来那度胺(又名: revlimid, lenalidomide, 雷利度胺，雷利米得, REVANA, 瑞法那，),是一种具备抗血管增生和抗肿瘤活性的新一代免疫调节剂。他是沙利度胺（Thliddomide）的升级产品，但较沙利度胺的副作用少。雷利度胺是目前主要用于治疗复发和难治性多发性骨髓瘤和5q染色体缺失的骨髓增生异常综合症。

适应症
多发性骨髓瘤，可以用于治疗至少接受过一种疗法的慢性骨髓瘤。

骨髓增生异常综合症，雷利度胺用于治疗5q染色体缺失的骨髓增生异常综合症引起的严重贫血。

主要毒副作用
1、是沙利度胺的化学结构类似物，因此它可能会引起致命性的胎儿毒性作用。
2、中心粒细胞减少和血小板减少是用雷利度胺治疗的常见毒副作用。
3、多发性骨髓瘤病人用雷利度胺治疗伴随着深静脉血栓和肺动脉栓塞发病率增加的危险。

4、除上述三类毒副作用以外，其它常见的副作用包括胃肠道的反应和淋巴系统的障碍。

Lenalidomide的作用机制和临床应用

Lenalidomide的作用机制

Lenalidomide属于新一类的口服抗癌药品，称为免疫调节药品（immunomodulatory drug；IMiDsâ），与thalidomide类似的是，它们都具有多重的作用，包含抗癌及抗发炎，其作用机转大致可分为免疫调节特性（immunomodulatory properties）及非免疫调节特性两部份（non-immunomodulatory properties）。

在免疫调节特性方面，它可藉由改变许多细胞介质（cytokines）的生成来影响免疫系统，达到提升免疫反应、增加免疫细胞活性及抑制发炎的效果。研究指出，lenalidomide可以增加T细胞（T cells）及自然杀手细胞（natural killer cells）的活性；促进T细胞的生成因子白介素2（interleukin 2；IL-2）及抗发炎介质白介素10（interleukin 10；IL-10）的生成；及抑制发炎介质，如甲型肿瘤坏死因子（a-tumor necrosis factor；TNFa）、白介素1b（interleukin 1b；IL-1b）的产生，藉由这些作用来影响免疫系统。而在非免疫系统调节特性上，它可藉由抑制血管内皮生长因子（vascular endothelia growth factor；VEGF）来抑制肿瘤细胞的血管生成作用，也可直接抑制肿瘤细胞的增生及诱发异常细胞的分解。透过在免疫及非免疫的调节，使得lenalidomide可以发挥比thalidomide更好的效果，相反的，thalidomide有的一些常见副作用，如嗜睡、便秘、神经疾病、皮肤发红等，在lenalidomide却很少见，而且，最重要的是thalidomide有致畸胎的作用，所以，若是性生活频繁的患者，在使用thalidomide期间，必须采取两种以上的避孕方式，而lenalidomide并无如thalidomide致畸胎的副作用，所以，患者在使用上也较安心。

Lenalidomide近期的临床应用

Thalidomide目前在美国只被核准用来治疗麻疯结节性红斑（ENL），对于多发性骨髓瘤（multiple myeloma；MM）尚在审核阶段；但是，在澳洲、纽西兰、土耳其及以色列，thalidomide已可用在标准疗法失败的多发性骨髓瘤患者。但是，致畸胎仍是一个潜在的非常危险的副作用，所以，thalidomide的使用皆须在严密的监控下。Lenalidomide的优点，让许多大型研究陆续展开，而有些已到第三阶段（phase III），以下为分析lenalidomide在不同的癌症进行的研究。

（一）、多发性骨髓瘤（multiple myeloma；MM）

多发性骨髓瘤为一种无法治愈的恶性B细胞疾病，患者的骨髓恶性细胞会不断的增生，导致正常细胞无法运作。依据卫生署数据显示，国人之发生率为每年十万人中有0.64人发生(男: 0.76人；女: 0.42人)，在国人癌症中占0.36 %，而血液肿瘤则占了13.8 %。此病好发于老年人(平均年龄为65岁)，仅有3%病患小于40岁。目前在美国，每年约有14000~15000个新患者，平均存活期为3~5年。目前高剂量的化学治疗加上干细胞移植，可以提高治疗效果及存活率，但是，此类疾病的复发率高，而且可使用的救援治疗很少。

