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1 대한내과학회지 : 제 88 권제 3 호 특집 (Special Review) - 혈액종양의새로운치료 다발골수종의새로운치료약제들 한림대학교의과대학한림대학교성심병원내과 김효정 Novel Agents for Treatment of Multiple Myeloma Hyo Jung Kim Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, Anyang, Korea Multiple myeloma (MM) is a neoplasm of clonal plasma cells that closely interacts with the bone marrow (BM) microenvironment. The overall survival of patients with MM has improved dramatically in the last 20 years, due primarily to the development of autologous stem cell transplantation and novel drugs, including a proteasome inhibitor (bortezomib) and immunomodulatory agents (thalidomide and lenalidomide), as well as advances in supportive care. However, this disease remains classified as an incurable hematological malignancy. Understanding the intracellular mechanisms and the interactions between plasma cells and the BM microenvironment has accelerated development of second- and third-generations of old novel agents or new agents with novel targeted mechanisms of action, such as monoclonal antibodies, cell cycle-specific drugs, and deacetylase inhibitors. Among them, carfilzomib and pomalidomide have been approved for treating patients with relapsed/refractory MM. Results of ongoing preclinical and clinical trials of novel agents provide hope for continuous improvements and a cure for MM in the near future. (Korean J Med 2015;88: ) Keywords: New drugs; Multiple myeloma 서론다발골수종은형질세포의악성종양으로골수에서증식하며골파괴와빈혈, 고칼슘혈증, 신장기능장애등의임상증상을특징으로한다. 1958년이후 30-0년간 melphalan, prednisone 요법을근간으로다발골수종의치료가이루어졌으나이후자가조혈모세포이식술, 면역중재약제 (immunomodulatory drugs, IMiDs) 인 thalidomide, lenalidomide와 proteasome 억제제인 bortezomib이개발되어 (Fig. 1) 이러한약제들을이용한치료는과거에비해반응률, 무진행생존율과전체생존율의유의한개선을이루어왔다 [1,2]. 일례로메이요클리닉다발골수종코호트연구에서자가조혈모세포이식후재발한환자들중 2000년이후신약사용이가능했던환자들은그이전재발한환자들에비해중앙전체생존기간이 Correspondence to Hyo Jung Kim, M.D., Ph.D. Department of Internal Medicine, Hallym University Sacred Heart Hospital, Hallym University College of Medicine, 22 Gwanpyeong-ro 170beon-gil, Dongan-gu, Anyang , Korea Tel: , Fax: , hemonc@hallym.or.kr Copyright c 2015 The Korean Association of Internal Medicine This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( which permits unrestricted noncommercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

