FDA已批准药物来那度胺(通用名：lenalidomide)用于治疗患亚型骨髓增生异常综合症（Myelodysplastic Syndrome，MDS）的病人。该亚型是5q缺失染色体异常（deletion 5q cytogenetic abnormality）的MDS病人。 MDS是一种异常的集合，包括骨髓不能正常发挥功能，并且身体不能制造足够的正常血细胞。患MDS的病人可能需要血液和血小板输注及抗生素疗法以抗感染。在临床试验中，接受来那度胺治疗的病人不再需要输血，多数病人3个月内不需要输血。输血免除期平均持续44星期。

“该新产品将为遭受这种罕见病的病人提供非常需要的治疗选择，在一些病例中，这种罕见病被发现已发展成致命型白血病。”FDA的CDER主任Steven Galson医学博士称。 MDS可以在其他疾病的药物疗法或放射疗法后生成，或者在无已知起因的情况下生成。一些类型的MDS可以发展成急性骨髓白血病（AML），一种生成太多白细胞的癌症类型。估计美国每年诊断出7000到12000 个MDS新病例。尽管MDS在所有年龄群发生，但在60岁以上的人群中发病率最高。典型症状包括体虚、疲劳、感染、易瘀伤、出血及发烧。来那度胺结构上类似于反应停（thalidomide），一种已知导致严重出生缺陷的药物。更多研究正在动物中进行，以解决当怀孕期间服用Revlimid是否也有导致出生缺陷的风险。尽管这些研究还在进行中，该公司正在一个称为RevAssist的旨在预防胎儿暴露的风险管理计划下销售来那度胺。

根据RevAssist，只有在该计划中登记的药剂师和处方者能处方和分发来那度胺。该计划要求病人，包括女性病人进行强制性孕期检测，以在开始服用 Revlimid前提供知情同意。医生将检查孕期测试，限制处方为一个月的邮寄供应，并将任何孕期服用报给FDA。当进一步关于出生缺陷的动物测试结果完成时，FDA和生产商将再评价该风险管理计划。来那度胺的标签将包括一个黑框警告（Black Box Warning）和一个关于胎儿暴露预防的药物指南（Medication Guide）。另外的黑框警告包括因血球计数抑制和血栓风险增加而可能需要降低剂量。常见的报道与Revlimid有关的副作用包括血小板减少（低血小板计数）、嗜中性白血球减少症（低白细胞记数）、腹泻、搔痒（痒）、皮疹和疲劳

REVLIMID® (lenalidomide) in combination with dexamethasone is indicated for the treatment of multiple myeloma (MM) patients who have received at least one prior therapy.

REVLIMID® (lenalidomide) is indicated for patients with transfusion-dependent anemia due to Low- or Intermediate-1–risk myelodysplastic syndromes (MDS) associated with a deletion 5q cytogenetic abnormality with or without additional cytogenetic abnormalities.

