynamic clonal evolution revealed that two subclones existed at the onset of disease, while the other two subclones were induced. Protein structural modeling and functional assays demonstrated that all four mutations impaired the binding of bortezomib to the 20 S proteasome, conferring different degrees of resistance. The authors further demonstrated two potential approaches to overcome drug resistance by using combination therapy for targeting proteolysis machinery independent of the 20 S proteasome.

Intramedullary nailing for pathological fractures of the proximal humerus caused by multiple myeloma: A case report and review of literature

BACKGROUND Multiple myeloma(MM)bone disease is indicative of MM,and reduces patient life quality.In addition to oncological,antineoplastic systemic therapy,surgical therapy in patients with MM is an essential treatment within the framework of supportive therapy measures and involves orthopedic tumor surgery.Nevertheless,there are few reports on intramedullary(IM)nailing in the treatment of MM-induced proximal humeral fracture to prevent fixation loss.We here describe a case of pathological fracture of the proximal humerus caused by MM successfully treated with IM nailing without removal of tumors and a review of the current literature.CASE SUMMARY A 64-year-old male patient complaining of serious left shoulder pain and limited movement was admitted.The patient was finally diagnosed with MM(IgAλ,IIIA/II).After treatment of the pathological fracture with IM nailing,the patient's function recovered and his pain was rapidly relieved.Histopathological examination demonstrated plasma cell myeloma.The patient received chemotherapy in the Hematology Department.The humeral fracture displayed good union during the 40-mo follow-up,with complete healing of the fracture,and the clinical outcome was satisfactory.At the most recent follow-up,the patient's function was assessed using the Musculoskeletal Tumor Society score,which was 29.CONCLUSION Early surgery should be performed for the fracture of the proximal humerus caused by MM.IM nailing can be used without removal of tumors.Bone cement augmentation for bone defects and local adjuvant therapy can also be employed.

INVESTIGATION OF REALGAR IN THE TREATMENT FOR MULTIPLE MYELOMA

Objective To observe the clinical effect of realgar on multiple myeloma and to investigate its mechanism. Methods MTT and double antibody cramped ELISA assay were used to detect the activity of interleukin-6(IL-6) and level of soluble interleukin-6 receptor(sIL-6R) of the bone marrow supernant in 15 multiple myeloma patients treated by realgar or not. Results The activity of interleukin-6 and level of soluble interleukin-6 receptor of multiple myeloma patients were significantly higher than that of control group(P<0.01). They were not apparently decreased after realgar was used for 50 days(P>0.05).The interleukin-6 activity of stage Ⅲ patients were much higher than that of stage Ⅰ or Ⅱ(P<0.05). There was no difference of the level of soluble interleukin-6 receptor between two groups(P>0.05). For the 15 patients who were treated by using realgar, 3 got complete remission(CR), 5 got partial remission(PR), 7 came to not remission(NR). Conclusion Realgar could not decrease the activity of interleukin-6 and level of soluble interleukin-6 receptor so as to inhibit the proliferation of tumor cells.

Orbital Involvement in Multiple Myeloma: A Case Report

Purpose: To report a retro-orbital localization of Multiple Myeloma (MM) describing its treatment and clinical result. Case report: A 50-years-old male patient with Magnetic Resonance Imaging (MRI) evidence of a retro-orbital mass with exophthalmos, due to the pathological diagnosis of MM, was referred for Radiation Therapy (RT). Discussion: The orbital involvement in Multiple Myeloma is rare and few cases are reported in the literature. The treatment of choice is RT alone with a prescribed dose ranging between 40 Gy and 45 Gy. In our patient the retro-orbital lesion, measuring 26 × 16 mm, was treated with Intensity Modulated Radiotherapy Technique (IMRT) delivering 4400 cGy with conventional fractionation. The treatment was well tolerated, the patient experienced a complete regression of the exophthalmos without any significant side effect.