在一项lenalidomide的第二期临床试验研究1中，为了要将骨髓抑制作用减到最小，设计了不同的给药剂量，对于两组复发性、顽固性多发性骨髓瘤患者，分别投与20天25毫克及10天50毫克的lenalidomide(两组皆已28天为一个治疗周期)，结果显示，25毫克组有较高的反应率(40%)，与50毫克组(15%)比较起来。评估一年后无事件存活率(event-free survival)为30%，存活率(overall survival)为61%。

在另一项较大型的研究1则发现，每天总剂量均为30毫克，连续服用21天，以28天为一个周期，但分为一天服用一次，一次30毫克，及一天服用两次，一次15毫克，反应率比较起来，两组疾病类似，就所有病患有24%治疗反应率(包括6%完全缓解)。此外有趣的是原本单独使用lenalidomide无效的病患，如再加上dexamethasone则会有33%治疗反应率。至于副作用方面之骨髓抑制反应，一天服用一次30毫克组的显然较少。

对于新的多发性骨髓瘤患者，lenalidomide可收到更好的效果。而不管是新的或是复发性的患者，研究显示，与dexamethasone或其它的药品并用，可以提高治疗效果，但是，与dexamethasone并用的疗法，可能会增加产生深部静脉血栓（deep vein thrombosis；DVT）的机会，所以，对于高危险群，可加入低剂量的水杨酸（aspirin）来预防。其余血液方面的副作用，如第三级/第四级的嗜中性白血球减少症（neutropenia），或血小板减少症（thrombocytopenia），可以藉由调整剂量或暂时停止用药来改善。

（二）、骨髓生成不良症候群及其它恶性血液疾病（myelodysplastic syndromes and other haematological malignancies）

骨髓生成不良症候群（Myelodysplastic syndromes；MDS）为造血细胞的恶性疾病，患者常因红血球生成功能不佳而有贫血的现象，估计全美每年约有7,000到12,000个新的病例被诊断出来，可能发生于各个年龄层，但主要仍是六十岁以上族群居多。这些患者使用lenalidomide后显示，对于红血球生成细胞有恢复的效果，可以使他们不再依赖输血，尤其在骨髓生成不良症候群分类中，属于第五对染色体长臂间隙基因缺损者（5q31 chromosome clonal interstitial deletion），其治疗反应率为最佳。

在一项研究3中，43名需要依赖输血（32名）或具贫血症状（11位）的骨髓生成不良症候群患者，他们以28天为一治疗周期，分别每天使用25毫克、10毫克，及每天10毫克，但只使用21天，持续治疗16周，进行药物反应之评估。其中有24位（56%）患者对治疗有反应，在32位原需依赖输血的患者中，已有20位（63%）不需再输血，而原本11位不需依赖输血的患者，有1位血红素增加超过2 g/dl，有3位患者的输血依靠度降低了50%，患者血红素中位数为13.2g/dl (范围：11.5-15.8)，追踪中位数为81周(范围：42-110)后，不需依赖输血的持续期中位数并未达到。如前所言，细胞遗传学与治疗反应率有明显关联性，其中治疗反应率最高为第五对染色体长臂缺损型（5q31.1 chromosome deletion）83%，其次为正常细胞核型57%，而其它异常核型的反应率仅为12%。

治疗期间因为白血球减少，或血小板减少的关系，有25位患者(58%)必须中断治疗或降低剂量；这也是本项试验中最常见的副作用，嗜中性白血球减少症（65%，皆超过第三级）及血小板减少症（74%；54%超过第三级）仍是最常见的副作用，其它副作用则较轻微且少见。