2 - Hyo Jung Kim. Novel agents for multiple myeloma - 연구분야이나본논문에서는주로다발골수종신약에대한 2, 3상임상시험결과가확인되어현재또는머지않은미래에주된치료제가될가능성이높은약제들을중심으로소개하고자한다. 본 론 Figure 1. Timeline of treatments for multiple myeloma. 23.9개월대 11.8개월 (p < 0.001) 로개선되었고, 새로진단받은다발골수종환자에서는 1997년전후를기준으로전체생존기간의 50% 개선 (29.9개월대.8개월, p < 0.001) 이보고되어다발골수종치료의새로운시대가도래했음을확인할수있었다 [1]. 또 2001년부터 10년간진단된다발골수종환자들을대상으로한다른코호트에서도전반 5년에비해신약들을좀더보편적으로 1차약제로사용하기시작한 2006 년부터의후반 5년간진단된환자들의중앙생존기간이.6 년대 6.1년으로향상되었고 (p = 0.002), 특히이식이어려운 65세이상의환자들에서 6년생존율이 31% 대 56% 로개선되어 (p = 0.002) 신약들의효과를임상시험군이아닌실제일반진료에서도확인할수있게되었다 [2]. 그러나이제 오래된신약 이라고칭할수있는약제들중 bortezomib은최근피하주사투입으로빈도가감소되었으나 [3] 말초신경염의발생과주 1-2회치료의번거로움, thalidomide와 lenalidomide는색전 / 혈전증의위험, thalidomide의말초신경염, lenalidomide의이차원발암 (second primary malignancy) 등약제사용에수반될수있는장애물과더불어궁극적으로종양세포약제내성의발생으로아직도상당수의환자는재발 / 불응 (relapsed/refractory) 상태로진행하게된다. 또한 IMiDs와 bortezomib 에모두불응상태인다발골수종환자는특히더예후가좋지않음이알려져있다 []. 따라서이를극복하기위한많은연구들이진행되면서더욱새로운신약후보들이발굴되어전임상및임상시험이활발히진행중이다. 이들은크게두군으로나뉘게되는데기존에사용하고있는약제들을기반으로개선된 2, 3세대신약군과다발골수종의병태생리기전에대한이해를기반으로개발된표적치료제이다. 또한단일약물의효과뿐아니라이론적으로약물협동작용 (drug synergy) 을기대할수있는약제간의병합요법도중요한연구주제이다. 다발골수종에대한신약의개발은지난 15년간눈부시게발전하여상전벽해의첨단 새로운 proteasome 억제제 Carfilzomib 은 epoxyketone 기반의 2세대 proteasome 억제제로서 20S proteasome의 chymotrypsin-유사 (β5) 소단위의활동을선택적으로억제하며다른 proteasome 억제제와상호교차작용이적은약제이다. Carfilzomib의 proteasome 억제기능은비가역적이며체내 (in vivo) 와체외 (in vitro) 에서모두용량및시간에의존적으로반응한다. 그결과종양세포내에 polyubiquitine화된단백질이축적되며세포자멸사 (apoptosis) 가유도된다 [5]. Bortezomib 을사용한적이없는재발 / 불응다발골수종환자에서 carfilzomib 단독요법을시행한 PX 연구에서 52.2% 의전체반응률 (overvall response rate) 과 13.1개월의중앙반응유지기간 (median response duration) 을보였다 [6]. 또한이전치료요법의중앙값이 5회인 266명의재발 / 불응다발골수종환자에게 carfilzomib 단독으로치료한 PX A1연구는 bortezomib과 lenalidomide에불응이거나부작용을감내할수없었던환자들이 80% 를차지하고있었으나 23.7% 의전체반응률과 7.8개월의중앙반응유지기간의우수한성적을보여 [7] 재발 / 불응다발골수종환자의탈출구가되어줄신약으로서의입지를다지게되었다. Carfilzomib을단독으로사용한 개의 2상임상시험에서발표된 526명의재발 / 불응환자들의부작용자료를모아분석한보고에따르면피로 (56%), 빈혈 (7%), 구역 (5%) 이가장흔한증상이었다. 비혈액학적부작용의대부분은 1/2도로경증이었으며 3/도의심한부작용은대부분이혈액관련결과이며가역적인소견을보였다. 그러나말초신경염은 1% 로 bortezomib 에비해상대적으로낮게발생한것과 7% 환자들에서심부전이발생한것이특이할만한소견이었다 [8]. 현재진행중인 carfilzomib 3상임상연구인 ENDEAVOR ( 재발한환자에서 carfilzomib + dexamethasone 대 bortezomib + dexamethasone 비교 ) 와 FOCUS ( 재발 / 불응환자에서 carfilzomib 대최상의지지적치료비교 ) 연구결과는 carfilzomib 단독요법의역할

3 - 대한내과학회지 : 제 88 권제 3 호통권제 655 호 에대한확답을줄수있을것이다. 재발 / 진행다발골수종환자에서표준요법중하나인 lenalidomide + dexamethasone (Rd) 에 carfilzomib을추가한 (CRd) 2상임상시험인 PX 에서전체반응률 77% 와중앙반응유지기간 22개월의괄목할만한성적을바탕으로 [9] 792명의재발다발골수종환자에서 CRd 요법과 Rd 요법을비교한 3 상임상시험의중간보고가최근발표되었다 [10]. CRd군대 Rd군의전체반응률 (overall response rate) 87% 대 67% (p < 0.001), 중앙무진행생존기간 (median progression free survival) 26.3개월대 17.6개월 (p = ), 2개월전체생존율 (overall survival) 73% 대 65% (p = 0.0) 로 CRd군이우월함을확인할수있었다. 앞으로장기추적을시행했을때중앙전체생존율의개선이확인된다면 CRd는재발다발골수종의표준치료요법의하나가될수있을것이다. 이러한결과들을바탕으로 2012년미국 FDA에서는 bortezomib과 IMiDs 의 2차이상의전치료를받고마지막치료에불응상태인다발골수종의치료에 carfilzomib의사용을허용하였다. 재발 / 불응다발골수종치료의좋은결과들을바탕으로 carfilzomib + cyclophosphamide + dexamethasone과병합요법으로 58명의새로진단된다발골수종환자에사용한 2상임상시험결과가최근발표되었는데 95% 의전체반응률및 9% 에서근완전반응 (near complete response [ncr]) 이상의높은반응률과 2년무진행생존율과전체생존율이각각 76% 와 87% 로고무적인결과를보였다 [11]. 