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血液学和血液病xueyexuehexueyebing

多发性骨髓瘤营养策略:姜黄素 淫羊藿 蘑菇提取物

时间:2021-02-03 16:12 阅读:176 来源:朴诺健康研究院

目  录

一、引言

二、骨髓瘤的生物学与发展

三、病因和风险因素

四、骨髓瘤的诊断和检测

五、分期与预测

六、常规疗法

七、治疗方案

八、新兴疗法

九、控制MM或MGU及SMM发展为多发性骨髓瘤的潜在靶点

十、饮食和生活方式的注意事项

十一、综合干预

十二、参考文献


一、引言

多发性骨髓瘤(MM)是一种成熟浆细胞癌,浆细胞是一种产生免疫球蛋白(抗体)的白细胞。抗体的产生通常是为了保护身体免受细菌等微生物的侵害。在多发性骨髓瘤中,单克隆浆细胞产生功能失调的单克隆免疫球蛋白(M-spike),这可能会抑制免疫系统,并对不同器官造成损伤。进展期的多发性骨髓瘤通常表现出部分或全部的一系列被称为CRAB征兆的症状:高血钙、肾功能衰竭、贫血、骨损伤和骨折。骨髓瘤也增加了患者被严重感染的风险[1,2]

多发性骨髓瘤起于被称为意义未明的单克隆丙种球蛋白病(MGUS)和郁积型多发性骨髓瘤(SMM)的先兆疾病。这三种情况一起代表了疾病的连续体。确定哪些患者将从低风险的先兆疾病发展为活动性多发性骨髓瘤是对医师的一项挑战,也是该研究领域的一个热点。大多数MGUS患者和一些SMM患者从未发展为活动性多发性骨髓瘤。总的来说,多发性骨髓瘤及其先兆疾病具有可变的临床过程,治疗相关的决定必须根据每个患者的个体风险状况进行调整[3]

骨髓瘤是美国第二常见的血癌[4]:每年预计有32000名患者被诊断患有骨髓瘤[5]。在五年的时间里,全世界大约有230000例患者[6]。骨髓瘤更常见于老年患者,确诊患者的年龄中位数在66-70岁之间[7]。50岁以上的一般人群中约有3%被认为患有MGU[8,9]。在这些人中,每年约有1%的人发展成骨髓瘤或相关癌症[3]

骨髓瘤被认为是目前的治疗方法无法治愈的。然而,自20世纪中期以来,可供选择的治疗方法的数量大幅度增加。治疗策略的最新进展,包括蛋白酶体抑制剂、免疫调节药物、免疫疗法等新型药物,以及自体干细胞移植的广泛应用,都延长了骨髓瘤患者的典型生存期。今天,骨髓瘤确诊后患者存活五年的可能性超过70%[10]


二、骨髓瘤的生物学与发展

血细胞和基因

血液主要由液体(主要是水)和三种不同类型的细胞组成:帮助形成血块和控制出血的血小板、向全身输送氧气的红细胞和作为免疫系统一部分的白细胞[11]。血细胞在骨髓(骨骼内的海绵组织)内生长发育。未成熟的血细胞被称为造血干细胞,它发育成年轻的前体血细胞,最终成熟为血小板、红细胞和白细胞,然后离开骨髓进入血液。

骨髓中产生的两种白细胞是B细胞和T细胞。当入侵的生物体进入体内时,B细胞成熟为浆细胞,浆细胞是产生抗体的细胞[12]。抗体(也称为免疫球蛋白)是在血液中循环并破坏入侵生物体(如细菌和病毒)的蛋白质。抗体是由两种不同的蛋白质组成的,这两种蛋白是根据其相对大小命名的。较小的蛋白质称为轻链,较大的蛋白质称为重链。每个抗体由两条重链和两条轻链组成。重链决定抗体的亚型。有五种不同的抗体亚型-IgM,IgG,IgA,IgE和IgD。轻链有两种类型:kappa(κ)和lambda(λ),它们中的任何一种都可以与重链结合,从而产生10种不同类型的免疫球蛋白。此外,轻链可独立于重链被分泌,并可作为自由轻链循环[13]

人体内的所有细胞都含有基因,这些基因指示了细胞的运作方式和构建新细胞的方式[11]。基因以脱氧核糖核酸(DNA)的形式储存,并组织成称为染色体的长链。DNA序列的变化,也就是所谓的突变,有可能将正常细胞转化为癌细胞。除了突变之外,染色体上还可能发生其他各种变化,包括丢失、增加和重排,以及基因表达方式的变化(表观遗传变化)。

骨髓瘤的基础知识

骨髓瘤的病理生物学是复杂的,这种疾病发展的许多方面的是人们了解甚少的。一般来说,骨髓瘤的发生是浆细胞的基因改变造成的。与健康的成熟细胞不同,骨髓瘤细胞不断分裂并产生更多的骨髓瘤细胞。这种癌细胞群的扩张发生在骨髓微环境中,可以排挤健康细胞,减少其他血细胞的产生。遗传不稳定和免疫监视功能的破坏等现象可导致恶性浆细胞群的扩张和多发性骨髓瘤的发展。此外,骨髓瘤细胞群在骨内的扩张会通过多种复杂机制干扰典型的骨转换,导致骨痛和病理性骨折[3]

骨髓瘤可以抑制骨髓微环境中健康抗体的产生,从而抑制由抗体介导的部分免疫反应[14]。由于抗体在保护机体免受细菌和病毒侵害方面起着重要作用,骨髓瘤患者容易受到细菌、病毒感染[15,16]

骨髓瘤细胞的产生会导致体内单克隆蛋白的增加。单克隆蛋白是完全相同的抗体,因为它们是由相同的(克隆的)浆细胞产生的。单克隆蛋白的另一个术语是M蛋白。大多数患者长的是产生M蛋白的IgG和IgA亚型的骨髓瘤细胞[17]。其余亚型不太常见。除了制造功能性抗体所需的两条重链和两条轻链外,骨髓瘤细胞还可能产生额外的轻链,这些轻链不与重链结合,被称为游离轻链[18]。这种类型的骨髓瘤被称为轻链骨髓瘤。临床医生可以通过骨髓瘤的类型来监测病情,预测骨髓瘤细胞对治疗的反应和整个病程。

代谢过程

身体中的所有细胞都需要能量才能发挥功能和存活。葡萄糖和谷氨酰胺是提供这种能量的两种关键营养素[19]。糖酵解是将细胞内的葡萄糖分解为细胞可利用的能量的过程[20]糖酵解可以在有氧或无氧条件下发生,尽管有氧糖酵解更有效。谷氨酰胺对细胞功能也很重要,因为它维持细胞代谢并且是细胞内核酸合成的前体物质[21]。谷氨酰胺进入细胞,通过谷氨酰胺分解代谢,产生谷氨酸、柠檬酸、天门冬氨酸和其他氨基酸[22,23]

与健康细胞相比,癌细胞有更大的代谢需求,因为它们在不断增殖和避免细胞死亡。它们通过改变与糖酵解和谷氨酰胺分解相关的代谢过程来满足这种增加的需求[24]。厌氧糖酵解被增强,以便为恶性细胞提供额外的能量,这种现象被称为“Warburg效应”[25]。因此,糖酵解不再是足够生物合成前体的来源。为了弥补这一点,癌细胞提高了谷氨酰胺分解的速率,从而增强了谷氨酰胺向α-酮戊二酸和细胞功能所需的其他氨基酸的转化[26]

骨髓瘤细胞也不例外,会改变其他癌细胞中的代谢途径[19]。己糖激酶II(HKII)催化糖酵解的第一步,并已被证明在多发性骨髓瘤细胞中有所增加[27]。磷酸烯醇丙酮酸转化为丙酮酸和三磷酸腺苷(ATP)是糖酵解的最后一步,这一步是丙酮酸激酶(PK)介导的。作为PK的一种亚型,PKM2在癌细胞中大量存在,并在骨髓瘤细胞中的表达增加,进一步促进了能量产生的增加[28]。骨髓瘤细胞也显示出谷氨酰胺分解增加的信号。骨髓细胞瘤病癌基因(MYC)通常在骨髓瘤细胞中过度表达[29],并促进细胞对谷氨酰胺的摄取,从而导致肿瘤生长和蛋白质合成增加[30]。研究人员正在研究将这些代谢中的改变作为药物靶点的不同方式[31]

症状

几乎所有骨髓瘤患者在病程中的某个时期都会出现贫血[17,32],表现为疲劳或全身无力。贫血的原因通常与骨髓抑制或肾脏损害有关,这会导致红细胞数量减少。骨髓瘤也能减少血液中血小板的数量。血小板在身体受伤时能够止血,血小板水平降低会导致出血瘀伤增加。

骨痛发生在大多数骨髓瘤患者中,通常局限于轴向骨骼(脊柱、胸腔和骨盆)[17]。当骨髓瘤细胞聚集并损伤健康骨骼时,会发生骨痛,使其更容易骨折。骨质破坏可导致高钙血,这可能导致过度口渴,恶心,困惑和便秘[33]

由于与疾病本身和常规治疗方案相关的多因素免疫缺陷,骨髓瘤细胞患者的细菌感染风险增加[34,35]。患者应监测自己的发热情况,因为这是身体抵抗感染的早期迹象。

大约一半的骨髓瘤细胞患者会出现肾功能不全[36]。这种损害可能是由于血液中高水平的钙或通过肾脏过滤进入尿液的单克隆蛋白的损害(骨髓瘤细胞患者尿液中检测到的单克隆蛋白称为Bence-Jones蛋白)[37]。骨髓瘤引起的肾损伤患者应避免使用非甾体类抗炎药(NSAIDs),如布洛芬或阿司匹林,因为这类药物可能会恶化肾功能。

由于周围的脊髓或浆细胞瘤压迫神经的骨骼破裂,骨髓瘤细胞患者有时会出现神经系统问题,虽然这些是相对罕见的表现[38]


三、病因和风险因素

年龄

骨髓瘤最常见于老年人。确诊活动性骨髓瘤患者的中位年龄为67-70岁[39]。早期骨髓瘤前体疾病,即意义未明单克隆免疫球蛋白血症(MGUS)的发病率在50-90岁男性中增加了4倍以上[40]。在美国的一个县,70岁以上人群的MGUS的患病率为5.3%,85岁以上人群的患病率为7.5%[41]

种族

黑人患MGUS的风险大约是白人的两倍[41,43],黑人患活动性骨髓瘤的发病率是白人的两到三倍[44]。亚洲人后裔患骨髓瘤的风险较低[45]

遗传学

基因的改变影响骨髓瘤和骨髓瘤前体疾病的发生和发展。而某些染色体区域和特定基因的改变已被确定在多发性骨髓瘤发病中起关键作用,有关研究正在进行中,以便更好地确定该疾病的遗传学背景并弄清潜在的治疗靶点[3.46]

随着时间的推移,新突变的产生可以影响MGUS、SMM和MM病例的演变和进展。在某些情况下,突变可导致从MGUS到SMM和MM的快速进展。骨髓瘤细胞有时会产生新的突变,使其对治疗更具抵抗力。事实上,一些证据表明,有些治疗方法会选择耐药克隆,这些克隆随后会扩大并导致复发[3.47]

有一些证据表明了骨髓瘤风险的遗传性。在一级亲属确诊的患者中,发生MGUS或骨髓瘤的风险大约高出2到4倍[48-50]。然而,家族性骨髓瘤的病例数据很少。

环境暴露

许多环境因素被认为与骨髓瘤发病有关,包括暴露于某些杀虫剂和辐射[51]。一项研究表明,大量暴露于辐射的放射科医生患骨髓瘤的风险增加[52]。另一项研究表明,职业暴露于某些化学品也与风险增加有关[53]。接触牲畜或杀虫剂的农业工人可能更容易患上这种疾病;然而,证明这种联系的证据相对较弱[54-56]

可控的风险因素

体重指数(BMI)较高的成年人更易患癌症,包括骨髓瘤[57-59]。在一项研究中,在考虑了年龄和体力活动后,与不肥胖的男性相比,肥胖(BMI为30 kg/m2或更高)的男性患骨髓瘤的风险增加了2.4倍[60]。体重指数超过30 kg/m2的女性患骨髓瘤的风险则增加了1.6倍。吸烟与骨髓瘤之间也存在着密切的联系[61]。这种联系似乎在女性和每天吸烟超过20支的人群中最为明显[62]

免疫衰老与骨髓瘤

骨髓瘤最常见于60岁以上的人。这种与年龄相关的骨髓瘤发病率增加与另一种称为免疫衰老的生理现象相吻合,免疫衰老指为与年龄相关的免疫系统下降,从而增加感染和自身免疫疾病的风险[63]