Phenylalanine deprivation inhibits multiple myeloma progression by perturbing endoplasmic reticulum homeostasis

Amino acid metabolic remodeling is a hallmark of cancer,driving an increased nutritional demand for amino acids.Amino acids are pivotal for energetic regulation,biosynthetic support,and homeostatic maintenance to stimulate cancer progression.However,the role of phenylalanine in multiple myeloma(MM)remains unknown.Here,we demonstrate that phenylalanine levels in MM patients are decreased in plasma but elevated in bone marrow(BM)cells.After the treatment,phenylalanine levels increase in plasma and decrease in BM.This suggests that changes in phenylalanine have diagnostic value and that phenylalanine in the BM microenvironment is an essential source of nutrients for MM progression.The requirement for phenylalanine by MM cells exhibits a similar pattern.Inhibiting phenylalanine utilization suppresses MM cell growth and provides a synergistic effect with Bortezomib(BTZ)treatment in vitro and murine models.Mechanistically,phenylalanine deprivation induces excessive endoplasmic reticulum stress and leads to MM cell apoptosis through the ATF3eCHOPeDR5 pathway.Interference with ATF3 significantly affects phenylalanine deprivation therapy.In conclusion,we have identified phenylalanine metabolism as a characteristic feature of MM metabolic remodeling.Phenylalanine is necessary for MM proliferation,and its aberrant demand highlights the importance of lowphenylalanine diets as an adjuvant treatment for MM.

CAR-T细胞治疗后复发/难治性多发性骨髓瘤患者的临床特征

目的分析嵌合抗原受体T(chimeric antigen receptor,CAR-T)细胞治疗后复发/难治多发性骨髓瘤(relapsed/refractory multiple myeloma,RRMM)患者的临床特征,初步探索此类患者未来可能的治疗策略。方法以2020年1月至2024年6月在首都医科大学附属北京朝阳医院住院治疗的RRMM患者为研究对象,分析CAR-T细胞治疗后复发的临床特征及生存情况。结果共收集14例符合条件的RRMM患者,均接受靶向BCMA的CAR-T细胞治疗,中位无进展生存时间为17个月(范围:3~47个月)。疾病复发进展时,1例仅表现为髓外复发,2例继发浆细胞白血病,11例为髓内复发;7例检查细胞遗传学,其中4例患者存在1个高危基因,1例患者存在2个高危基因。首次挽救治疗中,常用药物包括达雷妥尤单抗(6例)、泊马度胺(5例)、卡非佐米(3例),3例患者入组临床试验。13例患者可评价疗效,总有效率为61.5%(8/13),其中完全缓解率为30.8%(4/13),非常好的部分缓解率为23.1%(3/13)。中位随访时间为15个月(范围:1~32个月),中位无进展生存时间为7个月。截至末次随访,死亡6例,中位总生存期为32个月;1例患者出现第二肿瘤,类型为肺癌。结论接受CAR-T细胞治疗后RRMM患者常见多类药物耐药,挽救治疗疗效及预后不佳。

NF-κB信号通路与多发性骨髓瘤发病机制的相关性及靶向治疗作用的研究进展

通过对核因子kappa B信号通路进行阐述,分析其与多发性骨髓瘤(multiple myeloma,MM)发病机制的关系,及对其靶向治疗的相关研究进行综述,分析其现存的问题和未来发展的方向,以期为MM的靶向治疗提供新思路。

自体造血干细胞移植治疗多发性骨髓瘤的进展

多发性骨髓瘤是一种血液学恶性肿瘤,在过去的几十年里,大剂量美法仑联合自体造血干细胞移植已成为初治多发性骨髓瘤患者的核心治疗方案。诱导治疗、自体造血干细胞移植以及后续巩固和维持治疗是目前多发性骨髓瘤治疗的基本框架。达雷妥尤单抗等抗CD38单克隆抗体的引入改变了适合移植的多发性骨髓瘤患者的治疗模式,四联疗法成为新的标准诱导治疗。随着强效新型免疫疗法的引入,骨髓瘤的治疗格局正在发生变革性转变。笔者拟对在新药及新疗法时代,自体造血干细胞移植在多发性骨髓瘤中的研究进展进行综述。

自噬途径在药物治疗多发性骨髓瘤中作用的研究进展

多发性骨髓瘤(MM)是一种恶性血液肿瘤,其治疗常依赖于蛋白酶体抑制剂、免疫调节剂、类固醇等药物,但多数MM仍然会面临复发或转为难治性。自噬是一种2型细胞死亡机制,在MM病情进展中起着关键作用,包括促进MM细胞存活或促进其死亡的双相调控作用。本文就MM细胞在药物作用时其自噬活性的变化及对细胞增殖、凋亡的影响进行综述,旨在分析自噬途径在药物治疗MM中的作用,为靶向自噬治疗MM提供相关思路。