그외에도새로진단 된다발골수종치료에 CRd, carfilzomib + thalidomide + dexamethasone 요법등다양한복합요법의임상시험들이진행중으로 1차요법으로서의 carfilzomib에대한연구결과들의귀추가주목된다. Carfilzomib의유사구조체인 proteasome 억제제 oprozomib, bortezomib과같이 boron산을바탕으로한 ixazomib 등새로운경구용약제들의임상시험들도진행중이다. 새로운 IMiDs Pomalidomide는면역중재약제인 thalidomide의유도체로서직접적으로다발골수종세포의증식과혈관형성및종양세포를지지하는골수미세환경을억제하는것이체내및체외실험으로확인되었고 [12-1] 쥐각막모델에서 thalidomide에비해더강력한혈관형성억제효과를보였다 [13]. 또한 pomalidomide는자연살해세포 (natural killer cell) 를활성화시키고조절 T세포 (regulatory T cell) 를억제하여다발골수종에대한면역반응을증강시키는강력한면역중재효과를지녔다 [1]. 최근 cereblon으로알려진 (thalidomide의부작용인기형발생의일차적인표적 ) 물질이 lenalidomide 나 pomalidomide 의약제효과발생에필요하다는것이보고되었다 [1,15]. 2상임상시험결과들에서 pomalidomide와 dexamethasone 의병용요법은재발또는불응의다발골수종환자들의 1/3 에서부분반응 (partial response) 이상의효과와무진행생존기간이 개월로우수한성적을보여줌으로써 [16-20] (Table 1), Table 1. Clinical trials with pomalidomide in patients with relapsed/refractory multiple myeloma Reference Phase ± Dex n Prior lines Dose (mg) Schedule ORR PR (%) PFS (mon) OS (mon) [16] II Dex 60 2 (all 3) % d [17] II Dex 3 a (1-7) [18] II Dex 78% d Dex 67% d [19] II Dex Dex [20] II No Dex [21] III Pom Dex HD Dex 35 b 6 (3-9) 35 b 6 (2-11) 3 b 5 (1-13) 1 b 5 (2-10) c 5 (1-13) 113 c 302 a 5 (1-17) 153 a 5 (2-17) Dex, dexamethasone; ORR, overall response rate; PR, partial response; PFS, progression-free survival; OS, overall survival; Pom Dex, pomalidomide + dexamethasone; HD Dex, high dose dexamethasone. a Lenalidomide-refractory patients. b Lenalidomide and bortezomib refractory. c Previous lenalidomide and bortezomib. d OS at 6 months

4 - 김효정. 다발골수종의신약들 - 2차이상의전치료를받은다발골수종환자에서마지막에받은치료의반응이질병진행 (progressive disease) 상태인경우 2013년미국 FDA와유럽 European Medicines Agency (EMA) 에서는각각 pomalidomide 단독요법과 pomalidomide + dexamethasone 병합요법을허용하였다. 우리나라에서도 pomalidomide는 201년부터위와동일조건으로희귀의약품사용이지정되었다. 2상임상결과를바탕으로 bortezomib과 lenalidomide에실패한환자들에서 pomalidomide + dexamethasone군과고용량 dexamethasone 단독군으로무작위배정 3상비교임상시험인 MM-003 연구가진행되었다 [21]. 추적기간중앙값 10개월시점의무진행생존기간은병용요법군에서질병진행률이 52% 감소 ( 무진행생존기간 개월대 1.9개월, 위험비 = 0.8; 95% confidence interval [CI] ; p < 0.001) 하였고전체생존기간은 12.7개월대 8.1개월 ( 위험비 = 0.7; 9% CI ; p = 0.03) 로향상되었다. 분석시점에고용량 dexamethasone군환자들의 50%, 16개월의추적기간시점에는거의모든환자들이구제요법으로 pomalidomide + dexamethasone 를교차치료받았으므로분석시점에서 pomalidomide + dexamethasone 병합요법전체생존율의실제효과는과소평가되었을가능성도있겠다. Pomalidomide의약제안전성은 lenalidomide와유사하여대부분의고도독성반응은혈액관련부작용이었다. 현재 pomalidomide와 dexamethasone의병합요법외에도최상의조합을찾기위해다양한약제들 (carfilzomib, bortezomib, clarithromycin, cyclophosphamide, pegylated liposomal doxorubicin 등 ) 과의병합요법에대한임상시험들이활발히진행중이다. 