新的证据表明,免疫衰老与某些癌症(包括骨髓瘤)的风险增加之间存在关系[64,65]。导致这种情况发生的机制有多种。免疫衰老导致在血液中循环的炎症信号增加。这被认为给癌细胞创造了一个有利的环境,让它们生长和扩散。免疫衰老的另一个影响是骨髓产生的免疫细胞减少[63,66,67]。这阻碍了身体检测有害物质(如癌细胞)的能力。此外,骨髓瘤的治疗方案可进一步损害免疫功能。目前正在开发利用人体免疫系统对抗癌症的疗法。


四、骨髓瘤的诊断和检测

诊断

骨髓瘤的前体MGUS是一种无症状的非癌性疾病,患者血液中M蛋白的水平异常[68]。只有少数MGUS患者会发展为骨髓瘤。骨髓瘤有两个主要阶段:郁积(无症状)和有症状或活跃。郁积型骨髓瘤和活动性骨髓瘤的区别在于是否存在终末器官损伤或某些提示终末器官损伤发生的高风险的生物标志物。很少有活动性骨髓瘤发展为继发性浆细胞白血病(即:晚期浆细胞白血病),继发性浆细胞白血病具有很强的侵袭性且预后不良[69]。表1总结了MGUS、郁积型骨髓瘤和活动性骨髓瘤的典型诊断标准。

MGUS、郁积型骨髓瘤和症状性骨髓瘤的定义*

 意义未明单克隆丙种球蛋白病(MGUS)

意义未明的非IgM单克隆丙种球蛋白病:

  1. 血清单克隆蛋白(非IgM型)<30 mg/dL(<30 g/L)

  2. 克隆性骨髓浆细胞<10% 

  3. 没有终末器官损伤,如高钙血症、肾功能不全、贫血、骨损伤(CRAB)或浆细胞增殖障碍可导致的淀粉样变病

意义未明的IgM单克隆丙种球蛋白病

  1. 血清单克隆蛋白(非IgM型)<30 mg/dL(<30 g/L)

  2. 骨髓淋巴细胞浆细胞浸润<10%

  3. 无贫血、体质症状、高粘血症、淋巴结病、肝脾肿大或其他可归因于潜在淋巴增生性疾病的终末器官损害的表现

 意义未明的轻链单克隆丙种球蛋白病 

  1. FLC比率异常(<0.26或>1.65)

  2. 适度相关的轻链(iFLC)水平增加(比值>1.65的患者κFLC增加,比值<0.26的患者λFLC增加)

  3. 免疫固定中无免疫球蛋白重链表达

  4. 没有终末器官损伤,如高钙血症、肾功能不全、贫血、骨损伤(CRAB)或浆细胞增殖障碍可导致的淀粉样变病

  5. 克隆性骨髓浆细胞<10%

  6. 尿单克隆蛋白<500 mg/24 h

 郁积型(有症状)骨髓瘤 

血清单克隆蛋白(IgG或IgA)≥30 mg/dL(≥30 g/L)或尿单克隆蛋白≥500 mg/24 h和/或克隆性骨髓浆细胞10–60%

无骨髓瘤或淀粉样变病

 活跃性骨髓瘤 

克隆性骨髓浆细胞≥10%或活检证实骨性或髓外浆细胞瘤**和以下一个或多个可确认骨髓瘤的表现:

患骨髓瘤的表现:

存在由于潜在浆细胞增殖障碍导致的终末器官损伤(CRAB特征),具体而言:

  1. 高钙血症:血钙比正常上限高0.25 mmol/L以上(>1 mg/dL)或>2.75 mmol/L(>11 mg/dL)

  2. 肾功能不全:肌酐清除率<40 mL/min或血清肌酐>177μmol/L(>2mg/dL)

  3. 贫血:血红蛋白值比正常下限低2 g/dL以上(>20 g/L),或血红蛋白值<10 g/dL(<100 g/L)

  4. 骨病变:骨骼X线、CT或PET-CT下的一个或多个溶骨性病变

下列任何一种或多种恶性肿瘤生物标志物:

  1. 克隆性骨髓浆细胞百分比≥60%

  2. 相关:不相关血清自由轻链比(dFLC)≥100

  3. >1个MRI检查病灶

*在精通骨髓瘤治疗的临床医生的帮助下理解。

来源于国家综合癌症网络(NCCN)指南和2014年国际骨髓瘤工作组(IMWG)共识标准[70,71]

**克隆性应通过流式细胞术、免疫组织化学或免疫荧光显示的κ/λ轻链限制来确定。骨髓浆细胞百分比最好是从穿刺活检标本中估算出来的;如果抽取液和活检标本之间存在差异,应使用最高值。

骨髓瘤的检测

评估潜在的骨髓瘤病例应包含完整的病史调查和体检,包括神经系统检查。应重点重点重点检查任何与骨痛和感染有关的体征或症状。有时,骨髓瘤的检测会在单独的血常规检查发现异常时进行。如果怀疑患者患有骨髓瘤,应进行血液和骨髓检查,寻找骨髓瘤的证据[72,73]

包含鉴别的全血计数。全血细胞计数(CBC)提供了有关人体内红细胞、白细胞和血小板数量的信息[74]。包括检测每种类型的白细胞的鉴别测试。这些测试有助于确定患者免疫系统的状态,并有助于诊断贫血。

血液生化。血液生化可以提供有关血液电解质和肾功能标志物的信息。高水平的血钙可能是骨髓瘤中骨损伤的标志物[75]。血肌酐或尿素氮的异常可能表明肾受到损伤。

血清蛋白检测。血清定量免疫球蛋白试验检测血液中免疫球蛋白的数量和类型。通常包括IgG、IgM和IgA亚型[76]。血清免疫固定电泳显示血液中存在的M蛋白类型,而血清蛋白电泳(SPEP)测量血液中M蛋白的数量[77]。血清自由轻链分析可估计血清中自由轻链的数量,对轻链骨髓瘤患者特别有用。

尿蛋白检测。与血液蛋白质检测类似,尿蛋白质测试也可以测量尿液中M蛋白的数量和类型[77]

骨髓穿刺活检。为了确认骨髓瘤的诊断,需要采集一小块骨髓和少量骨髓抽取液进行检测,这通常是从髋骨中采集的。这些测试可以确定骨髓中骨髓瘤细胞的数量,还可以对骨髓瘤细胞进行额外的测试,如增殖率和是否存在遗传异常[78,79]

医学影像。X光可以用来检查骨髓瘤引起的骨损伤或骨折;但是,X光比其他类型的医学影像更不准确。低剂量的计算机断层扫描(CT),即一系列X射线放在一起组装一张图像[80],有时会与正电子发射断层扫描(PET)结合使用。PET扫描利用注射到血液中的药物识别可能有癌症的部位,具有高灵敏度[81]。对磁共振成像(MRI)(即一系列用磁铁拍摄的照片)的使用近来也有所增加,因为相比传统的医学影像,它能更准确地识别组织和骨髓中的异常[82-85]


五、分期与预测

分期

骨髓瘤确诊后,用分期来确定体内肿瘤负荷程度。骨髓瘤的分期主要有两种方法。国际分期系统(ISS)[86]是更常用的方法,它根据血液中β-2微球蛋白和白蛋白的含量将患者分为三个阶段。ISS经过修订,纳入了基于血乳酸脱氢酶和遗传异常的预后信息[7]。这一系统被称为修订的ISS(R-ISS)。第二个分期系统被称为Durie-Salmon分期[87],是根据骨髓肿瘤密度和其他器官损伤标志物将患者分为三个阶段,从而确定预后。    

表2:国际分期系统与修订的国际分期系统的比较*

方法期数标准
国际分期系统 (ISS)1

血清β2微球蛋白<3.5 mg/L
血清白蛋白>3.5 g/dL

2不符合国际分期系统1期或3其标准
3血清β2微球蛋白>5.5 mg/L
修订的国际分期系统 (R-ISS)1第1期的标准,且无高危染色体异常[(t4;14),t(14;16)del 17p],以及血清乳酸脱氢酶处于或低于正常值上限
2不符合修订的国际分期系统1期或3其标准
3第3期的标准,以及高危染色体异常,或血清乳酸脱氢酶高于正常值上限

*在精通骨髓瘤治疗的临床医生的帮助下理解。

来源于Palumbo等人[7]和国家综合癌症网络(NCCN)指南[70]

LDH,乳酸脱氢酶。

预后评分和高危人群

预后和风险分层对于帮助预测病程和确定患者从MGUS发展为郁积型骨髓瘤或从郁积型骨髓瘤发展为活动性骨髓瘤的可能性非常重要[88]。病情发展的风险通常通过人体内骨髓瘤细胞的数量、血液检测和其他有关遗传异常的测试来确定[89]。此外,风险分层被用于指导骨髓瘤的治疗。一般来说,为高风险患者使用更积极的治疗方法,而被分为低风险类别的患者通常使用较不积极的治疗方法以限制治疗的副作用[90]。然而,如何对患者进行最佳分层以及如何确定哪些患者可能从早期治疗中获益,是仍在进行辩论和研究的问题。

基于风险的郁积型骨髓瘤分层。郁积型骨髓瘤的表现是血液中M蛋白水平低,诊断时没有终末器官损伤;然而,郁积型骨髓瘤患者的疾病严重程度和病情发展风险可能有很大差异。因此,许多人试图开发出根据病情发展风险对患者进行准确分类的方法。

研发更好的方法来辨别从郁积型多发性骨髓瘤发展为活动性多发性骨髓瘤的高危患者,并根据病情发展风险对患者进行分层,是多发性骨髓瘤研究中非常活跃的领域。国际骨髓瘤工作组(IMWG)是骨髓瘤研究的前沿群体之一,在帮助建立目前公认的风险分层分类方面发挥了重要作用。在2019年美国临床肿瘤学学会年会上,与IMWG相关的研究人员介绍了他们最新的风险分层模型[91]。该模型为以下每个风险参数指定了一个分值:

  1. 自由轻链比率>20,

  2. 血清M蛋白> 2 g/dL,

  3. 骨髓浆细胞百分比>20%, 以及

  4. 存在高风险遗传因素[t(4,14), t(14,16), 1q gain, 或 del13q]

在适当地分配了分值后,将分值制成表格并分配到表3所示的病情发展风险类别中。

表3:从郁积型骨髓瘤发展为活动性多发性骨髓瘤的风险

风险分层风险因素数值 (分值)2年后病情发展的风险
低风险08%
低-中风险121%
中风险237%
高风险≥359%

利用基因组分析等新的风险分层策略正在研究中。最近的证据表明,某些细胞信号通路(如MAPK、APOBEC)相关的基因的突变可能有助于确定从郁积型多发性骨髓瘤进展为多发性骨髓瘤的高风险患者[92]。然而,这些类型的分析还没有被普遍纳入标准的风险分层评估,因为它们可能不适用于所有地方,而且需要更多的研究来验证其预测价值。希望这些新兴技术能在不久的将来改进风险分层算法。

活动性骨髓瘤的风险分层。骨髓细胞遗传学和荧光原位杂交(FISH)是两种可用于测量活动性骨髓瘤患者的遗传异常,以评估疾病的侵袭性的检测方法[93]。当遗传物质从染色体上丢失,被另一染色体获得,或者从一个染色体移到另一个染色体时,可能会发生异常。人体有23对染色体。可能使骨髓瘤患者处于更高病情发展风险的异常例子包括染色体4和14之间的遗传物质易位[简写为t(4;14)] 或17号染色体遗传物质丢失[简写为del(17p)][88]。建议所有患者在就诊时进行细胞遗传学评估[90]。根据细胞遗传学异常可将患者分到不同风险组,如表4所示。

表4:活动性骨髓瘤的风险分层

风险描述
标准所有其他异常,包括 t(11;14), t(6;14)
中风险t(4;14),,del(13),亚二倍体, PCLI >3% 
高风险del(17p), t(14;16), t(14;20) 
*建议所有患者在就诊时进行细胞遗传学评估[90]

来源于Mikhael等人[90]

IgH,免疫球蛋白重链;t(),易位;del(),缺失;PCLI,浆细胞标记指数。


六、常规疗法

化学疗法

化学疗法使用静脉或口服药物杀死异常细胞或阻止新细胞的产生。用于治疗骨髓瘤的化学疗法通常与类固醇等其他药物联合使用。这些药物也会影响正常细胞,因此要在不同的治疗天数中服用,然后休息。化学治疗剂可以干细胞移植之前单独使用,或在干细胞移植之后用于维护。