Important Safety Information
CONTRAINDICATIONS:
Pregnancy Category X:
Lenalidomide is contraindicated in pregnant women and women capable of becoming pregnant. Females of childbearing potential may be treated with lenalidomide provided adequate precautions are taken to avoid pregnancy
Allergic Reactions:
REVLIMID is contraindicated in patients who have demonstrated hypersensitivity (e.g., angioedema, Stevens-Johnson syndrome, toxic epidermal necrolysis) to lenalidomide
WARNINGS AND PRECAUTIONS:
Fetal Risk:
REVLIMID is an analogue of thalidomide, a known human teratogen that causes life-threatening human birth defects. An embryofetal development study in non-human primates indicates that lenalidomide produced malformations in the offspring of female monkeys who received the drug during pregnancy, similar to birth defects observed in humans following exposure to thalidomide during pregnancy. If REVLIMID is used during pregnancy, it may cause birth defects or death to a developing baby
Females of childbearing potential must be advised to avoid pregnancy while on REVLIMID. Two effective contraceptive methods should be used during therapy, during therapy interruptions, and for at least 4 weeks after completing therapy
Male Patients: It is not known whether lenalidomide is present in the semen of patients receiving the drug. Therefore, males receiving REVLIMID must always use a latex condom during any sexual contact with females of childbearing potential, even if they have undergone a successful vasectomy
Reproductive Risk and Special Prescribing Requirements (RevAssist® Program):
Because of this potential toxicity and to avoid fetal exposure, REVLIMID is only available under a special restricted distribution program called "RevAssist." Prescribers and pharmacists registered with the program can prescribe and dispense the product to patients who are registered and meet all the conditions of the RevAssist® program
Hematologic Toxicity—Multiple Myeloma:
REVLIMID can cause significant neutropenia and thrombocytopenia
Patients taking REVLIMID for MM should have their complete blood counts monitored every 2 weeks for the first 12 weeks and then monthly thereafter
In the pooled MM studies Grade 3 and 4 hematologic toxicities were more frequent in patients treated with the combination of REVLIMID and dexamethasone than in patients treated with dexamethasone alone
Patients may require dose interruption and/or dose reduction
Deep Vein Thrombosis:
Venous thromboembolic events (predominantly deep venous thrombosis and pulmonary embolism) have occurred in patients with MM treated with lenalidomide combination therapy and patients with MDS treated with lenalidomide monotherapy
Allergic Reactions:
Angioedema and serious dermatologic reactions including Stevens-Johnson syndrome (SJS) and toxic epidermal necrolysis (TEN) have been reported. These events can be fatal. Patients with a prior history of Grade 4 rash associated with thalidomide treatment should not receive REVLIMID. REVLIMID interruption or discontinuation should be considered for Grade 2-3 skin rash. REVLIMID must be discontinued for angioedema, Grade 4 rash, exfoliative or bullous rash, or if SJS or TEN is suspected, and should not be resumed following discontinuation for these reactions
Tumor Lysis Syndrome:
Fatal instances of tumor lysis syndrome have been reported during treatment with lenalidomide. The patients at risk of tumor lysis syndrome are those with high tumor burden prior to treatment. These patients should be monitored closely and appropriate precautions taken
Tumor Flare Reaction:
Tumor flare reaction has occurred during investigational use of lenalidomide for chronic lymphocytic leukemia (CLL) and lymphoma, and is characterized by tender lymph node swelling, low grade fever, pain and rash. Treatment of CLL or lymphoma with lenalidomide outside of a well-monitored clinical trial is discouraged
DRUG INTERACTIONS:
Erythropoietic agents, or other agents, that may increase the risk of thrombosis, such as estrogen containing therapies, should be used with caution in MM patients receiving lenalidomide with dexamethasone
USE IN SPECIAL POPULATIONS:
Nursing Mothers:
It is not known whether REVLIMID is excreted in human milk
Because of the potential for adverse reactions in nursing infants, a decision should be made whether to discontinue nursing or the drug, taking into account the importance of the drug to the mother
Geriatric Use:
Since elderly patients are more likely to have decreased renal function, care should be taken in dose selection. Monitor renal function
Renal Impairment:
Since REVLIMID is primarily excreted unchanged by the kidney, adjustments to the starting dose of REVLIMID are recommended to provide appropriate drug exposure in patients with moderate or severe renal impairment (CLcr < 60 mL/min) and in patients on dialysis
ADVERSE REACTIONS:
Multiple Myeloma
In the REVLIMID/dexamethasone treatment group, 269 patients (76%) underwent at least one dose interruption with or without a dose reduction of REVLIMID compared to 199 patients (57%) in the placebo/dexamethasone treatment group
Of these patients who had one dose interruption with or without a dose reduction, 50% in the REVLIMID/dexamethasone treatment group underwent at least one additional dose interruption with or without a dose reduction compared to 21% in the placebo/dexamethasone treatment group
Most adverse events and Grade 3/4 adverse events were more frequent in MM patients who received the combination of REVLIMID/dexamethasone compared to placebo/dexamethasone
Adverse reactions reported in ≥15% of MM patients (REVLIMID/dexamethasone vs dexamethasone/placebo): fatigue (44% vs 42%), neutropenia (42% vs 6%), constipation (41% vs 21%), diarrhea (39% vs 27%), muscle cramp (33% vs 21%), anemia (31% vs 24%), pyrexia (28% vs 23%), peripheral edema (26% vs 21%), nausea (26% vs 21%), back pain (26% vs 19%), upper respiratory tract infection (25% vs 16%), dyspnea (24% vs 17%), dizziness (23% vs 17%), thrombocytopenia (22% vs 11%), rash (21% vs 9%), tremor (21% vs 7%), weight decreased (20% vs 15%), nasopharyngitis (18% vs 9%), blurred vision (17% vs 11%), anorexia (16% vs 10%), and dysgeusia (15% vs 10%)
Myelodysplastic Syndromes
Thrombocytopenia (61.5%; 91/148) and neutropenia (58.8%; 87/148) were the most frequently reported adverse events observed in the del 5q MDS population
Other adverse events reported in ≥15% of del 5q MDS patients (REVLIMID): diarrhea (49%), pruritus (42%), rash (36%), fatigue (31%), constipation (24%), nausea (24%), nasopharyngitis (23%), arthralgia (22%), pyrexia (21%), back pain (21%), peripheral edema (20%), cough (20%), dizziness (20%), headache (20%), muscle cramp (18%), dyspnea (17%), pharyngitis (16%), epistaxis (15%), asthenia (15%), upper respiratory tract infection (15%)
DOSAGE AND ADMINISTRATION:
Treatment is continued or modified based upon clinical and laboratory findings. Dosing modifications are recommended to manage Grade 3 or 4 neutropenia or thrombocytopenia or other Grade 3 or 4 toxicity judged to be related to REVLIMID
For other Grade 3 or 4 toxicities judged to be related to REVLIMID, hold treatment and restart at next lower dose level when toxicity has resolved to ≤Grade 2
Please see full Prescribing Information, including Boxed WARNINGS, CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS, and ADVERSE REACTIONS.