Lenalidomide也被研究用于其它血液恶性疾病，如骨髓纤维变性（myelofibrosis）、慢性淋巴性白血病（chronic lymphocytic leukemia）、淀粉样变性病（amyloidosis）及Waldenstrom氏大球蛋白血症（waldenstrom’s macroglobulinemia），目前初步的研究结果都蛮令人振奋的。

（三）、实体肿瘤（solid tumors）

Lenalidomide最初被用于研究的实质固态肿瘤为转移性恶性黑色瘤，虽然安全性够，但是得到的效果并不好，所以计划终止了。目前针对实质固态肿瘤的研究还包括非Hodgkin氏淋巴瘤（non-Hodgkin’s lymphoma）、非小细胞肺癌（non-small cell lung cancer；NSCLC）及胰脏、前列腺、脑部、肾脏、卵巢等部位的肿瘤。

Brand Name:	Revlimid
Generic Name:	lenalidomide
Company:	Celgene
FDA Clinical Phase:	Approved for use, in combination with dexamethasone (Decadron), for multiple myeloma patients who have received at least one prior therapeutic treatment.

Description

Revlimid, which is a molecular derivative of thalidomide (Thalomid), was introduced in 2004 as a treatment for multiple myeloma. Revlimid in combination with dexamethasone is currently a common therapeutic treatment for multiple myeloma patients. Revlimid is more potent than thalidomide in inhibiting tumor production, and it also produces less severe adverse drug reactions than other drug agents of its kind.

Mechanism of Action

Although the exact mechanism of Revlimid has yet to be fully characterized, it has been shown to possess several properties key to combating tumor production.

Revlimid acts as an antineoplastic agent, a drug that inhibits the development of abnormal tissue masses known as neoplasms. The danger of antineoplastic agents, which includes cancer chemotherapy drugs, is widely acknowledged because they harm both healthy cells and cancerous cells. These drugs are still thought to be beneficial to cancer patients with a life-threatening disease, such as multiple myeloma.

Revlimid is also an immunomodulatory agent, which is a drug that encourages a patient’s immune system to attack and destroy myeloma cells. Immunomodulatory agents are able to induce immune responses and inhibit inflammation. They also enhance the activity of T cells and natural killer cells, which are specialized white blood cells that help kill cancer cells.

Additionally, Revlimid acts on angiogenesis, a process involving the growth of new blood vessels, to restrict the blood vessel growth necessary for the development of tumors.

Revlimid may also alter the production and activity of cytokines, which are involved in the growth and survival of certain cancer cells. It is believed that Revlimid affects the genes that direct the cell’s growth and activity, particularly those associated with cytokines, apoptosis (cell death), and metabolism.

History

Revlimid, initially known as CC-5013, is a thalidomide analog that was developed by the biopharmaceutical company Celgene to be more potent and cause fewer side effects than thalidomide.

Celgene initiated a series of clinical trials pairing Revlimid with dexamethasone. These studies revealed that the Revlimid-dexamethasone regimen for patients with relapsed or refractory multiple myeloma was superior to the standard treatment of high-dose dexamethasone. As a result, in June 2006 the FDA granted approval of Revlimid for use in combination with dexamethasone.

Nonetheless, the Revlimid-dexamethasone treatment is complicated by high rates of venous thromboembolism, which is the process by which blood clots occur and travel through the veins. Additional clinical trials are currently underway to prevent the Revlimid-associated venous thromboembolism.

Usage in Multiple Myeloma

For the past 10 years, Revlimid has successfully treated both inflammatory disorders and cancers due to its broad range of activities. Revlimid may be used alone or in combination with dexamethasone for treatment of multiple myeloma. The Revlimid-dexamethasone combination has been shown to be more effective than either drug taken alone. This regimen is currently FDA-approved for the treatment of multiple myeloma patients who have received at least one prior therapeutic treatment.

The National Comprehensive Cancer Network (NCCN), which develops cancer treatment guidelines based on clinical trial results, considers Revlimid an appropriate treatment option for recurrent diseases, including multiple myeloma, that prove unresponsive to other treatments. NCCN guidelines also recommend Revlimid-dexamethasone as a possible primary induction therapy for non-transplant candidates.