蛋白酶体抑制剂是一类常用药物,其作用是破坏癌细胞用来避免正常细胞死亡的机制[94]。 硼替佐米(Velcade)是常用的蛋白酶体抑制剂的一种[95-98]。 它与另一种抗癌药来那度胺(Revlimid)和类固醇药物地塞米松一起用于骨髓瘤的一线治疗[70,99-101]。硼替佐米在21天或28天的周期内分四次给药。用这类药物观察到的副作用类似于其他化学治疗剂,包括手脚麻木,恶心,疲劳,便秘和头痛。应该皮下给药以减少周围神经病变的风险[102]

预防蛋白酶体抑制剂引起的周围神经病变(PN)

蛋白酶体抑制剂引起的周围神经病变是一种限制治疗的副作用,这意味着由于PN的严重性,患者通常必须停药。能在使用抗多发性骨髓瘤药物时防止发生周围神经病变是最好的,这样患者就无需停止有效的治疗。

一项对33例即将开始接受含硼替佐米治疗的多发性骨髓瘤新确诊患者进行的II期前瞻性研究,评估了持续六个月每天两次400毫克二十二碳六烯酸(DHA)、600毫克α-硫辛酸、60毫克维生素C和10毫克的维生素E的组合是否可以降低治疗的神经毒性[103]。在分析时,有25位患者完成了该项研究。使用上述组合物六个月后,有10名患者没有症状,并且无人因为痛苦的神经病变而中断治疗。

由于维生素C可能会干扰硼替佐米,因此在此期间服用硼替佐米的人禁止使用维生素C[104]。同样,一些体外证据表明硫辛酸可能会干扰硼替佐米的抗骨髓瘤活性[105]。由于一些证据表明硫辛酸可能在硼替佐米引起周围神经病时有用,因此需要更多的研究来评估硫辛酸在骨髓瘤患者中的临床应用安全性和实用性。

硼替佐米与天然物质的潜在相互作用

绿茶提取物

2009年发表的一项研究发现,绿茶儿茶素,特别是表没食子儿茶素没食子酸酯(EGCG),在细胞培养以及小鼠骨髓瘤细胞中均阻断了硼酸基蛋白酶体抑制剂药物(例如硼替佐米)的作用[106]。使用非硼酸基的蛋白酶体抑制剂时则没有发现有这种相互作用。其他几项研究报道,绿茶也会抵抗硼替佐米的作用。因此,服用硼替佐米的人应避免服用绿茶提取物[104,107-109]

维生素C

如本文后面的维生素C部分所述,有一项动物研究表明维生素C可能会干扰硼替佐米的抗多发性骨髓瘤作用[110]。其他一些体外研究也发现了一些证据,表明维生素C可能会干扰硼替佐米的作用[110-112]。另一方面,一项小型临床研究发现,包括低剂量维生素C在内的天然制剂有助于抑制与蛋白酶体抑制剂相关的周围神经病,因此需要更多的研究来评估维生素C和硼替佐米之间的潜在的交互作用。 不过,大多数肿瘤学家会谨慎行事,建议不要将维生素C与硼替佐米联合使用[103,113]

口服维生素C干扰硼酸基蛋白酶体抑制剂的可能性似乎仅是这类药物所独有的。静脉注射(药理的)抗坏血酸已与化学疗法安全地结合用于许多不同的癌症,包括多发性骨髓瘤[114]。也有研究将静脉维生素C与硼替佐米联合使用,并特别指出其疗效和安全性,而不是干扰性。在几项对使用静脉注射维生素结合三氧化二砷(Trisenox)、美法仑(Evomela)、地塞米松及硼替佐米等不同药物的治疗多发性骨髓瘤的化疗方案的研究中,发现了良好的耐受性和良好的疗效[115,116]

硫辛酸

体外研究的初步证据表明,硫辛酸可能会干扰硼替佐米的抗骨髓瘤作用[105]。用α-硫辛酸(ALA)加硼替佐米一起培养骨髓瘤细胞时,其生存能力约为仅用硼替佐米培养的骨髓瘤细胞的生存能力的两倍。此外,同一项研究表明,与未处理的对照骨髓瘤细胞相比,仅用硫辛酸培养骨髓瘤细胞可刺激其生长并提高其生存能力。进行这项研究的研究人员总结说:“根据我们使用多发性骨髓瘤细胞系的体外研究结果,我们的数据表明ALA有可能会拮抗硼替佐米的抗多发性骨髓瘤作用。因此,ALA可能会对硼替佐米对多发性骨髓瘤患者的治疗效果产生负面影响,这还需要进一步研究,特别是如果ALA被认为是与硼替佐米相关的神经病变的干预措施的话。”

免疫调节剂

免疫调节药物(IMiDs)通过多种机制对抗癌症。它们能增强免疫系统,让身体对抗癌症。它们还可以通过切断肿瘤的血液供应和利用炎症途径直接减缓肿瘤的生长,尽管尚不清楚这些机制对IMiDs治疗骨髓瘤的疗效有多大助益[117-118]

沙利度胺(Thalomid)是第一种用于治疗骨髓瘤的药物,但由于其严重的副作用,近来对它的应用有所减少。在撰写本文时,来那度胺一种具有更强的耐受性的更有效的免疫调节剂,是骨髓瘤治疗的主要药物[119,120]。它可以与其他药物联合用于骨髓瘤的初始治疗,或单独用于长期维持治疗[70]。在28天的周期里,每天口服一次来那度胺,服用21天。来那度胺的副作用包括低红细胞、白细胞和血小板计数、腹泻以及疲劳。来那度胺对未出生的孩子毒性极大,可导致出生畸形。有生育潜力的妇女以及她们的伴侣在服用来那度胺时必须采取避孕措施[121]。 泊马度胺(Pomalyst)是另一种用于治疗在先前治疗后复发的骨髓瘤的免疫调节药物。

糖皮质激素

糖皮质激素是一种类固醇,可以通过各种机制调节基因表达并诱导癌细胞死亡[122]。它们是骨髓瘤治疗的重要部分[123]

最常用的糖皮质激素是地塞米松,常与化疗药物、免疫抑制剂和靶向治疗(如硼替佐米、来那度胺、环磷酰胺(环磷酰胺)和达鲁单抗(达扎来昔))联合使用[124,125]。地塞米松是在骨髓瘤一线治疗和复发治疗中最推荐使用的药物之一。糖皮质激素的副作用包括体重增加、体液潴留、血糖升高、骨骼变脆和感染风险增加[126,127]。由于这些副作用,不建议长期使用糖皮质激素。

靶向治疗

靶向治疗是针对骨髓瘤特定机制的药物。与化疗不同,这些药物通常针对癌细胞,对健康细胞的影响较小;因此,它们的副作用较少[128]

靶向治疗的一个例子是达鲁单抗。达鲁单抗是一种治疗性抗体,可与骨髓瘤细胞上的蛋白质结合并诱导细胞死亡[129,130]。它最常与其他药物联合使用,作为不符合造血干细胞移植(SCT)条件的患者首选方案的一部分[70]。它可以每周服用一次,每两周服用一次,或者每月一次,这取决于患者接受达鲁单抗治疗的时间[131]。达鲁单抗的副作用可能包括疲劳、恶心、血细胞计数低以及给药时的输液部位反应[132]。患者在服用达鲁单抗前应接受其他药物,以降低发生皮肤反应的风险。

干细胞移植

干细胞移植(Stem cell transplant,SCT)是一种造血干细胞的移植,将通常来源于供体的骨髓、外周血或脐带血的干细胞移植到骨髓在干细胞移植前被高剂量化疗破坏的受体身上。SCT的目标是通过使用高剂量的化疗来消灭骨髓细胞,包括癌细胞和正常细胞,同时让注入的干细胞中生长出健康的造血干细胞并形成新的血细胞,从而对抗癌症。这个过程称为植入,大约需要2到4周[133-137]。这些新细胞生长成健康的骨髓,并且可以产生非癌血细胞。

干细胞移植有两种类型——自体和异体。“自体”是指病人自己的干细胞被移植回他或她的身体。“异体”是指将另一个具有类似特征的人的干细胞移植到患者体内。异体移植的风险更大,接受同种异体移植的患者通常比接受自体移植的患者有更多的副作用[138]。找到合适的供体也很困难。由于这些原因,自体移植被认为是骨髓瘤患者的标准治疗方案[70]

自体造血干细胞移植是骨髓瘤治疗的一个重要组成部分,所有符合条件的患者都应考虑自体造血干细胞移植;然而,这是一种强度大的手术,并非所有人都能经受得住[70,139-141]。患者在手术前服用药物清除现有的癌细胞并为移植做好准备,然后在手术后再次服用药物维持对肿瘤的控制[70,138]。是否应在病程早期或复发时进行SCT是一个有争议的问题。到2020年底,有证据表明早期SCT会导致更深层次的反应,但可能不会提高总体生存率。因此,接受移植的决定必须是基于治疗肿瘤团队和患者考虑等因素的个体化的选择[142]

移植后,通常通过评估血清或尿液中的单克隆M蛋白水平来衡量疗效。游离轻链测量可用于血清或尿液中检测不到M蛋白水平的患者。也可以利用骨髓免疫组织化学或免疫荧光。一些专家采取的一种方法是在SCT后100天对患者进行评估,然后每隔3到4个月重新评估一次患者的情况是否良好。治疗后的反应程度可以预测生存率,但这在骨髓瘤研究界是有争议的(见下面“评估反应”一节)[142]

药物治疗可能导致严重的副作用(如恶心、呕吐、免疫系统变弱)。接受移植的资格取决于患者的年龄、健康状况和其他疾病相关因素,但进行移植的决定应包括患者与其医生之间的讨论。

辐射

放射治疗利用强能量束杀死癌细胞或阻止癌细胞生长。骨髓瘤最常用的放射治疗是体外放射治疗。它主要用于被称为浆细胞瘤的一个单一的,局部的骨髓瘤细胞团[70,143.144]。放射治疗也可以损害健康细胞和引起副作用。

辐射疗法的常见副作用包括疼痛或辐射部位皮肤的其他变化。随着时间的推移,病人也可能因辐射而产生疲劳和恶心。

支持性疗法

骨髓瘤会对包括肾脏在内的多个器官造成损害。如果患者出现肾损伤,保持充足的水分摄入和避免使用肾毒性药物(如非甾体抗炎药)是很重要的[145]。由于骨髓瘤减少了红细胞的生成,红细胞数低的患者可能会发生贫血。医生可能会建议使用促红细胞生成素(EPO)治疗以帮助红细胞再生。骨髓瘤还会通过抑制免疫系统增加患者感染的风险。可使用疫苗和预防性抗生素来降低感染风险[148-150]

解决骨骼健康问题

骨病几乎影响所有骨髓瘤患者。大约60%的患者在诊断时出现骨痛(特别是背部或胸部)[17,38],大约20?25%的患者在诊断时出现病理性骨折、压缩性骨折或骨质疏松症[17]。这些骨相关的症状给骨髓瘤患者造成了巨大负担,降低其生存率,增加治疗费用,同时降低了生活质量[38,151,152]

骨重建是维持健康骨骼的重要部分。它是通过旧骨的再吸收(通过被称为破骨细胞的细胞)和新骨的形成(通过被称为成骨细胞的细胞)的微妙平衡来实现的[153]。骨髓瘤患者细胞因子表达的增加导致骨转换的不平衡,其特征是破骨细胞的增加和成骨细胞活性的降低[154,155]。这意味着骨正在被吸收,但没有被新骨取代[156],表现为溶骨性骨病变、骨变弱、释放到血液中的钙增加。

由于与骨髓瘤骨病的发病率和死亡率相关,大多数专家建议具有溶骨性病变和/或骨量减少或骨质疏松症的多发性骨髓瘤患者使用破骨细胞抑制剂治疗。然而,对于没有明显骨损伤或骨质减少/骨质疏松症的患者,潜在的益处还不太明确,因此专家们对最佳治疗方法的意见存在分歧。一些人建议所有需要治疗的多发性骨髓瘤患者使用破骨细胞抑制剂,不管他们是否患有骨病,而另一些人则建议在没有骨病的患者中避免使用这些药物。使用破骨细胞抑制剂的决定应根据具体情况而定[70]

帕米膦酸盐和唑来膦酸盐(Reclast)是两种通过减少骨吸收而起作用的双膦酸盐,它们在骨髓瘤中都能发挥类似的减少骨相关症状的作用[157-161]。狄诺塞麦(Denosumab),一种治疗性抗体,也能通过减少骨吸收而起作用,与双膦酸盐具有相似的骨健康益处,但它更适用于肾功能不全的患者[162]。所有接受双膦酸盐或狄诺塞麦治疗的受试者都应接受钙、维生素D治疗,并定期对颌骨骨坏死进行牙科监测[70]