一：雷利度胺的化学特性
雷利度胺，沙利度胺的类似物，化学名是3-（4-氨基-1-含氧 1，3-二氢-2H-异吲哚-2-黄色）哌啶-2，6-土为四。化学式 C13H13N3O3 , 克分子量259.3。

二：雷利度胺治疗多发性骨髓瘤的作用机制

雷利度胺通过多种机制抑制骨髓瘤细胞的生长。
1、雷利度胺直接诱导骨髓瘤细胞G1期生长停滞，甚至诱导耐药瘤细胞的凋亡。
2、雷利度胺抑制骨髓瘤细胞与骨髓基质细胞的黏附，克服细胞黏附诱导的药物抵抗（CAM-DR）。
3、雷利度胺抑制骨髓瘤细胞和骨髓基质细胞的生物学活性，抑制细胞因子的分泌（IL-6, IL-1β,IL-10, TNFα），这些细胞因子在促进骨髓瘤细胞的生存，生长，药物抵抗，迁移，粘附分子表达等方面发挥重要作用。雷利度胺抑制LPS（脂多糖）刺激单核细胞分泌TNFα/IL-1β的作用是反应停的几千倍。
4、雷利度胺抑制骨髓瘤细胞和骨髓基质细胞分泌VEGF（血管内皮生长因子），bFGF（碱性成纤维细胞生长因子），抑制血管新生。