Revlimid may also be used with Velcade (bortezomib), with or without dexamethasone, in both relapsed and refractory myeloma and in newly diagnosed patients.

The two-drug combination, known as Rev-Vel, appeared to be very effective in a small clinical trial with patients who had received several prior therapeutic treatments. In this study, 73 percent of patients responded to the therapy, and 36 percent of patients experienced significant reductions in monoclonal (M) protein levels. Multiple myeloma is characterized by increased production of M protein, an abnormal monoclonal serum antibody, and a decline in M protein levels is therefore indicative of a successful treatment. The patients in this trial also showed a prolonged response of 39 weeks to this treatment.

Revlimid is currently being studied in combination with several other cancer drugs: torisel (temsirolimus), HuLuc63, dacetuzumab (with dexamethasone), and LBH-589 (with dexamethasone).

Dosage & Administration

Revlimid, which is administered orally, is available in four capsule strengths: 5 mg, 10 mg, 20 mg, and 25 mg. Physicians typically prescribe a starting dose of 25 mg of Revlimid, in combination with 40 mg of dexamethasone, in treatment cycles of 28 days.

Blood counts should be checked every two weeks for the first 12 weeks of therapy and at least monthly thereafter. Treatment may be interrupted based on the results of the blood tests and on the patient’s general condition.

In standard Revlimid-dexamethasone regimens, patients take Revlimid on days 1-21 of each 28-day treatment cycle, with treatment resuming on day 1 of the next 28-day cycle. Patients take dexamethasone on days 1-4, 9-12, and 17-20 of each 28-day treatment cycle for the first four months. Starting at month five, patients only receive dexamethasone on days 1-4 of each month.

Side Effects

A wide range of side effects is possible with Revlimid treatment. Studies have demonstrated the frequency of side effects usually increases as the Revlimid dose is increased, and higher dosages have been associated with more severe side effects.

Potential side effects associated with Revlimid-dexamethasone treatment are fatigue, muscle cramps, rash, and insomnia.

Patients are recommended to exercise regularly and to eat and drink proper amounts in order to avoid fatigue. It is important to get sufficient rest to build up energy.

Patients may also experience muscle cramps, which are sudden pains that resemble a tightening or hardening in the muscle, and are recommended to speak with a physician immediately.

Another common side effect is rash, which may range in severity from mild irritation to obvious changes in skin color. Several cases of Stevens-Johnson syndrome and toxic epidermal necrolysis have been reported in patients taking Revlimid, though it is not yet clear whether Revlimid is the cause. Because these conditions are life-threatening, patients should contact a physician immediately upon noticing any unusual rash or skin reaction.

Revlimid may also cause chronic sleep disturbances, which may lead to irritability, problems concentrating, depression, and anxiety.

Patients taking Revlimid with dexamethasone may experience gastrointestinal disorders, including constipation and diarrhea. Although the risk of severe constipation is low for these patients, mild constipation may be reduced or eliminated by exercising regularly, drinking plenty of water, and maintaining a high-fiber diet.

Recent studies have indicated that patients taking Revlimid-dexamethasone for an extended period of time (longer than eight months) experience significantly more diarrhea than patients taking dexamethasone alone. For the majority of patients, the diarrhea started after treatment had elapsed for 19 months. Patients experiencing diarrhea should inform their physician as soon as possible so it can be treated. The symptoms of diarrhea may be minimized by eating small, frequent meals and avoiding dairy products, spicy foods, caffeinated and carbonated foods and drinks, and high-fiber and high-fat foods.

More serious side effects associated with Revlimid are low blood counts and deep vein thrombosis.

Patients undergoing Revlimid-dexamethasone treatment may experience a decrease in the production of white blood cells (neutropenia), platelets (thrombocytopenia), or red blood cells (anemia). Blood tests should be administered regularly to monitor blood count levels. For patients experiencing neutropenia, a physician may prescribe a growth factor to increase the white blood cell count.