维生素K与多发性骨髓瘤患者的骨健康

维生素K是一种脂溶性维生素,存在于许多食物中,也可作为膳食补充剂。天然维生素K有两种:维生素K1和维生素K2。另一种形式,维生素K3,是一种合成形式,摄入后在肝脏中被转化为维生素K2[163]。维生素K通过各种途径抑制破骨细胞活性,从而减少骨吸收,以改善骨健康[164,165]。一项研究表明,与未服用维生素K补充剂的妇女相比,每天服用45毫克维生素K2(美纳曲酮)的骨质疏松症的日本妇女较少发生骨折[166]。两项随机对照试验的结果表明,维生素K2有类似的降低骨折风险的作用,对骨密度也有益处,尤其是对日本患者[167,168]。每天补充维生素K1(植酸二酮)也可降低骨折风险[169]

体外研究的初步证据表明,维生素K2除了对骨骼健康有益外,还可能发挥一些抗骨髓瘤的作用(见下文“综合干预”一节中关于维生素K的讨论)[170]

值得注意的是,大多数支持维生素K对骨骼健康产生积极影响的证据都存在于患骨质疏松症的妇女中,即使在这一人群中,其他研究的结果也相互矛盾[171.172]。此外,对男性和绝经前女性运动员的研究表明,其骨健康没有因此得到改善[167.173]。因此需要对多发性骨髓瘤中维生素K对骨健康的影响进行严密的研究。


七、治疗方案

孤立性浆细胞瘤的治疗

孤立性浆细胞瘤是尚未发展成骨髓瘤的单个浆细胞团。这种情况很罕见。由于这个肿块是孤立的,可以采用放射治疗和/或手术治疗,可能有治愈的潜力。孤立性浆细胞瘤有两种类型:起源于骨(骨的)和累及软组织(骨外)的浆细胞瘤[70.174]。对这两种类型的孤立性浆细胞瘤进行放疗和手术治疗(如果需要的话)取得了良好的治疗效果和病情控制[75.176]。患者在接收治疗后受到密切关注,以监测疾病复发情况。

郁积型骨髓瘤的治疗

一般来说,约60%的患者在10年内会从郁积型骨髓瘤发展为活动性骨髓瘤[177]。然而,患者之间病情发展的风险差异很大,一些非常高风险的患者在两年内病情恶化的可能性为80-90%。治疗方案取决于患者病情恶化的可能性。被确定为病情发展风险较低的患者可能不需要治疗,而是要定期接受密切监测。另一方面,那些被认为存在病情发展高风险的患者可能会接受一些与治疗活动性骨髓瘤相同的药物进行治疗。有许多正在进行的研究试图找出辨别哪些郁积型多发性骨髓瘤患者具有高病情发展风险的最佳方法并及确定理想治疗方案[178]

国家综合癌症网络(NCCN)指南[70]建议每三到六个月对所有郁积型骨髓瘤患者进行一次监测;然而,梅奥诊所建议[179]应基于疾病发展的风险决定监测频率。根据这些建议,低风险患者可能每六个月接受一次监测,以检测疾病发展情况。中危患者可以每三到四个月复查一次疾病发展情况。高危郁积型骨髓瘤患者应每两到三个月进行一次监测,并应考虑参加临床试验,以防止或延缓病情发展。

一些新的证据表明早期治疗可以延缓病情发展为活动性骨髓瘤的过程并延长总生存期,尽管到2020年底这一点仍有很大争议,还需要更多的试验来阐明其总体益处[70]。一项针对119例高危郁积型骨髓瘤患者的研究表明,与仅观察组相比,地塞米松和来那度胺联合治疗延长了病情发展为活动性骨髓瘤的时间,延长了3年的总生存期。随后的一项中位数约为6年的研究分析显示,来那度胺在延缓病情发展时间方面继续发挥作用:治疗组尚未达到病情发展时间的中位数,而观察组的发展时间中位数为23个月。观察组中86%的受试者发展为活动性骨髓瘤,而使用来那度胺加地塞米松的实验组中只有39%的受试者发展为活动性骨髓瘤[180,181]。一项发表于2020年的最新研究显示,在182名高风险的郁积型多发性骨髓瘤患者中,来那度胺单用可延缓症状性疾病的发展,并延长无发展生存期。来那度胺组有一半的受试者对治疗表现出反应,来那度胺组的1年、2年和3年生存率分别为98%、93%和91%,而观察组的对应生存率分别为89%、76%和66%。亚组分析显示,在高危患者中病情无发展生存获益明显,但在中危患者中不明显。来那度胺组41%的参与者发生严重不良反应[182]

基于这些有前景的研究结果,一些专家现在推荐对高风险郁积型多发性骨髓瘤患者联用来那度胺加地塞米松或单用来那度胺,而不仅是观察。值得注意的是,在这些研究中,对确定患者有高风险发展为活动性骨髓瘤的标准并没有统一定义,许多专家继续建议对低风险郁积型多发性骨髓瘤患者进行更密集的治疗,而不是常规治疗[70]。重要的是,这是一个非常活跃的研究领域,也是骨髓瘤研究界争论不休的问题。启动早期治疗的决定必须在个案的基础上做出,必须包含具有治疗骨髓瘤经验的医生对风险和利益的仔细考虑。

症状性骨髓瘤的治疗

新确诊的症状性骨髓瘤患者应接受联合用药治疗。初始治疗取决于患者是否有资格接受自体SCT。以下列出了根据NCCN指南为有资格和无资格接受移植的患者提供的首选药物治疗方案。患者还应根据其症状接受骨骼健康药物治疗和其他支持性治疗。

表5:基于NCCN指南的骨髓瘤首选初始治疗方案*

有资格接收SCT的患者的骨髓瘤治疗:

硼替佐米、来那度胺、地塞米松

硼替佐米、环磷酰胺、地塞米松

无资格接收SCT的患者的骨髓瘤治疗:

硼替佐米、来那度胺、地塞米松

达鲁单抗、来那度胺、地塞米松

来那度胺、地塞米松(小剂量)

硼替佐米、环磷酰胺、地塞米松

**在精通骨髓瘤治疗的临床医生的帮助下理解。

来源于NCCN指南[70]

SCT,干细胞移植

以下提供了一种适用于符合自体SCT条件的患者的基于风险的治疗算法。初始治疗包括三到四个周期的诱导治疗,在标准风险和中等风险患者中使用硼替佐米、来那度胺和地塞米松(VRd),在高危患者中使用卡非佐米(Kyprolis)、来那度胺和地塞米松(KRd)。所有初始治疗方案均应包括低剂量地塞米松(每周一次,40毫克),因为与高剂量地塞米松相比,使用低剂量地塞米松具有更高的总生存率和更低的毒性[183]。诱导治疗后应进行早期或延迟移植。移植后可使用来那度胺或蛋白酶体抑制剂进行维持治疗,以降低疾病恶化的风险[70]。维持治疗可延长无发展生存期,并可提高总生存率。维持治疗期间所用药物的选择将取决于风险分层和患者的其他具体特征。一般建议至少进行两年维持治疗。目前正在开展有关研究,以确定长期维持治疗是否能带来超过药物毒性风险的益处[142]

表6:基于风险的符合SCT条件的患者治疗算法*


标准风险中风险高风险
初始治疗3-4个周期的VRd3-4个周期的VRd3-4个周期的VRd或KRd 
移植#早期或延迟的ASCT  早期ASCT早期ASCT
维持治疗来那度胺以硼替佐米为主以卡非佐米或硼替佐米为主

 *在精通骨髓瘤治疗的临床医生的帮助下理解。

来源于Rajkumar等人[88]和NCCN指南[70]

#启动早期ASCT或延迟到第一个病情恶化迹象出现再启动的决定必须基于个人的基础情况做出。尽管早期ASCT被大多数机构视为标准治疗,但早期移植是否优于延迟移植仍有争议。需要更多的研究。

缩写:VRd,硼替佐米,来那度胺,地塞米松;KRd,卡非佐米,来那度胺,地塞米松;ASCT自体干细胞移植。

被诊断为骨髓瘤的患者可能由于虚弱或年龄原因而不符合SCT的要求。不符合SCT条件的高危患者可接受硼替佐米、来那度胺、地塞米松(VRd)的初步治疗,然后使用硼替佐米或以硼替佐米为基础的方案进行维持治疗。建议分类为标准风险的患者接受达鲁单抗、来那度胺和地塞米松(DRd)或硼替佐米、来那度胺、地塞米松(VRd),然后使用来那度胺和达鲁单抗或单独使用来那度胺进行维持治疗。体弱或75岁以上的患者在病情发展前可接受来那度胺和地塞米松治疗[70]

表7:基于基于风险的不符合SCT条件的患者治疗算法*


标准风险中风险、高风险
初始治疗8-12个周期的VRd或DRd 8-12个周期的VRd
维持治疗来那度胺或来那度胺-达鲁单抗  硼替佐米或以硼替佐米为主
*在精通骨髓瘤治疗的临床医生的帮助下理解。

**如果患者身体虚弱,用Rd治疗直到病情恶化。

源自Rajkumar等人[88]和NCCN指南[70]

VRd,硼替佐米,来那度胺,地塞米松;Rd,来那度胺,地塞米松。

由于与活动性骨髓瘤相关的器官损害发生率高,应考虑给予所有最初诊断为骨髓瘤的患者适当的支持治疗。也可以给接受骨髓瘤治疗的患者开药来控制潜在的副作用。例如,接受免疫调节剂(如来那度胺)的患者,尤其是与大剂量糖皮质激素联合使用的患者,发生血栓并发症的风险显著增加,应接受预防性阿司匹林治疗。同样,那些接受蛋白酶体抑制剂治疗的患者应该接受预防性抗病毒治疗,以预防多发性骨髓瘤患者常见的病毒性传染病,如带状疱疹[70]。

评估反应

治疗后,医生将根据症状和体内残留的骨髓瘤细胞数量来评估患者的反应情况。如下所示,对治疗的反应一般分为完全性、部分性、轻微性或进行性。复发的定义:最初对治疗产生积极反应,随后病情恶化。

表8:国际骨髓瘤工作组的骨髓瘤反应标准*

类别定义
完全缓解血液或尿液中没有M蛋白,以及骨髓中的浆细胞在5%以下没有浆细胞瘤(如果之前有)
部分缓解血液中M蛋白减少50%或以上,以及24小时尿M蛋白减少90%或以上,以及骨髓浆细胞减少50%或以上,以及孤立性浆细胞瘤(如果之前有)体积缩小50%或以上
轻微缓解血液中M蛋白减少25%至50%以下,以及尿液中M蛋白减少50%至89%以下,以及浆细胞瘤(如果之前有)体积缩小25%至50%以下
病情加剧血液中M蛋白增加25%或以上(至少0.5 g/dL),或尿液中M蛋白增加25%或以上(至少200 mg/24小时),或血液中浆细胞数量增加50%或以上,或骨髓浆细胞百分比增加10%或以上,或现有病灶或新病灶的大小增加50%或以上。

*在精通骨髓瘤治疗的临床医生的帮助下理解。

来源于Kumar等人[184]和NCCN指南[70]

复发性骨髓瘤的治疗

大多数骨髓瘤患者会在病程中的某一时刻复发[185]。复发性疾病的治疗应考虑既往治疗、复发时间和疾病严重程度。初次接受自体SCT治疗成功且有持久反应的患者可考虑进行第二次移植[70]。首次复发患者的首选治疗方案包括三种药物方案,其中包含蛋白酶体抑制剂(如硼替佐米、卡非佐米)[186]或单克隆抗体(如,达拉图单抗、埃洛图珠单抗[Empliciti]) [187,188] 。对再次复发的治疗应侧重于未用于治疗最初复发的疗法。


八、新兴疗法

本章节概述了骨髓瘤治疗规划中的几个临床进展。截至2020年年中,本节所述的治疗方法均未被批准用于骨髓瘤的一线治疗,尽管有些疗法已被批准用于先前接受过治疗的患者。这些临床进展代表了骨髓瘤研究的一些重要进展,但需要更多的研究将这些进展转化为常规临床疗法。