雷利度胺也通过免疫调节作用如增强细胞毒T细胞，NK细胞的作用（分泌IL-2，INF-r）治疗骨髓瘤。雷利度胺还能够抑制破骨细胞的产生。

1、对骨髓瘤细胞的直接作用：

Mitsiades N [1] 等研究发现雷利度胺诱导骨髓瘤细胞G0/G1期生长停滞与p21上调和/或casepase-8活化介导的凋亡有关。

等研究显示雷利度胺还通过抑制LPS介导Cox-2和PEG2的产生发挥抗肿瘤作用。Mitsiades[3]还发现雷利度胺能够抑制NF-κb的活性，NF-κb在骨髓瘤细胞的细胞周期调节，细胞生存，抗凋亡，细胞因子的产生发挥重要作用，因此雷利度胺可以通过抑制NF-κb治疗骨髓瘤，并且还发现NF-κb活性受抑制能够增强和恢复对其它化疗药物的敏感性。Stewart [4]等报告Wnt信号拮抗剂DKK-1与雷利度胺的免疫调节作用有关。此外雷利度胺还能下调骨髓瘤细胞中β-catenin（β-连锁蛋白）的表达。β-catenin作为Wnt信号传导通路中的重要成员，与骨髓瘤侵袭和转移有关。
2、抗血管新生作用：

雷利度胺通过对内皮细胞功能的多种抑制作用来抑制血管新生和转移：发现雷利度胺以剂量依赖的方式持续地抑制动脉环血管芽和内皮细胞索带的形成。还发现雷利度胺抑制钙粘蛋白5，β-连环蛋白， CD31，黏附功能蛋白之间的结合（它们对内皮细胞索带形成发挥重要作用）。研究还发现雷利度胺抑制VEGF诱导的PI3K-Akt（磷脂酰肌醇3激酶/蛋白激酶B）信号途径，该途径调节粘连结合的形成。也可以通过影响生长因子诱导的Akt 磷酸化来抗血管新生。

3、免疫调节作用：
雷利度胺比沙利度胺能更有效地刺激T细胞增殖，减少肿瘤坏死因子（TNF-a）和白介素-6的产生。雷利度胺刺激T细胞增殖的作用是沙利度胺的50-2000倍。增加白介素-2及IFN-γ的产生是反应停的50-100倍。

研究发现雷利度胺对LPS刺激的单核细胞有抗炎作用（减少TNF-а的产生），对抗-CD3刺激的T细胞有共刺激作用（促进T细胞增殖及促炎性细胞因子产生），增强NK细胞抗瘤细胞的细胞毒作用。该研究还发现雷利度胺强烈地抑制T调节细胞的增殖和抑制功能。抑制IL-2介导的FOXP3阳性CTLA-4阳性CD25(高)CD4+T调节细胞，雷利度胺通过这种机制可能会克服肿瘤患者的肿瘤特异性免疫的屏障。
CD1d-限制性自然杀伤细胞（iNKT ）是抗肿瘤免疫反应中重要的免疫调节细胞，进展性多发性骨髓瘤由于iNKT 细胞的数量和功能的缺陷阻碍了它的抗肿瘤作用。CD1d-限制性iNKT细胞系产生大量的抗肿瘤细胞因子Th1，具有强大的抗骨髓瘤细胞的细胞毒作用。雷利度胺通过增加Th1细胞因子和减少Th2细胞因子从而增强iNKT细胞系的Th1极化作用。

Lenalidomide Generic Name: Lenalidomide (LEN-a-LID-oh-mide)Brand Name: Revlimid
Lenalidomide may cause severe birth defects or death of the fetus if used during pregnancy. Lenalidomide is similar to thalidomide, which causes life-threatening birth defects.

Females who are able to become pregnant and who take Lenalidomide :

must not become pregnant;
must avoid sexual contact with men or use at least 2 forms of effective birth control for 4 weeks before starting Lenalidomide , while taking Lenalidomide , during dose interruptions, and for 4 weeks after stopping Lenalidomide ;
must have a negative pregnancy test 10 to 14 days before starting Lenalidomide and again within 24 hours before starting Lenalidomide ; and
must have a pregnancy test every week for the first 4 weeks after starting Lenalidomide and then every 2 to 4 weeks thereafter while using Lenalidomide .
Women who experience abnormal menstrual bleeding, miss their menstrual period, become pregnant, or suspect for any reason they may be pregnant while taking Lenalidomide must stop taking it and contact their doctor immediately.