Deep vein thrombosis (DVT) involves blood clot formation in the deep veins of the body, and if a clot dislodges, it may travel to other areas and block blood flow to vital organs. Researchers estimate that approximately 70 percent of all critical blockages of lung blood vessels originate from DVT in the pelvis or lower extremities.

In initial trials of Revlimid-dexamethasone, 11 percent of patients developed serious blood clots, compared to four percent of patients taking only dexamethasone. Due to this increased risk, it is now recommended that all patients undergoing Revlimid-dexamethasone treatment also take blood thinners to reduce the chance of developing blood clots. The most commonly used blood thinner is aspirin, although Coumadin (warfarin) and heparin may also be prescribed.

The most serious side effect associated with Revlimid is the potential for severe birth defects or fetal death. Revlimid is an analog of thalidomide, a known potent human teratogen. Teratogens significantly disturb the development of an embryo or fetus. Although Revlimid has not been tested in pregnant women, it has harmed unborn animals in animal testing.

When taken immediately prior to conception or during pregnancy, Revlimid can cause severe, life-threatening birth defects or fetal death. As part of a restricted-access program discussed in further detail below, patients must practice abstinence or use contraception in order to receive Revlimid.

Drug Interactions

Revlimid has been reported to interact with digoxin, estrogens and progestins (found in birth control pills and hormone replacement therapies), and Coumadin. Patients taking any of these medications are advised to speak with a physician.

In addition, caffeine, alcohol, cigarettes, and street drugs may affect the action of Revlimid. Patients should speak with a physician if they are using any of these drugs in combination with Revlimid.

Precautions

As a result of its severe effects on unborn fetuses, Revlimid is only available under a restricted distribution program known as RevAssist. RevAssist, which involves physicians, patients, and pharmacists, provides a registry for drug use and mandates that patients undergo education and authorization prior to receiving Revlimid. Females of childbearing potential must also undergo routine pregnancy tests prior to prescription of Revlimid.

All females of childbearing potential taking Revlimid must use two separate forms of effective birth control at the same time. In addition, they must initiate contraception at least four weeks prior to therapy.

Because Revlimid may be present in male ejaculate, all males receiving Revlimid must abstain from heterosexual contact or use a latex condom during sexual contact with a woman who is or could become pregnant. Male patients must not donate sperm while taking Revlimid and for at least four weeks following the end of treatment.

Ongoing Clinical Trials

Open

Phase 2:

• Weill Medical College of Cornell University: Phase 2 Study of Thalidomide, Clarithromycin (Biaxin), Revlimid, and Dexamethasone for Newly Diagnosed Multiple Myeloma (T-BiRD) (NCT00538733)
• New York University School of Medicine: Combination of Revlimid, Melphalan (Alkeran) and Dexamethasone as First Line Treatment for Multiple Myeloma (NCT00843310)

Phase 3:

• National Cancer Institute (NCI): Revlimid and Dexamethasone With or Without Velcade (bortezomib) in Treating Patients With Previously Untreated Multiple Myeloma (NCT00644228)
• Gesellschaft fur Medizinische Innovation: Comparison of 25mg Versus 5 mg Revlimid as Maintenance Therapy in Patients With Multiple Myeloma (NCT00891384)

Closed

Phase 2:

• Weill Medical College of Cornell University: Phase 2 Study of Clarithromycin (Biaxin), Revlimid, and Dexamethasone for Untreated Multiple Myeloma (NCT00151203)
• National Cancer Institute of Canada: Revlimid and Melphalan in Treating Patients With Previously Untreated Multiple Myeloma (NCT00305812)

Phase 3:

• National Cancer Institute (NCI): Revlimid and Dexamethasone With or Without Thalidomide in Treating Patients With Multiple Myeloma (NCT00098475)
• National Cancer Institute (NCI): Dexamethasone With or Without Revlimid in Treating Patients With Previously Untreated Stage I, Stage II, or Stage III Multiple Myeloma (NCT00064038)

For a more detailed listing of clinical trials involving Revlimid, please check the U.S. government’s clinical trials Web site.