参加临床试验

骨髓瘤的新治疗方法正在开发和研究中。特别是对于某些不符合可用治疗标准或无法从当前疗法中收益的患者,临床试验可能提供其合适的选择,在可用时应予以考虑。

多发性骨髓瘤研究基金会提供寻找和参与研究性治疗的临床试验的信息。

第二代蛋白酶体抑制剂

第一代蛋白酶体抑制剂,如硼替佐米,会引起严重的不良反应,如四肢麻木。它们也与高复发率有关。第二代蛋白酶体抑制剂的作用方式与第一代相同,但具有更高的应答率、新的给药途径、较低的副作用发生率[189]。卡非佐米布是一种经批准的第二代蛋白酶体抑制剂,通过静脉(IV)输注,作为先前接收过骨髓瘤治疗的患者的联合疗法的一部分[70,190]。伊沙佐米 (恩莱瑞)是一种每周口服的蛋白酶体抑制剂,被批准用于治疗骨髓瘤[191]。目前正在研究奥罗佐米,一种类似卡非佐米的可以口服的药物[192];FDA已经指定它为治疗Waldenstr?m巨球蛋白血症的罕见病药物。随着临床的进步,骨髓瘤的口服药物变得越来越重要,接收治疗的患者的寿命也越来越长。Marizomib是另一种新的第二代蛋白酶体抑制剂,在复发/难治性多发性骨髓瘤患者中显示出很不错的效果[193,194]

单克隆抗体

Daratumumab是一种单克隆抗体,截至本文撰写时,它已被批准作为多发性骨髓瘤的单一疗法。另一种单克隆抗体elotuzumab被批准作为复发性或难治性多发性骨髓瘤联合治疗的一部分。另外几种单克隆抗体正处于临床发展的不同阶段。由于单克隆抗体可以靶向癌细胞的许多不同部位,因此有许多开发有效的治疗方法的可能性。例如,GSK2857916(belantamab)是一种针对骨髓瘤细胞上BCMA受体的抗体。在一项I期研究中已经进行了对其的研究,发现它对复发/难治性骨髓瘤患者具有良好的耐受性和有效性[195,196]。在2020年8月,FDA允许 belantamab可加速批准用于至少接受过四次治疗的复发性多发性骨髓瘤患者[197]

三期临床研究(IKEMA)的中期分析表明,在中位数为20.7个月的随访后,与未使用伊沙妥昔单抗(Kd)的卡非佐米和地塞米松联合用药相比,单克隆抗体伊沙妥昔单抗(Sarclisa)与卡非佐米和地塞米松(称为Isa-Kd)的联用可提高复发性或难治性多发性骨髓瘤患者的无进展生存期。在Isa-Kd组中,近30%的患者在微小残留疾病检测(治疗后是否仍能在体内检测到骨髓瘤细胞)中呈阴性,而Kd组中只有13%呈阴性。研究人员总结认为,Isa-Kd“代表了治疗复发性多发性骨髓瘤患者的一种可能的新标准疗法。” [198]

目前基于单克隆抗体的疗法面临的主要研究挑战之一是确定能有效地增强应答,同时保持合理的安全性助剂或联合疗法 [196]。在本文撰写时,许多单克隆抗体的临床试验正在招募或在预招募受试者。有关这些试验的更多信息,请访问ClinicalTrials.gov。

CAR-T疗法

嵌合抗原受体T细胞(CAR-T)疗法是一种从体内取出免疫细胞并加以修饰以识别癌细胞的技术。免疫细胞随后被放回体内与癌症作斗争。CAR-T疗法最近已被批准用于其他癌症,它并具有长期控制疾病的潜力,但在骨髓瘤治疗中的应用仍在研究中[199-201]。最近公布了一项针对B细胞成熟抗原(BCMA)的CAR-T疗法bb2121的I期试验结果[202]。难治性骨髓瘤患者疾病对治疗反应良好;然而,许多受试者经历了包括神经毒性在内的副作用。在对复发性和难治性骨髓瘤患者进行的III期研究中,正在进行一项临床试验,以对bb2121和标准的三联疗法进行比较[203]

疫苗

目前正在研究针对骨髓瘤细胞高度表达的蛋白的疫苗。与传统疗法相比,疫苗通常耐受性良好,副作用较少。一种有前景的正在开发中的候选疫苗(ImMucin),最近被应用在一项包括在自体SCT后病情加重的的多发性骨髓瘤患者的I/II期临床试验中进行了研究[204]。在接受疫苗治疗的15名患者中,有11名在41个月的随访期内病情有所好转或保持稳定。

组蛋白去乙酰化酶抑制剂(HDACis):帕比司他

由于多发性骨髓瘤有复发和发展为难治性疾病的倾向,已在复发或难治性骨髓瘤的情况下对许多通常用于其他癌症的抗癌药物专门进行了试验,以期减轻治疗失败和复发。组蛋白去乙酰化酶抑制剂(HDACis)是一类在这方面显示出前景的药物,尤其是已证明了其疗效和耐受性的帕比司他(Farydak)。2015年,帕比司他获得了FDA的加速批准,可用于至少接受过两种先前治疗方案(包括硼替佐米和IMiD)的多发性骨髓瘤患者[205]。2019年,一项对19项试验和近2200名患者的数据进行的荟萃分析(Meta分析)发现,帕比司他与其他两种组蛋白去乙酰化酶抑制剂(伏立诺他胶囊(Zolinza)和ricolinostat(总体缓解率(ORRs)分别为0.51和0.38))相比,具有更高的总体缓解率(0.64)。硼替佐米治疗无效的骨髓瘤患者的ORR为0.36,来那度胺治疗无效的骨髓瘤患者的ORR为0.43。研究人员得出结论,含有帕比司他的治疗方案对复发性难治性多发性骨髓瘤患者有效且耐受[206]。还需要更多的试验来进一步验证帕比司他在治疗难治性多发性骨髓瘤方面优于其他HDACis。

在MGUS/SMM/MM中具有潜在用途的再利用药物

在过去的几十年里,人们对重新利用现有药物用于预防和/或治疗癌症的兴趣增加了。与最近上市的新抗癌药物相比,重新利用的药物通常具有成本优势和更全面的安全性记录。缺点是通常由于缺乏对私营部门进行对现有非标示用途药物的临床试验的财政激励,有关的疗效数据不太可靠[207]。然而,有些药物在治疗癌症方面具有良好的生物学合理性,并有观察证据或初步试验数据的支持,表明其具有对某些癌症有益的潜在应用价值。以下是对几种在多发性骨髓瘤及其前体疾病中有前景的药物的简要总结。

表 9: 在MGUS/SMM/MM中具有潜在用途的再利用药物



用于MGUS/SMM/MM的可能性
药物标准用途是否有临床前数据/生物学合理性?是否有应用于MGUS/SMM /MM的观测数据?是否有应用于MGUS/SMM /MM的介入数据?
β受体阻滞剂(普萘洛尔)主要是心血管疾病[208-217] [208-218]
他汀类药物(如辛伐他汀、洛伐他汀、阿托伐他汀)胆固醇管理[219-223] [224-227]  是,但是尚处于初步阶段[228,229]
二甲双胍糖尿病/血糖控制[230-231][232-235]
PDE-5抑制剂(如西地那非、他达拉非)男性性功能障碍,良性前列腺增生,肺动脉高压[236-246]是,但尚处于初步阶段,一项关于MM的小型、未发表的试验(n=13)显示缺乏应答导致提前终止[247]。有一项关于MM的病例报告[248]和一项关于Waldenstrm巨球蛋白血症的II期研究[249],这是一种独特但与MM相似的癌症。
COX-2抑制剂(如塞来昔布)镇痛,消炎,解热[239,250-261] 是,但截至2020年中期的结果并未表明有益处[262,263]
全反式维甲酸(ATRA)急性早幼粒细胞白血病[237,264-277]是,但是初步的[278-280]。一项研究表明,全反式维甲酸仅在与化疗联合使用时有效,单独使用时无效[281]
抗组胺药(如西咪替丁、氯雷他定、雷尼替丁)过敏性疾病[285-305]是,但是尚处于初步阶段[306]  
白细胞介素-2(例如,小剂量普洛列金)免疫疗法可应用于某些癌症治疗中,但应用有限[307-312]是,但是初步的[313,314]。一项研究发现rIL-2与rHuman IFNα-2a联合使用没有益处[315]
克拉霉素大环内酯类抗生素引用于根除幽门螺杆菌和其他一些感染[316-318](有限的)[319]是,但是尚处于初步阶段[320-325]  
*尽管此表中的药物得到了不同程度的初步证据的支持,表明理论上它们在MGUS/SMM/MM中是有益的,但没有一种药物在严格的临床试验中得到过验证。此外,其中一些药物可能会引起药物相互作用或副作用,其中一些可能是严重的。不应在没有合格医疗机构同意和监督的情况下,在标准骨髓瘤治疗方案中添加非标准用途的再利用药物。


九、控制MM或MGUS及SMM发展为多发性骨髓瘤的潜在靶点

随着研究的进展,对MGUS、SMM和MM的分子生物学的了解不断加深,特别是在过去的十年中,靶向治疗方法已经协助改善了多发性骨髓瘤的治疗。一些推动MGUS/SMM/MM病情固化和发展的途径也可能被天然药物或再利用药物所靶向。以下是一些可作为天然药物或再利用药物潜在干预靶点的途径。

核转录因子κB(NF-κB)

核转录因子-κB(NF-κB)调节有关增殖、血管、存活和凋亡的许多基因的转录,这使NF-κB成为控制疾病的一个有吸引力的靶点[326]。目前一些能抑制NF-κB的药物已被批准用于治疗MM,包括沙利度胺和硼替佐米[327]

骨髓瘤中持续活跃的NF-κB导致炎症介质 [例如,胰岛素样生长因子,白细胞介素-6,血管内皮生长因子,骨髓微环境中的巨噬细胞炎性蛋白1α(MIP-1α)]水平升高[328]。这些介质的净作用是增加骨髓瘤细胞的骨降解和增殖。

NF-κB通过NF-κB配体的细胞因子受体激活剂(RANKL)的作用参与破骨细胞的产生(破骨细胞生成)。狄诺塞麦是一种单克隆抗体,通过抑制RANKL与NF-κB受体激活剂(RANK)的结合来控制MM患者的骨损失,后者通常会刺激破骨细胞主导的骨损失。抑制NF-κB也可能干预RANK/RANKL破骨细胞的骨丢失。

有新的信息表明,破骨细胞和骨髓瘤细胞之间存在一个正反馈循环,这形成了两类细胞增殖和激活的恶性循环[329]。NF-κB是这个循环的一个组成部分。因此,抑制NF-κB有可能同时破坏破骨细胞的生成和骨髓瘤细胞的增殖/活性。

在众多抑制NF-κB的天然药物中,姜黄素是被研究得最为深入的药物之一[330,331]。其他的NF-κB激活的天然抑制剂包括白藜芦醇、熊果酸、辣椒素、水飞蓟宾、水飞蓟素、没药甾酮白花丹素[332-334]。槲皮素除了能干预NF-κB的激活外,同时还具有增强成骨细胞的作用[335]。厚朴中的一种多酚化合物和厚朴酚能破坏NF-κB介导的骨损失,对骨具有合成代谢和抗分解代谢的双重作用[336-338]。甘草次酸,甘草根中的一种化合物,也能通过抑制NF-κB来抑制RANKL诱导的破骨细胞生成。

MAPK通路

丝裂原活化蛋白激酶(MAPK)通路在细胞增殖和分化中起着重要作用[341]。参与MAPK通路的基因突变在MM患者中最常见,存在于在高达一半的新诊断的MM患者身上 [342,343]。MAPKs分为三个家族:ERKs、JNKs和p38。过度激活MAPK通路的最常见原因之一是RAS蛋白的突变,这种蛋白能调节细胞生长、增殖和分化[344]。最近使用下一代测序(NGS)的研究表明,RAS蛋白家族突变在骨髓瘤进展过程中累积。在MGUS和MM细胞中都发现了导致其组成性激活的NRAS和BRAF突变[345]。因此,失调的MAPK通路提供了一个吸引人的靶点,通过它,新疗法可能可以破坏从MGUS到MM的发展。

有趣的是,因为有证据表明他汀类药物可以抑制一些激活MAPK通路的过程,他汀类药物引起了癌症研究人员的兴趣。他汀类药物可抑制Ras和Rho等小GTP酶的异戊烯化,这能激活丝裂原活化蛋白(MAP)激酶MEK/ERK级联调节细胞的增殖、存活和凋亡[346-349]。在骨和前列腺癌细胞中,他汀类药物可通过抑制ERK/Bcl-2通路来减少细胞增殖和诱导细胞凋亡[350-352]。观察证据表明他汀类药物的使用可能与MM患者较低的MM发病率以及更好的预后相关[224,226,227,353]。一些初步的介入证据表明他汀类药物可能对治疗MM有帮助[228,,229],但需要更严格的研究来阐明他汀类药物的使用是否能对MM的临床进程或其前体疾病有积极的影响。