多发性骨髓瘤骨病微环境改变与治疗进展

多发性骨髓瘤骨病(MBD)是多发性骨髓瘤(MM)患者临床常见的并发症,骨相关事件的发生严重影响患者的生存质量与预后。MBD的发病机制涉及生理性骨重塑的失衡,如破骨细胞的过度激活、成骨细胞的抑制及微环境中骨细胞、骨髓基质细胞及免疫细胞等多种细胞与细胞因子的相互作用。目前MBD的治疗在标准抗骨髓瘤治疗基础上,控制肿瘤进展,同时在适应证范围内使用骨相关药物作用于骨重塑。为防止骨破坏,在抗骨吸收的同时,诱导新骨形成来修复现有病变是必不可少的,目前多种新型骨靶向药物在临床前及临床试验中表现出抗骨病作用。本文总结了骨髓微环境改变、骨重塑机制及治疗的新进展。

靶向BCMA CAR-T治疗RRMM的局限性及优化策略

嵌合抗原受体T细胞(CAR-T)免疫疗法快速发展,为多发性骨髓瘤(MM)治疗带来新的曙光,尤其B细胞成熟抗原(BCMA)作为迄今为止最成功的靶标,靶向BCMA CAR-T疗法可以使MM的症状获得持久且深度的缓解,在复发难治性多发性骨髓瘤(RRMM)治疗中取得突破性进展。但由于抗原逃逸、CAR-T衰竭等因素,多数患者仍会进展或复发,靶向BCMA CAR-T治疗后复发或难治患者的后续治疗缺乏标准方案。同时,复杂、昂贵且耗时的个性化CAR-T制造流程也限制其临床疗效的发挥。针对此现状,该综述总结了靶向BCMA CAR-T治疗的局限性及其机制,同时结合MM治疗领域新进展,提出改善进展或RRMM患者结局的潜在优化治疗策略。

早期序贯治疗联合ASCT对中高危多发性骨髓瘤的临床疗效及对PD-1/PD-L1、T细胞和B细胞功能的影响

目的:分析早期序贯治疗联合自体造血干细胞移植(ASCT)对中高危多发性骨髓瘤的临床疗效及对PD-1/PD-L1、T细胞和B细胞功能的影响。方法:选择2019年1月—2022年5月南阳市中心医院收治的90例中高危多发性骨髓瘤患者作为研究对象,依照随机信封法分为观察组和对照组。对照组患者采用常规化疗方案进行治疗,观察组在对照组的基础上采用早期序贯治疗联合ASCT方案干预和治疗。干预治疗半年后对患者临床疗效进行评估,治疗前及治疗后半年时检测外周血中CD3^(+)T细胞、CD4^(+)T细胞、CD8^(+)T细胞、PD-1及PD-L1蛋白表达水平,检测受试者血清中T细胞相关细胞因子IFN-γ、TNF-α及B细胞相关抗体IgA、IgM和IgG水平情况。结果:观察组治疗临床疗效显著优于对照组,差异有统计学意义(χ^(2)=13.586,P<0.05);治疗后,两组患者血中CD3^(+)T细胞、CD4^(+)T细胞水平均显著升高,CD8^(+)T细胞水平显著降低,差异有统计学意义(t=7.299、2.521、12.629,P<0.05);治疗后,两组患者血清中PD-1及PD-L1蛋白均显著降低,差异有统计学意义(t=16.315、11.161,P<0.05);治疗后,两组患者血清中IFN-γ、TNF-α蛋白均显著升高,差异有统计学意义(t=30.046、32.084,P<0.05);治疗后,两组患者血清中IgA蛋白显著降低,IgM和IgG蛋白均显著升高,差异有统计学意义(t=47.013、50.959、27.694,P<0.05)。结论:联合早期序贯治疗联合ASCT对中高危多发性骨髓瘤患者干预可有效提高临床疗效,控PD-1及PD-L1水平,改善T细胞和B细胞功能。