Clinical Trial Results

Low-dose Steroid Combined with Revlimid Prolongs Survival Compared with High-dose Steroid for Multiple Myeloma Treatment (2007): Preliminary results from a large, randomized clinical trial for patients with newly diagnosed multiple myeloma has shown that a low dose of the steroid dexamethasone, in combination with Revlimid, is associated with improved survival when compared to a treatment regimen with Revlimid and a higher, standard dose of dexamethasone. More information may be found at the National Cancer Institute’s Clinical Trial Results Web site.

BiRD Combination Therapy Results in High Complete- and Overall-Response Rates in Treatment-Naive Symptomatic Multiple Myeloma (2008): This trial determined the safety and efficacy of the combination regimen clarithromycin (Biaxin)-Revlimid-dexamethasone (BiRD) as first-line therapy for multiple myeloma. A combined complete response rate of 39 percent was achieved, and 74 percent of the patients achieved at least a 90 percent decrease in protein levels. The major adverse events were venous thromboembolism, dexamethasone-related morbidity, and cytopenia, or a reduction in blood cell production. The full description of trial results may be found in the journal Blood.

Revlimid, doxorubicin (Adriamycin), and Dexamethasone (RAD) in Patients with Relapsed and Refractory Multiple Myeloma (2009): Researchers conducted a phase 1-2 trial combining Revlimid with doxorubicin and dexamethasone for relapsed and relapsed-refractory myeloma to determine tolerability and efficacy of this novel regimen, delivered for six 28-day cycles. The overall response rate was 73 percent for the whole study. For participants receiving the highest dose (25 mg Revlimid, 9 mg adriamycin, 40 mg dexamethasone, 6 mg pegfilgrastim),, the overall response rate was 77 percent, with 74 percent attaining a complete response to the treatment. The full description of trial results may be found in the journal Blood.

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雷利米得（来那度胺胶囊）-用于治疗骨髓增生异常综合症

[摘要]  目的 探讨雷那立度胺治疗复发难治性多发性骨髓瘤患者的疗效。方法  对6例使用雷那立度胺的多发性骨髓患者临床资料进行分析。结果: 6例复发难治性多发性骨髓瘤患者接受2个周期雷那立度胺治疗后3例部分缓解，3例进展。结论: 雷那立度胺可有效治疗复发难治性多发性骨髓瘤患者。

[关键词] 雷那立度胺 多发性骨髓瘤

雷那立度胺是一种更为有效的沙立度胺类似物，免疫调节功能更强大且安全性更高，它通过调节肿瘤细胞的微环境及大量的细胞因子而发挥作用，早期的临床研究证实能够有效地治疗复发难治性多发性骨髓瘤[1]。大量随机实验证明雷那立度胺联合地塞米松治疗对传统化疗无效的多发性骨髓瘤患者有较高的疗效。我们用雷那立度胺治疗难治复发性的多发性骨髓瘤患者，现将结果报告如下。

病例和方法

1、病例特点：男性4例，女性2例。年龄53-66岁。1例合并糖尿病，高血压。

非分泌型1例, lgGλ λ轻链双克隆型1例，λ轻链型3例，lgGκ型1例。Ⅲa期3例， Ⅲb期3例。病程为1-5年。

6例患者既往接受过6个周期以上的方案化疗，包括MP （马法兰+强的松），VAD(长春地辛+表阿霉素+地塞米松)，COMP(环磷酰胺+诺唯本+爱克兰+强的松),CTD(异环磷酰胺+反应停+地塞米松)，万珂（单用或联合），反应停（单用或联合）等。其中1例接受过2次自体干细胞移植，1例接受过放疗。均规律使用双磷酸盐。全部病理均在接受多程万珂（6-10次）化疗后病情仍进展或复发时给予雷那立度胺方案化疗。

2、使用方法：2例接受雷那立度胺单用方案（雷那立度胺10-25mg/1-21d），4例接受雷那立度胺联合方案（雷那立度胺20mg /1-21 d，异环磷酰胺 500mg，强的松 60mg1-4 d /第1，3周或地塞米松 10mg 1-4 d /第1，3周 ）。