Males who take Lenalidomide :

must either avoid sexual contact with women who are pregnant or could become pregnant while taking Lenalidomide and for 4 weeks after stopping Lenalidomide ; OR
must use a latex condom during sexual contact with women who are pregnant or could become pregnant for as long as they are taking Lenalidomide and for 4 weeks after stopping Lenalidomide , even if they have had a successful vasectomy.
Men who have unprotected sexual contact with a woman who is pregnant or may become pregnant or who thinks for any reason that their sexual partner may be pregnant should contact their doctor immediately.

All patients who take Lenalidomide :

It is not known if Lenalidomide passes into semen. Female partners of men taking Lenalidomide should call their doctor if they become pregnant.
All patients must receive and understand all oral and written warnings about the risks of using Lenalidomide .
All patients must be able to follow the instructions for using Lenalidomide and for using effective birth control methods if they are sexually active.
Lenalidomide may cause an increased risk of blood clots in the veins and lungs. Call your doctor right away if you experience shortness of breath, chest pain, or pain or swelling in the arms or legs.
Lenalidomide often lowers the number of white blood cells and platelets in the blood. Call your doctor right away if you experience unusual bleeding or bruising, fever, chills, or sore throat.
Blood counts should be checked each week for the first 8 weeks after starting Lenalidomide and at least once a month thereafter. If low blood counts develop, it may be necessary to lower the dose or stop treatment. Sometimes blood transfusions and treatment with other medicines may be necessary. Keep all doctor and lab appointments while using Lenalidomide .
Lenalidomide is used for:
Treating anemia in patients who have certain types of myelodysplastic syndrome (MDS). It is also used along with dexamethasone to treat a certain type of cancer (multiple myeloma) in certain patients.

Lenalidomide is an immunomodulatory medicine. Exactly how it works is not known.

Do NOT use Lenalidomide if:
you are allergic to any ingredient in Lenalidomide
you are pregnant, planning to become pregnant, could become pregnant, or become pregnant during treatment with Lenalidomide
you have had a severe allergic reaction (eg, rash; hives; hoarseness; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue) or a severe rash (eg, red, swollen, blistered, or peeling skin) from Lenalidomide in the past.
Contact your doctor or health care provider right away if any of these apply to you.

Before using Lenalidomide :
Some medical conditions may interact with Lenalidomide . Tell your doctor or pharmacist if you have any medical conditions, especially if any of the following apply to you:

if you are breast-feeding
if you are taking any prescription or nonprescription medicine, herbal preparation, or dietary supplement
if you have allergies to medicines, foods, or other substances
if you have kidney problems or if you receive dialysis
Some MEDICINES MAY INTERACT with Lenalidomide . However, no specific interactions with Lenalidomide are known at this time.

This may not be a complete list of all interactions that may occur. Ask your health care provider if Lenalidomide may interact with other medicines that you take. Check with your health care provider before you start, stop, or change the dose of any medicine.

How to use Lenalidomide :
Use Lenalidomide as directed by your doctor. Check the label on the medicine for exact dosing instructions. Check the label on the medicine for exact dosing instructions.

Lenalidomide comes with an extra patient information sheet called a Medication Guide. Read it carefully. Read it again each time you get Lenalidomide refilled.
Lenalidomide can only be prescribed and dispensed through a special program. Make sure you understand all warnings and instructions for using Lenalidomide . Ask your doctor or pharmacist if you have any questions about this program or the use of Lenalidomide .
Lenalidomide may be taken with or without food.
Swallow Lenalidomide whole with water. Do not break, crush, or chew before swallowing.
Women who are able to become pregnant (including those who have started menopause within the last 24 months) must use at least 2 methods of effective birth control while taking Lenalidomide , unless they are not sexually active. These birth control methods must be used for at least 4 weeks before starting Lenalidomide , while taking Lenalidomide , during dose interruptions, and for 4 weeks after stopping Lenalidomide . Talk with your doctor about which methods of effective birth control may be appropriate for you.
Men who take Lenalidomide must use a latex condom during any sexual contact with a woman who is pregnant or could become pregnant for as long as they are taking Lenalidomide and for 4 weeks after stopping Lenalidomide . This includes men who have had a vasectomy.
If you miss a dose of Lenalidomide , take it as soon as you remember that day. If you do not remember until the next day, skip the missed dose and go back to your regular dosing schedule. Do not take 2 doses at once.
Ask your health care provider any questions you may have about how to use Lenalidomide .