PI3K/AKT/mTOR信号通路

雷帕霉素(mTOR)信号通路的磷酸肌醇3-激酶(PI3K)/蛋白激酶B(AKT)/哺乳动物靶点在MM细胞中被异常激活,这诱导了细胞凋亡[354,355]。由于其在调节恶性浆细胞的增殖、生长、存活和迁移的重要作用,PI3K/AKT/mTOR通路是MM病理生理学和病情进展的关键。因此,mTOR通路已成为MM的新兴治疗靶点[354,356-358]

二甲双胍是一种一线糖尿病药物,具有许多潜在的有益的非靶向效应,已成为一些癌症的潜在可行治疗药剂[359-365]。由于二甲双胍靶向癌细胞中的多种信号通路,有关其作用机制的许多问题仍然没有答案[363,366]。不过,二甲双胍有两种潜在的公认的抗癌机制。首先,二甲双胍激活AMP活化蛋白激酶(AMPK),从而抑制下游AKT/mTOR信号传导,进而抑制细胞增殖[367-369]。与这一假设相符的是,二甲双胍可通过激活AMPK和抑制人MM细胞系中的mTORC1和mTORC2以及包括AKT在内的下游促生存信号通路引起细胞周期停滞而不发生凋亡[370]。二甲双胍还可以通过激活AMPK和抑制人MM原代细胞和细胞系中的mTORC2来抑制IL-6信号并增加细胞死亡[230]。第二,二甲双胍的抗癌作用似乎也是由生长因子胰岛素和胰岛素样生长因子1(IGF-1)的循环水平降低所导致的,这阻止了AKT/mTOR下游信号的激活,抑制了细胞增殖并诱导细胞凋亡[371,372]。事实上,二甲双胍通过抑制PI3K/AKT/mTOR下游信号通路抑制MM细胞增殖并诱导其凋亡[373]

血管生成

血管生成即新生血管的生长。这些血管为肿瘤生长提供血液和营养[374]。骨髓中MM的固化需要血管生成来为为其创造有利的微环境[375]。研究表明,血管生成的增加(即血管生成开关)是从浆细胞瘤或MGUS发展为MM的必要步骤[376]。来源于克隆性浆细胞以及骨髓中的破骨细胞和基质细胞的血管生成介质与侵袭性增加和预后不良有关。几种用于治疗MM的药物主要是抗血管生成药物(如沙利度胺)[377],这可能是控制MM的一种有效的治疗策略。

对于MGUS或SMM患者,具有抗血管生成作用的天然化合物是值得研究的,其目的不一定是治疗,而是防止病情发展为MM。天然存在的具有抗血管生成作用的化合物包括多酚、生物碱、植物激素和萜烯,这些物质可以在水果、蔬菜、草药和香料中找到[378]。一些已被充分研究的天然抗血管生成药物包括浆果中的鞣花酸、大豆中的类异黄酮(genestein)、白藜芦醇、水飞蓟素和表没食子儿茶素3-没食子酸酯(EGCG)[377]

免疫相关靶点

除了异常信号外,恶性细胞还会利用包括诱导免疫抑制的肿瘤微环境在内的多种免疫逃逸机制来逃避免疫破坏。髓源性抑制细胞(MDSCs)是一种未成熟髓细胞的多样性群体,在癌症期间扩张,具有强大的免疫抑制活性,在MGUS和MM的病理生理学中发挥关键作用[379,380]。非必需氨基酸L-精氨酸的代谢是MDSC免疫抑制中首个被发现的机制[236,381]。具体来说,L-精氨酸是诱导型一氧化氮合酶(iNOs,生成NO)和精氨酸酶1(Arg-1)的底物。MDSCs中两种酶的增加导致肿瘤微环境中L-精氨酸的缺乏,从而导致T细胞功能的损害[380]。此外,NO产量的增加通过抑制IL-2下游通道造成对T细胞功能的抑制[382,383]

从系统的角度来看,有许多天然药物对免疫功能有支持作用,可能可以降低感染的风险。预防感染的一般免疫支持应从确保充足的支持免疫功能的营养素(如维生素D、锌)开始[384]。然后,可以考虑从传统上用于免疫支持并经过当前研究验证的植物或蘑菇中的提取物。最著名的免疫支持性天然药物包括紫锥菊、接骨木、灵芝和舞茸[385]。在一项对患有浆细胞瘤的小鼠的研究中,添加到他们的食物中的紫锥菊导致了骨髓和脾脏中自然杀伤(NK)细胞的增加,使浆细胞瘤细胞引起的免疫抑制部分失效,并且未影响T细胞或B细胞免疫谱系(即体液免疫)[386]

白细胞介素-6(IL-6)是一种免疫细胞因子,以自分泌和旁分泌的方式维持血浆细胞的克隆群[387]。IL-6是MM骨微环境中的关键信使,对其信号传导的抑制作为MM的一种潜在治疗方法最近得到了重新利用[388]。虽然通过结合单克隆抗体对IL-6抗体的直接抑制并未带来益处,靶向附近的基质细胞(如脂肪细胞)产生的IL-6可能是更有效的治疗策略[389]。 IL-6可能被棉酚、小白菊内酯和姜黄素等天然药物抑制[390]

与大多数自发缓解的病例一样,有两例完全缓解的病例报告,似乎是免疫介导的。第一个病例来自1955年,一名男性肝炎患者在患病后其潜在的多发性骨髓瘤得到痊愈[391]。第二个病例是一名开始使用中药复方,黄芪桂枝五物汤(HGWT)的女性,黄芪桂枝五物汤是一种含有大量黄芪的配方[392]。黄芪是亚洲医学中常用的免疫补药。在2017年发表报告之前,患者病情稳定。在她病情稳定的18年中,她有过一次病情加重的情况。当时她服用黄芪的剂量增加到了原来的四倍,从每天30克增加到120克,随后她的病情恢复了稳定。


十、饮食和生活方式的注意事项

饮食方面的注意事项

许多研究已经评估了某些饮食习惯与多发性骨髓瘤发病风险之间的关系。2007年发表的一项研究发现,在康涅狄格州的妇女中,特定食物使用量的增加与多发性骨髓瘤风险降低有关。这些食物包括煮熟的西红柿、十字花科蔬菜、鲜鱼和食源性维生素A。另一方面,这项研究发现,大量食用奶油汤、果冻、冰淇淋和布丁与多发性骨髓瘤风险增加有关。这项研究还显示了一些趋势,表明增加碳水化合物的摄入可能会增加患病风险,而摄入更多的维生素D和钙可能会降低患病风险[393]

2001年的一项研究调查了539名多发性骨髓瘤患者和1989名对照者的饮食模式。研究人员发现,食用更多的鱼和十字花科蔬菜能降低多发性骨髓瘤的风险。有趣的是,这项研究还发现维生素C补充剂的使用与骨髓瘤风险降低有关[394]

2016年,意大利的研究人员发表了一份研究报告,他们研究了各种动物源性食品与非霍奇金淋巴瘤和多发性骨髓瘤风险之间的关联。他们研究了基于16000多个非霍奇金淋巴瘤患者和3600多个多发性骨髓瘤患者开展的33个独立研究的数据。分析表明,食用更多的鱼和海鲜与多发性骨髓瘤风险降低有关,而食用更多的红肉和奶制品与非霍奇金淋巴瘤风险增加有关。研究人员得出结论,“动物源性食品可能在非霍奇金淋巴瘤和多发性骨髓瘤的发病中起作用,红肉和奶制品有增加患病风险的趋势,而鱼类则有降低患病风险的趋势。我们的研究结果有力支撑了减少红肉摄入,用蔬菜、豆类和鱼类代替红肉的建议。”[395]

美国著名大学和医院的合作研究小组在2020年2月发表了一项引人注目的研究,他们发现饮食不仅可能影响骨髓瘤的发病风险,而且可能影响确诊后的生存率。这项研究包含了对护士健康研究和卫生专业人员随访研究的423例MM患者的前瞻性生存分析。研究人员检验了受试者在确诊前对健康饮食指数的坚持程度以及随后的存活率和死因。他们发现,每增加一个健康饮食指数的标准差,与MM相关的死亡率就会减少15-24%。相反,在坚持不健康饮食模式的情况下,每增加一个标准差,MM特异性死亡的发生率就高出16-24%。研究人员说,“……我们在多种饮食模式研究中的一致发现首次表明,具有更健康的诊断前饮食习惯的MM患者可能比那些饮食不太健康的患者存活时间更长。”[396]

前一段所述的研究是2019年由同一研究小组进行的一项研究的后续研究,他们在该研究中评估了饮食模式和骨髓瘤风险。在这项研究中,科学家们发现促炎饮食模式和与胰岛素抵抗相关的饮食模式与男性骨髓瘤风险增加有关。具体来说,坚持炎症饮食模式引起16%的多发性骨髓瘤风险增加。在骨髓瘤患病风险和更多地坚持与胰岛素抵抗相关的饮食模式之间也观察到了可能(尽管不具有统计学意义)的正相关。炎症饮食模式的坚持程度是通过评估引发三种炎症标志物(IL-6、CRP和TNF-α)的食物摄入频率来确定的。与这些炎症生物标志物增加相关的食物包括加工后的红肉、精制谷物和高糖饮料。反之,与这些炎症生物标志物水平较低相关的食物包括绿叶蔬菜和咖啡[397]

其他证据表明,更多的水果摄入可能与较低的从MGUS发展成MM的风险相关。在2018年发表的一项研究中,研究人员分析了5700多名参与者的数据,作为冰岛的一项基于人口的研究的一部分,这些参与者提交了食物食用频率问卷。分析表明,与那些不常吃水果的人相比,在晚年每周至少吃三次水果的患有MGUS的人,从MGUS发展为MM的可能性要小得多[398]

心理健康

骨髓瘤是一种抑制身体抵抗感染能力的疾病。心理健康是维持健康免疫系统的重要部分[399]。患者应专注于减轻压力和获得足够的睡眠,以支持免疫健康。

确诊骨髓瘤可能是让人难以承受的。有一些互助小组可以帮助患者更好地了解自己的病情,帮助他们度过这段困难时期。

戒烟

吸烟与骨髓瘤的发病密切相关,尤其是对女性和重度吸烟者而言[60,61]。吸烟的骨髓瘤患者必须停止吸烟。可通过非营利组织提供有用的信息和资源找到各种戒烟项目[49,160]。疾病控制和预防中心(CDC)也有提供有助于戒烟的资源。

体重和体育活动

研究表明,肥胖(体重指数为30 kg/m2或更高)[400]的人患骨髓瘤的风险更高[60]。不仅是对多发性骨髓瘤的情况而言,就算在一般情况下,健康饮食以保持适当的体重也是一种重要的对生活方式的改善。运动也有助于保持健康的BMI[60]。需要注意的是,骨髓瘤引起的骨病使患者在运动时骨折的风险增加。在开始执行运动方案之前,患者应该与他们的医生讨论体育活动的风险和益处。

表10:体重指数(BMI)计算*

测量单位公式与计算
示例
公斤和米

体重(千克)/身高(米)2=BMI千克/米2

体重指数的计算公式是体重(千克)除以身高(米)的平方。如果高度是以厘米为单位测量的,则除以100将其转换为米。

81kg/1.8m2=25kg/m2
磅和英寸

703 x 【体重(磅)/身高(英寸)2】=BMI千克/米2

当使用美式测量单位时,磅应该除以英寸的平方。然后乘以703,从磅/英寸2转换为公斤/米2

703 X (1801bs/71in2)=25kg/m2
*在有经验的临床医生的帮助下理解。


十一、综合干预

下文所述的综合干预是传统骨髓瘤治疗的一部分。尽管这些干预措施已被证明对某些疾病相关指标产生积极影响或能改变骨髓瘤病理学中涉及的生物途径,但患者在开始使用任何药物的新方案之前,始终应先咨询精通骨髓瘤治疗的临床医生。

请注意,这里描述的一些干预措施对MM或其前体疾病具有良好的生物学合理性,但还没有在严格的临床试验中得到验证。本部分中详细讨论的天然制剂在一些研究中表明对于MGUS/SMM/MM比较适用。关于这些药物的大部分数据都只是初步的结果,相关试验的规模也比较小。但无论如何,以下天然药物可能对MGUS/SMM/MM患者有潜在的益处。

食用菌

姬松茸(AbM)是一种传统的食用菌和药用菌。AbM具有免疫调节特性,可能有益于MGUS/MM患者 [401]。蘑菇通常含有支持免疫的多糖,而AbM因为具有几种化合物而具备有效的抗血管化作用[402]。AbM富含β-葡聚糖,它可以通过激活补体系统来调节免疫系统[403,404]。AbM还含有独特的化合物,如琼脂碱,它被证明能诱导致死白血病和骨髓瘤细胞[327]。这种蘑菇的抗肿瘤特性已在几种不同癌症的小鼠模型中得到证实[405]