단클론항체다발골수종의치료를위한신약중최근주목받고있는약제들은단클론항체들로 CS1, CD38, CD0, CD56, CD138, BAFF, IL6, KIR 등다양한타깃에대한다양한항체들이개발되어전임상및임상연구가진행중이다 [22]. 이중에서 elotuzumab 이유망한선두주자로떠오르고있다. CS1은형질세포, 자연살해세포및 CD8+ T세포에발현되는당단백이며 elotuzumab 은 CS1에직접작용하는인화항체 (humanized antibody) 로자연살해세포매개항체의존성세포독성작용 (antibody dependent cellular cytotoxicity) 을유발하는것으로알려져있다 [23]. Elotuzumab 을단독으로사용했을때 의효과는탁월하지않았지만 [2] lenaliomide, dexamethasone 과병합요법으로 elotuzumab 을재발 / 불응환자에적용한 1/2 상임상연구에서는 8% 의부분반응이상, 29개월무진행생존기간의우수한결과가보고되었다 [25]. 현재다발골수종신환과재발 / 불응환자를각각대상으로 lenalidomide + dexamethasone과 lenalidomide + dexamethasone + elotuzumab 의비교 3상임상시험들이진행중이다. CD38 항체인 daratumumab 단독요법도현재임상시험이진행중으로고무적인중간보고가발표된바있다. 알킬화제제 (Alkylator) 알킬화제제는수십년간다발골수종치료의근간이되는약제로현재까지도 melphalan과 cyclophosphamides는중요한병합치료요법중하나이다. Bendamustine은알킬화제에퓨린유사체고리 (purine analog ring) 가결합된화학구조이다. 다발골수종신환을대상으로한 melphalan + prednisone과 bendamustine + prednisone의 3상임상시험에서치료실패까지의기간이유의하게향상된결과가확인되었고 [26], 이를바탕으로현재유럽에서는자가조혈모세포이식이불가능하면서기존의신경병증으로 proteasome 억제제나 thalidomide 사용이어려운다발골수종신환에서 bendamustine 사용이허가되었다. 또한재발 / 불응환자에서단독또는 bortezomib, thalidomide, lenalidomide 등과의병합요법에대한여러 2상임상연구에서도 26-86% 의전체반응률을보이고있으므로 [22] 더나은조합을찾기위해다른신약들과병합요법의여러임상시험들이계속진행되고있다. 탈아세틸화효소억제제 (Deacetylase inhibitors) 탈아세틸화효소억제제는히스톤을과아세틸화시켜유전자발현에영향을주게되며암세포에서종양유전자 (oncogene) 나종양억제유전자 (tumor suppressor gene) 의발현에관여하여항암효과를나타내게된다 [27]. 탈아세틸화효소억제제와약물협동작용이기대되는 bortezomib과의병합요법에대한 1/2상임상시험의기대되는반응률들을바탕으로 [22] vorinostat + bortezomib 과위약 + bortezomib의 3상임상시험 (Vantage 088) 에서중앙무진행생존기간이 7.3개월대 6.8 개월로통계적인의미는있었으나 (p = 0.01) 임상적의의를기대하기어려웠다 [28]. 재발 / 불응다발골수종환자들을대상으로강력한경구전체- 탈아세틸화효소억제제 (pan-deace

5 - The Korean Journal of Medicine: Vol. 88, No. 3, tylase inhibitor) 인 panobinostat 또는위약을 bortezomib + dexamethasone 요법에추가하여 3상비교한연구에서중앙무진행생존기간은 panobinostat 병용군이 11.99개월로 8.08개월인위약병용군에비해유의하게길었다 ( 위험비 0.63, 95% CI , p < ) [29]. 또한전체반응률은유사했으나완전반응률이 27.6% 대 15.5% 로 panobinostat 병용군이유의하게좋은결과를보여주고있다. 부작용은 panobinostat 군에서혈소판및림프구감소, 설사등이더많이발생함을알수있었다. 앞으로장기추적연구를통하여전체생존율의결과를확인하는것이재발 / 불응환자에서이두약제병합요법의유효성여부를확정하게될것이다. 그외의약제들 Kinesin spindle protein 억제제인 Arry-520, aurora kinase A 억제제, CDK 억제제, hsp-90 억제제, AKT 억제제인 perifosine, mtor 억제제, farnesy-transferase 억제제, plitidepsin, vemurafenib, zalypsis, veliparib 등많은약제들이현재전임상또는 1상임상시험중이다. 결 다발골수종의병태생리에대한이해와 실험실에서병상까지 의빠른적용의결과, thalidomide, lenalidomide 와 bortezomib의 1세대약제에재발 / 불응또는부작용으로사용이불가능했던다발골수종환자에서도이제장기생존을기대할수있는약제인 carfilzomib과 pomalidomide를임상에서사용할수있게되었다. 또한단클론항체, kinesin spindle protein 억제제등새로운기전의약들이개발되어앞으로이들약제들의용량및스케줄, 병합요법등의임상결과들을통해현재다발골수종이완치가불가능한병이라는전제조건이머지않은장래에만성혈액질환, 궁극적으로는완치가가능한혈액질환의하나가되기를기대해본다. 