3、疗效及安全性评价：患者2个疗程后行骨髓细胞学，血清蛋白电泳，免疫球蛋白定量，尿本周氏蛋白定性及定量，免疫固定电泳，血常规，尿常规，肝功能，肾功能，电解质，血糖，x线，B超，心电图等检查。

结果

1、 疗效 

疗效标准；直接指标：1、血清或尿中M蛋白比治疗前减少50%以上，2、浆细胞肿瘤两个最大直径之积缩小50%以上，3、溶骨性损害再钙化。间接指标：1、骨髓中浆细胞减少80%以上或降至<5%  2、血红蛋白上升20g/l 或红细胞压积上升0.06（不输血情况下）持续1个月以上 3、高血钙降至正常 4、血尿素氮降至正常 5、日常生活自理状况改善。

部分缓解的标准：直接指标至少有一项达到要求或间接指标至少有两项达到要求。
2、 不良反应主要为：乏力，胃肠道反应，周围神经炎，血小板，血红蛋白、白细胞不同程度下降。其中1例发生Ⅲ级血液学毒性，将雷那立度胺减量后好转，其它副反应给与对症处理或观察后好转或稳定。均未出现肝功，肾功，心脏，肺等重要脏器的不良反应或加重，未出现深静脉血栓。

讨论

近年来随着对多发性骨髓瘤的发病机制研究日益深入，MM的治疗进展很快，治疗的方法不断增加，疗效也明显提高。除传统化疗，自体干细胞移植外，靶向治疗新药如沙立度胺，硼替佐米，雷那立度胺给MM的治疗带来了新希望，大大提高了完全缓解率，无病生存时间，甚至总生存时间。本文6例MM患者均接受过万珂化疗，其中5例接受过反应停治疗，1例接受过2次自体干细胞移植，但病情最终复发或进展（甚至多次复发），在这种治疗难度非常大的情况下我们给与雷那立度胺治疗，结果3例达到部分缓解，3例进展,说明雷那利度胺的疗效是肯定的。且雷那立度胺的副反应轻微，可通过对症处理减轻或消失。1例出现3级血液学毒性，可能与合并肾功能不全，药物代谢较慢致使药物浓度偏高有关，药物减量后逐渐恢复。

雷那立度胺治疗MM的作用机制与沙立度胺相似[2]：雷那立度胺能够下调肿瘤细胞微环境中的大量促肿瘤细胞生长的细胞因子，同时活化NK细胞及T细胞抗肿瘤的效应。几项临床实验如雷那立度胺联合脂质体阿霉素治疗复发难治MM；雷那立度胺联合克拉霉素，地塞米松作为一线方案治疗新诊断的MM均取得了较好的疗效。万珂+雷那立度胺+地塞米松治疗复发难治或新诊断的临床实验也会提供更多的经验[3]。Weber DM等[4]的研究显示雷那立度胺联合地塞米松与单用地塞米松治疗复发难治MM的CR+nCR+PR率分别为61%和19.9%；中位进展时间分别为11.1月和4.7月；中位总生存时间分别为29.6月和20.2月，P值均小于0.0001；比较严重的副反应主要为中性粒细胞减少，静脉血栓。Niesvizley R[5]的研究发现，肾功能不全患者肌苷清除率与雷那立度胺所致的骨髓抑制时间呈负相关，p<0.0001,对于肾功能不全患者应根据肌苷清除率决定雷那立度胺的初始用量。

雷那立度胺治疗的6例患者既往应用6个周期以上的方案化疗，全部病例均在接受多程硼替佐米治疗复发，疗效显著。患者至少接受了两个周期的雷那立度胺治疗，毒副反应是可以处理的。

综上所述，雷那立度胺可用于治疗复发难治性骨髓瘤患者且仍会取得较好的疗效、副反应较少，可以控制。新药间无明显交叉耐药，为我们治疗多发性骨髓瘤提供了一个新的选择.