除了具有良好的免疫效果外,AbM还具有抗衰老作用,这意味着它可以防止发生染色体损伤[406,407]。这可能与MM特别相关,因为从MGUS到MM再到难治性MM的发病过程中,基因易位和缺失是必要条件。

AbM对MGUS/MM患者具有的潜在作用是基于一项小规模的研究得出的,之后需要通过更大规模的临床试验进行验证[331]。在这项研究中,40名患者随机接受安慰剂或三种蘑菇提取物(82.4%AbM、14.7%猴头菌和2.9%舞茸)与化疗和SCT联合治疗。根据实验室发现,接受安多糖治疗的患者(n=19)免疫反应会有所增强。然而,治疗组和安慰剂组的临床结果没有差异。鉴于初步数据表明,AbM对于MM患者可能有用,同时它也是一个维持免疫力的不错选择。进一步的研究可阐明使其发挥最大效用的形式、剂量和患者群体[408]

阿拉伯木聚糖

阿拉伯木聚糖(Arabinoxylan)是一种半纤维素(即植物细胞壁中发现的一类化合物),来源于富含营养的水稻硬外层,它已被证明能刺激免疫系统。Biobran或MGN-3是一种含有阿拉伯木聚糖的专利产品,它利用香菇(香菇菌丝体)中的酶分解特定的半纤维素化合物(半纤维素B)并产生独特的免疫调节产品。MGN-3已在实验室试验和人体中证明具有免疫调节作用[332,333,409]。几种动物癌症模型显示阿拉伯木聚糖具有抗肿瘤和化学预防作用,其作用可能归因于免疫调节和诱导癌细胞凋亡[410-412]

临床前研究表明,阿拉伯木聚糖可以刺激巨噬细胞吞噬活性,增强NK细胞活性,并促进IL-2(一种参与调节白细胞的细胞因子)的产生[410,413-416]。MGN-3在一个小规模临床试验中也被证明可以提高NK细胞活性。该试验招募了年龄较大的参与者[417]。此外,一项临床试验对80名健康参与者的研究表明,补充阿拉伯木聚糖可增加干扰素(IFN)-γ的产生,这是一种先天性和适应性免疫所必需的细胞因子[418]。这些研究结果很有趣,因为免疫抑制是MGU/SMM和骨髓瘤的标志。

在2018年对11项癌症患者(包括骨髓瘤)临床研究的回顾中,研究人员得出结论,MGN-3可以“通过上调患者的免疫系统来补充传统的癌症治疗,特别是在增强NK细胞活性方面……它可以作为补充免疫治疗来减少副作用,改善治疗结果,提高长期生存率。” [419]一项研究发现,补充MGN-3可提高各种恶性肿瘤患者的生存率。但研究人员指出,大多数研究都是小规模和短期的。

MGN-3已经在骨髓瘤中进行了特异性检测。一项使用人类多发性骨髓瘤(U266)细胞系的体外研究发现,当MGN-3或姜黄素添加到细胞培养基中时,MM的增殖受到抑制。当两者联合使用(100μg/mL MGN-3加10μM姜黄素)时,具有协同效应,导致U266骨髓瘤细胞计数减少87%,细胞凋亡增加2.6倍[420]。一项小型初步研究评估了6个月的时间内姜黄素(95%姜黄素的6克/天)和MGN-3(2克/天)在10 MGUS/MM的患者和10例0/1期慢性淋巴细胞白血病(CLL)患者上的完整血细胞计数。[421]半数MGUS/MM患者在基线检查时出现中性粒细胞减少。在10名MGUS/MM患者中,8名患者的中性粒细胞计数有所增长。此外,10 MGUS/MM患者中有4例出现血沉(ESR)降低,表明全身炎症降低。此外,在一项针对48名骨髓瘤患者的小型随机研究中(32名患者每天服用2克MGN-3,16名患者服用安慰剂),MGN-3增加了先天免疫系统的活性,包括增加NK细胞活性、髓系树突状细胞水平和Th1相关细胞因子的活化。这些都是针对MM固有不平衡的特性[332]。有必要对mgu/MM患者使用MGN-3进行进一步研究。

姜黄素

“姜黄素”是一个术语,通常宽泛地指含有天然存在的姜黄素(如姜黄素,去甲氧基姜黄素和双去甲氧基姜黄素)的姜黄根(Curcuma longa)提取物。对姜黄素的研究通常是使用从姜黄根中提取的高浓度提取物(姜黄素含量大于90%),而不是整个姜黄根(姜黄素含量仅为3-5%)。其主要因为有研究表明高剂量姜黄素在MGUS/MM治疗中有益处。

关于姜黄素对MGUS/MM的潜在调节作用的研究展现了包括抑制增殖、诱导凋亡和抑制破骨细胞的形成在内的可能的作用机理 [384,422,423]

姜黄素的抗MM作用非常有趣,足以引发持续的姜黄素类似物(药物)的研究,以寻找新的多靶点抗骨髓瘤药物[424-426]。许多成熟的骨髓瘤生长和进展途径,包括STAT3、MAPK、IL-6、NF-κB,RANKL都受到姜黄素直接或间接影响。

转录因子NF-κB通常与骨髓瘤发病有关,其从胞浆到细胞核的释放被姜黄素抑制。特别对于MM,姜黄素(如二阿魏酰甲烷)的加入通过抑制NF-κB重建了细胞凋亡[427]。骨髓瘤是姜黄素具有促凋亡作用的多种癌症类型之一[428]

STAT3必须磷酸化才能被激活,这一过程可由IL-6诱导,IL-6是一种细胞因子,在MM患者中通常很高。一项细胞研究表明,姜黄素能迅速可逆地阻断IL-6对STAT3的激活,其剂量可在人体内达到(10μM)[429]

两项小型研究评估了高剂量姜黄素对MGUS/MM患者的影响。在一项针对MGU患者(n=26)的研究中,每天补充姜黄素(4克/天)可产生良好的效果,包括最高水平(>20克/升)患者的M蛋白减少,27%的患者的骨吸收标志物(尿中1型胶原的n-末端肽)减少[430]

在第二项研究中,MGUS和SMM患者被随机分为每天服用4克姜黄素或安慰剂[431]。研究组在三个月后进行交叉分组,从最初随机分为另一组。因此,研究开始时服用姜黄素的受试者在三个月后就开始服用安慰剂了。在完成六个月的交叉研究后,参与者可以选择继续进行开放标签研究,使用高剂量姜黄素(每天8克)。补充姜黄素可以改善疾病进展和骨代谢变化的指标。作者的结论是“……姜黄素可能有可能减缓MGUS和SMM患者的疾病进程。”

在一项为期12周的不同剂量范围研究(2、4、6、8、10和12克/天)中,联合或不联合10 mg/d胡椒素使用,每种剂量招募了6名MM患者 [432]。在12周时病情至少是稳定状态的患者被允许继续试验长达一年。虽然没有客观的反应(n=29名参与者),12名患者继续治疗12周以上,5名患者在一年内稳定。在每个月的时间点,大多数参与者的组成性活性NF-κB、STAT3和COX-2都显著降低。作者提出,姜黄素应“进一步研究,无论是单独或作为一个调节剂的化疗耐药与其他活性剂相结合。”

有一个公开的案例表明,使用大剂量姜黄素作为单一药物可以稳定病情[433]。一名被诊断为ISSⅢ期MM并接受了两种既往的标准治疗的57岁女性患者,每晚服用8克姜黄素。MM疾病的所有客观指标(M蛋白、骨显像)稳定,该患者在研究发表时(即5年后),病情没有进一步发展。

多重耐药性是控制MM的一个主要障碍,目前用于该疾病的每一种靶向药物的耐药人群最终都会克隆性增加。除了姜黄素的直接抗MM作用外,还有初步数据表明姜黄素具有对MM细胞对抗MM药物的致敏作用。例如,姜黄素通过多种机制增强了卡非佐米对MM细胞(U266细胞)的细胞毒性,包括通过影响NF-κB和诱导细胞周期阻滞[434]。在MM小鼠模型中,姜黄素防止了硼替佐米和沙利度胺的化学耐药性,通过NF-κB介导的机制增强其细胞毒性作用并增加细胞凋亡[435]。应考虑将姜黄素与靶向药物一起用于MM的临床试验,以确保联合用药是安全的,并确定应用的最佳剂量。

海参

海参属于棘皮动物门(也包括海星和沙钱)。几个世纪以来,海参作为一种具有多种生物活性的传统药物和功能性食品受到人们的重视。这些生物体含有多种具有治疗特性的化合物,包括三萜苷、类胡萝卜素、硫酸软骨素和胶原蛋白,以及多种维生素、矿物质等[436]。一种海参制剂TBL-12,已经应用在了无症状多发性骨髓瘤的II期临床试验中[437]

各种海参提取物已证明其特性可能对MGUS/SMM或活动性骨髓瘤患者有用。临床前体外研究和动物研究表明,海参提取物具有有力的抗肿瘤作用[438,439]。提取物似乎通过许多在骨髓瘤中很重要的机制发挥其作用,包括抑制血管生成因子[440,441]、激活免疫NF-κB细胞[442,443],以及通过NF-κB和MAPK信号通路刺激巨噬细胞[444,445]。免疫增强效应可能有助于延缓MGUS/SMM到活动性骨髓瘤的发展,而抗肿瘤效应可能对活动性骨髓瘤有益。海参提取物在临床前研究中也显示出抗炎活性。这一点很重要,因为炎症是MGUS/SMM和骨髓瘤发病机制中的关键因素[446]。在免疫抑制的大鼠中,海参提取物降低了炎症因子(如IL-6和TNF-α)的血清水平[447]。在抗胰岛素小鼠中也观察到类似的结果[448]。此外,海参提取物似乎对骨骼也有一些好处:体外研究表明,海参提取物可以抑制分解骨骼的破骨细胞的发育,并促进骨髓源性干细胞向造骨细胞的分化[450]。这些效应可能有助于减缓MGUS/SMM向活动性骨髓瘤发展,并有助于治疗与活动性骨髓瘤相关的骨病变。

在TBL-12的开放性临床试验中,20例无症状多发性骨髓瘤患者每天服用80mL海参提取物。这些患者都是病情发展的高风险或中等风险患者。随访72个月后,治疗耐受性良好,无进展生存率的中位数优于预期结果[437]。需要进一步的临床试验来确定早期干预和海参提取物,是否可为MGUS/SMM或活动性骨髓瘤患者提供总体生存益处和健康益处。

Omega-3脂肪酸(EPA和DHA)

Omega-3多不饱和脂肪酸(PUFAs)在细胞结构和功能中起着关键作用,包括细胞信号转导和炎症的消退,它们具有更直接的抗炎作用。值得注意的是,它们能抑制炎症调节因子和转录因子NF-κB。在癌症并发症的背景下,对Omega-3多不饱和脂肪酸进行了广泛的临床和临床前研究[451]。人体研究表明摄入Omega-3多不饱和脂肪酸可提高癌症患者的存活率[451,452]。Omega-3多不饱和脂肪酸二十二碳六烯酸(DHA),主要来源于海洋生物(如鱼类),临床前研究报道,当它与抗癌药物联合使用时,可增加耐药细胞系中癌细胞对抗肿瘤药物的敏感性[452]

体外实验中,二十碳五烯酸(EPA)和DHA能通过扰动线粒体和激活caspase-3来抑制NF-κB活性和诱导细胞凋亡,作用于人MM细胞。EPA和DHA也增加了人MM细胞对蛋白酶体抑制剂硼替佐米的敏感性[454]。在使用地塞米松的同时,用EPA和DHA刺激人U266 MM细胞可增加MM细胞凋亡,这表明omega-3脂肪酸增加了MM细胞对地塞米松的敏感性[454]。MM细胞对地塞米松的敏感性增加与抑癌基因p53和miR-34a的表达增加和Bcl-2的表达减少相关。因此,EPA和DHA通过依赖于NF-κB的p53/miR-34a/Bcl-2调控网络增加MM细胞对地塞米松的敏感性[455]

截至2020年年中,没有任何调查omega-3多不饱和脂肪酸对MGUS或SMM患者的影响的临床研究。然而,一些临床研究已经开展了对EPA和DHA对血液系统恶性肿瘤的影响和治疗的副作用的研究。

一项包含了12例急性淋巴细胞白血病和6例急性骨髓系白血病患者的具有前瞻性的、随机、单中心、开放性的临床试验,研究了EPA作为高能量和高蛋白质补充剂的一部分的作用。试验结束时,观察到癌症引起的体重减轻和儿童患者整体状况得到改善。急性期蛋白水平的下降归功于EPA的有益作用[456]