중심단어 : 신약 ; 다발골수종 론 REFERENCES 1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood 2008;111: Kumar SK, Dispenzieri A, Lacy MQ, et al. Continued improvement in survival in multiple myeloma: changes in early mortality and outcomes in older patients. Leukemia 201;28: Moreau P, Pylypenko H, Grosicki S, et al. Subcutaneous versus intravenous administration of bortezomib in patients with relapsed multiple myeloma: a randomised, phase 3, non-inferiority study. Lancet Oncol 2011;12: Wang TF, Ahluwalia R, Fiala MA, et al. The characteristics and outcomes of patients with multiple myeloma dual refractory or intolerant to bortezomib and lenalidomide in the era of carfilzomib and pomalidomide. Leuk Lymphoma 201;55: Demo SD, Kirk CJ, Aujay MA, et al. Antitumor activity of PR-171, a novel irreversible inhibitor of the proteasome. Cancer Res 2007;67: Vij R, Wang M, Kaufman JL, et al. An open-label, single-arm, phase 2 (PX ) study of single-agent carfilzomib in bortezomib-naive patients with relapsed and/or refractory multiple myeloma. Blood 2012;119: Siegel DS, Martin T, Wang M, et al. A phase 2 study of single-agent carfilzomib (PX A1) in patients with relapsed and refractory multiple myeloma. Blood 2012;120: Siegel D, Martin T, Nooka A, et al. Integrated safety profile of single-agent carfilzomib: experience from 526 patients enrolled in phase II clinical studies. Haematologica 2013; 98: Wang M, Martin T, Bensinger W, et al. Phase 2 dose-expansion study (PX ) of carfilzomib, lenalidomide, and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood 2013;122: Stewart AK, Rajkumar SV, Dimopoulos MA, et al. Carfilzomib, lenalidomide, and dexamethasone for relapsed multiple myeloma. N Engl J Med 2015;372: Bringhen S, Petrucci MT, Larocca A, et al. Carfilzomib, cyclophosphamide, and dexamethasone in patients with newly diagnosed multiple myeloma: a multicenter, phase 2 study. Blood 201;12: D Amato RJ, Lentzsch S, Anderson KC, Rogers MS. Mechanism of action of thalidomide and 3-aminothalidomide in multiple myeloma. Semin Oncol 2001;28: Lentzsch S, Rogers MS, LeBlanc R, et al. S-3-Aminophthalimido-glutarimide inhibits angiogenesis and growth of B-cell neoplasias in mice. Cancer Res 2002;62: Dimopoulos MA, Leleu X, Palumbo A, et al. Expert panel consensus statement on the optimal use of pomalidomide in relapsed and refractory multiple myeloma. Leukemia 201; 28:

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Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ

Pharmacotherapeutics Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee Univ Application of New Pathogenesis on the Drug Treatment of Diabetes Young Seol Kim, M.D. Department of Endocrinology Kyung Hee University College of Medicine & Hospital E mail : ycell2@yahoo.co.kr Abstract