Important safety information:
Lenalidomide may cause dizziness. This effect may be worse if you take it with alcohol or certain medicines. Use Lenalidomide with caution. Do not drive or perform other possibly unsafe tasks until you know how you react to it.
Lenalidomide may reduce the number of clot-forming cells (platelets) in your blood. Avoid activities that may cause bruising or injury. Tell your doctor if you have unusual bruising or bleeding. Tell your doctor if you have dark, tarry, or bloody stools.
Lenalidomide may lower the ability of your body to fight infection. Avoid contact with people who have colds or infections. Tell your doctor if you notice signs of infection like fever, sore throat, rash, or chills.
Lenalidomide may increase the risk of blood clots in certain patients. Tell your doctor at once if you notice shortness of breath; chest pain; or pain, tenderness, or swelling of an arm or leg.
Do not donate semen, sperm, or blood while taking Lenalidomide or within 4 weeks after stopping Lenalidomide .
Inform your doctor if you are taking an HIV protease inhibitor (eg, ritonavir); griseofulvin, rifampin, rifabutin, penicillin, amoxicillin, ampicillin, or other antibiotic medicines; St. John's wort; modafinil; phenytoin; or carbamazepine because these medicines may decrease the effectiveness of hormonal contraceptives (eg, birth control pills).
Lab tests, including pregnancy tests and complete blood cell counts, may be performed while you use Lenalidomide . These tests may be used to monitor your condition or check for side effects. Be sure to keep all doctor and lab appointments.
Use Lenalidomide with caution in the ELDERLY; they may be more sensitive to its effects.
Lenalidomide should be used with extreme caution in CHILDREN younger than 18 years old; safety and effectiveness in these children have not been confirmed.
PREGNANCY and BREAST-FEEDING: Use of Lenalidomide during pregnancy may cause severe birth defects and death of the fetus. If you think you may be pregnant, miss your menstrual period, experience unusual menstrual bleeding, or stop using birth control, contact your doctor at once. If you become pregnant while using Lenalidomide , consult an obstetrician/gynecologist experienced in reproductive toxicity. It is not known if Lenalidomide is found in breast milk. Do not breast-feed while taking Lenalidomide .
Possible side effects of Lenalidomide :
All medicines may cause side effects, but many people have no, or minor, side effects. Check with your doctor if any of these most COMMON side effects persist or become bothersome:

Back pain; constipation; cough; diarrhea; dizziness; dry mouth or skin; headache; increased sweating or night sweats; loss of appetite; nausea; stuffy or runny nose; tiredness; trouble sleeping; vomiting; weakness.

Seek medical attention right away if any of these SEVERE side effects occur:
Severe allergic reactions (rash; hives; hoarseness; itching; difficulty breathing; tightness in the chest; swelling of the mouth, face, lips, or tongue); blood in the stools or vomit; chest pain; dark urine; fast, slow, or irregular heartbeat; fever, chills, or sore throat; muscle cramps; muscle or joint pain; pain, numbness, tingling, tenderness, or swelling of the arms or legs; painful or difficult urination; red, swollen, blistered, or peeling skin; severe tiredness or weakness; shortness of breath; stomach pain; unusual bruising or bleeding.

This is not a complete list of all side effects that may occur. If you have questions about side effects, contact your health care provider. Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. You may also report side effects at http://www.fda.gov/medwatch.

If OVERDOSE is suspected:
Contact 1-800-222-1222 (the American Association of Poison Control Centers), your local poison control center (http://www.aapcc.org ), or emergency room immediately.

Proper storage of Lenalidomide :
Store Lenalidomide at 77 degrees F (25 degrees C). Brief storage at temperatures between 59 and 86 degrees F (15 and 30 degrees C) is permitted. Store away from heat, moisture, and light. Do not store in the bathroom. Keep Lenalidomide out of the reach of children and away from pets.