一项随机临床试验研究了补充EPA和DHA对22例接受化疗的急慢性白血病和淋巴瘤(霍奇金和非霍奇金)患者炎症标志物和长期生存率的影响。研究发现,与仅接受化疗的患者相比,接受补充剂(持续9周,每天食用2克鱼油(含EPA和DHA))和化疗的患者的C-反应蛋白(CRP)和CRP/白蛋白比值降低更多。与对照组相比,食用鱼油的患者总的长期生存时间也更长(化疗开始后465天)。这些发现表明了营养物质相关的炎症风险的改善,由此建议接受化疗的恶性血液病患者同时补充鱼油,以提高长期生存的可能性。

一项多机构的II期合作小组研究对43例诊断为晚期血液系统恶性肿瘤(包括白血病、淋巴瘤和多发性骨髓瘤)的患者进行了研究,以检验高剂量鱼油补充剂对减缓恶性肿瘤引起的恶病质患者体重减轻和改善其生活质量的潜力。在持续约1.2个月的时间内,患者每天补充高剂量omega-3多不饱和脂肪酸胶囊,胶囊含4.7克EPA和2.8克DHA。研究数据显示,24例患者体重稳定,6例体重增加>5%,6例体重下降≥5%。体重增加的患者生活质量评分更高。因此,补充高剂量omega 3多不饱和脂肪酸有助于一部分患者的体重稳定或体重增加,从而提高了该组患者的生活质量[458]

类异黄酮(genestein)

类异黄酮是一种主要存在于大豆中的异黄酮,已被证明具有广泛的生物活性,包括抗癌活性[459]。在MM细胞中,类异黄酮(40mm)增加了miR-29b的表达并抑制了NF-κB。抑制NF-κB导致细胞增殖减少、caspase-3活性增加和细胞凋亡[460]

骨髓基质细胞(BMSCs)是促进骨髓瘤细胞存活和增殖的关键细胞。类异黄酮可下调骨髓间充质干细胞中的NF-κB,当共同培养这两种细胞类型时,可减少MM细胞的扩增[461]。此外,类异黄酮抑制了细胞蛋白酶体活性[462],这可能对MM患者有益,因为蛋白酶体抑制剂是MM的标准治疗药物。在临床环境中,类异黄酮可增强NK细胞活性[463]

一项对220名MM患者和220名配对对照组进行的流行病学研究表明,饮食中摄入大豆与MM发病风险的降低有关[464]。在13名接受化疗的转移性结直肠癌患者中对类异黄酮(每天60毫克,每两周服用7天)进行了测试,结果发现其安全又耐受性良好,并且对疗效有潜在的积极影响,包括增加NK细胞活性[463]。在16名胰腺癌患者中,剂量高达1600毫克/天的一种新的晶型类异黄酮与标准治疗结合,可使血清中类异黄酮的最大浓度达到1μM[465]。因为类异黄酮遵循线性剂量-反应曲线[466],这表明临床相关剂量高达800毫克/天的类异黄酮不应导致血清水平超过0.5mM。在此剂量下,类异黄酮可能有助于促进癌症患者NK细胞介导的抗肿瘤反应。然而,MM患者可能希望避免剂量大于800毫克/天的类异黄酮,因为体外实验证明类异黄酮浓度高于0.5 mM对NK细胞功能有不利影响[467]

绿茶提取物(EGCG)

绿茶(Camellia sinensis)的主要化学成分是茶多酚,它对包括癌症在内的多种人类疾病具有多种治疗作用。绿茶中的茶多酚由儿茶素组成,包括表儿茶素(EC)、表儿茶素-3-没食子酸酯(ECG)、表没食子酸酯(EGC)和表没食子酸酯(EGCG)。在这些成分中,EGCG是含量最丰富的茶多酚[468,469]

EGCG通过诱导细胞凋亡、坏死和自噬对细胞死亡机制的影响已在体外研究和几个临床前模型中得到了充分的证实[470-472]。EGCG的抗癌作用也在MM细胞中得到了证实[473]

一项I期试验发现,在CLL患者中,含有EGCG(多酚E)的浓缩绿茶制剂在剂量高达2000毫克(每天两次)时仍具有良好的耐受性,并能产生一些积极的临床效果[474,475]

注意:绿茶可能与硼替佐米相互作用。更多信息请参见标题为“硼替佐米与天然物质的潜在相互作用”的侧栏。

淫羊藿素

淫羊藿素是一种从传统中草药大花淫羊藿(又名角山羊草)中提取的黄酮类化合物。它的细胞毒作用被认为是通过多种机制诱导对肿瘤细胞的杀伤和抑制多种癌细胞的扩散实现的,包括抑制细胞增殖,阻断细胞周期[338]。对使用淫羊藿素控制MM的研究主要集中在对其抑制信号转导通路,从而改善MM细胞的凋亡的能力的研究[340,476]

淫羊藿素已被证明能逆转某些骨髓瘤细胞表现出的耐药性[339]。淫羊藿素也有可能通过增加其他成骨机制中的骨形态发生蛋白(BMP)来增加骨形成,从而使MM患者的骨再生[477]。还需要进一步开展临床试验以探索淫羊藿素在MM患者中的应用潜力。

小白菊内酯

小白菊内酯是一种天然存在于小白菊(Tanacetum parthenium)植物中的倍半萜内酯,已知具有多种抗癌作用[478]。在模拟骨髓微环境的三维组织培养实验中,培养骨髓瘤干细胞。小白菊内酯和穿心莲内酯(来自穿心莲)都抑制了骨髓瘤干细胞的生长[479]。然而,一旦加入骨髓基质中的细胞,只有小白菊内酯保持其细胞毒性作用。

除了小白菊内酯对骨髓瘤干细胞的作用外,它还通过结合TRAF6抑制骨髓瘤细胞中NF-κB的活化,有效抑制了细胞增殖并诱导细胞凋亡[480]

小白菊内酯可诱导四种不同骨髓瘤细胞系的凋亡,但不会损害正常淋巴细胞[481]。在本细胞实验中,N-乙酰半胱氨酸的加入完全阻止了细胞凋亡,表明这种作用是由活性氧(ROS)介导的。这证实了一项表明小白菊内酯是通过产生ROS诱导细胞凋亡早期的细胞研究 [482]

蛋白水解酶

在世界范围内,酶都与传统的癌症治疗方法一起被广泛使用[483]。最常用的癌症治疗方案附加治疗制剂是蛋白水解酶或胰酶。关于酶在癌症中的益处的研究相当少,但现有文献报道的其主要益处是减少化疗和放疗的副作用[484]

一项小规模的研究表明,蛋白水解酶对接受化疗的MM患者有更好的疗效。在这项试验中,对接收口服酶片(包括100毫克木瓜蛋白酶、40毫克胰蛋白酶和40毫克糜蛋白酶)的265名骨髓瘤患者(IIII期)进行了研究。患者接受标准化疗或标准化疗附加口服酶制剂(每日三次,每次两片)[485]。该剂量从化疗第一天开始执行,12个月后减为每日三次一片。在疾病的各个阶段,酶加化疗组获得缓解或病情稳定的患者人数明显高于单纯化疗组。与单纯化疗相比,接受酶补充加化疗的III期骨髓瘤患者(n=54)存活时间更长(83个月对比47个月;p=0.0014)。虽然这个小试验很有趣,但在提出任何关于服用酶的建议之前,还需要进行安慰剂对照研究。

静脉注射维生素C(抗坏血酸)

MM患者可能会维生素C不足。一项针对50名MM患者(ISS II期)的研究发现,与对照组相比,MM患者的氧化应激(每丙二醛水平)更高,酶(谷胱甘肽过氧化物酶、超氧化物歧化酶和过氧化氢酶)和非酶(维生素C和E)抗氧化剂的活性更低[486]

静脉注射维生素C,有时被称为药理学抗坏血酸,已被广泛研究用于包括血液系统癌症和多发性骨髓瘤的癌症临床前治疗[487]。药理学抗坏血酸的抗癌活性与口服抗氧化剂维生素C的作用机制不同,目前还没有证据显示它对杀死癌细胞或肿瘤有效[488,489]。多种抗坏血酸药物的临床试验正在计划、进行或已经完成。大多数此类试验将静脉注射维生素C与化疗相结合,其中一些试验报告了鼓舞人心的结果[487,490]

安全提示:一些体内数据表明,维生素C可能会干扰硼替佐米等硼酸基蛋白酶体抑制剂的疗效[110]。因此,服用硼替佐米的MM患者在服用维生素C补充剂之前,应与其肿瘤科医生沟通(见标题为“硼替佐米与天然药物的潜在相互作用”的侧栏)。

维生素D

维生素D是一种当皮肤暴露在阳光下会产生的类固醇化合物。维生素D的受体遍布全身。基于这种广泛的分布,维生素D参与了人体内几乎所有系统的生理内稳态调节[491]。有些食物(例如脂肪较多的鱼、蘑菇)含有少量维生素D,但想到达到充足的循环水平,通常需要口服补充剂或肌肉注射。

鉴于维生素D对钙稳态的影响,临床上对MGUS/MM患者使用维生素D的考虑应当慎重。MM的典型症状之一是高钙血症,需要考虑到维生素D通过优化肠道吸收和减少肾脏对钙的清除来保持钙含量的正常生理作用。相反,缺乏维生素D预示着MM患者预后较差。考虑到维生素D含量过低和过高对患者都是风险,谨慎的做法可能是对MGUS/MM患者中循环维生素D和钙的含量进行定期监测。

最近的研究表明,低维生素D状态与包括MM在内的多种癌症的高风险和较差的预后相关 [492,493]

维生素D缺乏与MM有关,即使在阳光充足的热带气候中也是如此[494]。在一项评估骨转移或多发性骨髓瘤患者的维生素D水平的单一机构研究中,根据作者的说法,维生素D缺乏“非常普遍”[495]。在MM患者中,平均维生素D水平略低于15纳克/毫升,这一数值很低,即使是健康人也会出现骨质流失。

关于循环维生素D(如25-羟基胆甾醇)的最佳水平存在一些争议。然而,人们一致认为低于20ng/mL的水平代表严重缺乏,会导致骨质流失[496,497]

一项评估了83名骨髓瘤患者和维生素D水平的研究显示,维生素D缺乏(<10 ng/mL)与骨髓中血浆细胞水平升高有关[498]。此外,补充维生素D可显著增加血红蛋白、白细胞和红细胞水平,并改善血小板水平。

维生素K

维生素K是维持成骨细胞和破骨细胞在正常骨转换中的稳态所必需的。虽然缺乏关于补充维生素K(mg/MM)的效果的人体数据,但MM的许多骨降解机制可能是维生素K维持骨健康作用的靶点。

其他类型的增生性骨髓疾病(如骨髓增生异常和白血病)有许多种,但只有与MM相关的浆细胞克隆群表现出附近微环境中的骨破坏。这一特征被认为是浆细胞瘤/MM浆细胞增殖过程的关键。虽然尚未发现所有MM病例都有的一个独特的确定机制,但很明显,刺激或抑制破骨细胞和成骨细胞作用的骨调节蛋白的表达存在不平衡(表11)。

表11:与MM患者骨降解严重程度相关的过度表达蛋白*

由…产生抑制附近的成骨细胞刺激附近的破骨细胞
MM细胞DKK1, SRP-3, HGF, MIP-1alphaMIP 1-alpha, IL-32, BDNF
基质细胞激活素A受体(Activin A)RANKL, GDF15, 脑源性神经营养因子(BDNF)
*汇编自Borset等人[507]的骨髓瘤患者为什么会有骨病:历史的回顾

维生素K似乎也通过对破骨细胞和成骨细胞的双重作用而对骨转换产生有利的影响,这两种作用源于维生素K对NF-κB活化的抑制[508]

体外研究的初步证据表明,维生素K2除了对骨骼健康有益外,还可能发挥一些抗骨髓瘤的作用。当骨髓瘤细胞与不同浓度的维生素K2共同培养时,其生长受到抑制,凋亡增加[170]

在多发性骨髓瘤的啮齿类动物模型中,白花丹素,一种从印度阿育吠陀医学植物白花丹中提取的维生素K的类似物,已被证明能抑制RANKL和抑制破骨细胞的生成[509]。在对其的应用作出任何结论之前,应进行进一步的人体研究。


声明:本文提出了许多问题,这些问题可能会随着新数据的出现而发生变化。 我们建议的营养或治疗方案均不用于确保治愈或预防任何疾病。Piping Rock健康研究院没有对参考资料中包含的数据进行独立验证,并明确声明对文献中的任何错误不承担任何责任。


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