今日の臨床サポート

多発性骨髄腫

著者: 安倍正博 徳島大学大学院医歯薬学研究部 血液・内分泌代謝内科学分野

監修: 木崎昌弘 埼玉医科大学総合医療センター

著者校正/監修レビュー済:2021/04/07
参考ガイドライン:
患者向け説明資料

概要・推奨   

  1. 無症候性骨髄腫患者に対する従来の化学療法は、生存期間の延長効果は認められなかったが、高リスク無症候性骨髄腫患者に対するレナリドミド+デキサメタゾン療法は予後の改善効果を認めている(推奨度1)。
  1. 若年者症候性骨髄腫患者に対して自家造血幹細胞移植併用大量メルファラン療法は通常量化学療法と比べて無増悪生存期間を延長させると考えられ推奨できる(推奨度1)。
  1. 若年者症候性骨髄腫患者における移植を前提とした寛解導入療法ではボルテゾミブを含むレジメンが推奨される(推奨度1)。
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  1. 再発・難治性の多発性骨髄腫に対するカルフィルゾミブとデキサメタゾンとの2剤併用療法において、週1回カルフィルゾミブ20/70mg/m2+デキサメタゾン併用が、週2回カルフィルゾミブ20/27mg/m2+デキサメタゾン併用に比べ、無増悪生存期間を延長した(推奨度2)。
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薬剤監修について:
オーダー内の薬剤用量は日本医科大学付属病院 薬剤部 部長 伊勢雄也 以下、林太祐、渡邉裕次、井ノ口岳洋、梅田将光による疑義照会のプロセスを実施、疑義照会の対象については著者の方による再確認を実施しております。
※薬剤中分類、用法、同効薬、診療報酬は、エルゼビアが独自に作成した薬剤情報であり、
著者により作成された情報ではありません。
尚、用法は添付文書より、同効薬は、薬剤師監修のもとで作成しております。
※薬剤情報の(適外/適内/⽤量内/⽤量外/㊜)等の表記は、エルゼビアジャパン編集部によって記載日時にレセプトチェックソフトなどで確認し作成しております。ただし、これらの記載は、実際の保険適用の査定において保険適用及び保険適用外と判断されることを保証するものではありません。また、検査薬、輸液、血液製剤、全身麻酔薬、抗癌剤等の薬剤は保険適用の記載の一部を割愛させていただいています。
(詳細はこちらを参照)
著者のCOI(Conflicts of Interest)開示:
安倍正博 : 講演料(ヤンセンファーマ,第一三共,武田薬品工業,セルジーン),研究費・助成金など(セルジーン,小野薬品工業,武田薬品工業,ブリストル・マイヤーズスクイブ),奨学(奨励)寄付など(中外製薬,サノフィ,協和キリン,ファイザー,帝人ファーマ,武田薬品工業,MSD,アステラス製薬)[2021年]
監修:木崎昌弘 : 講演料(ブリストル・マイヤーズスクイブ,ヤンセンファーマ,ノバルティスファーマ,セルジーン,MSD,小野薬品,武田薬品,大日本住友製薬),研究費・助成金など(武田薬品),奨学(奨励)寄付など(協和キリン,中外製薬,武田薬品,小野薬品,第一三共)[2021年]

改訂のポイント:
  1. 新たな臨床試験結果から抗骨髄腫薬の適応拡大、および新たな併用療法が可能となっているため、それらの変更に対応する形で改訂を行った。

病態・疫学・診察

疾患情報(疫学・病態)  
  1. 多発性骨髄腫(multiple myeloma)は、B細胞の終末分化段階である形質細胞の単クローン性(腫瘍性)増殖を特徴とする疾患である。多段階発癌過程を経てMGUSより移行する。大多数の症例では単クローン性形質細胞の骨髄内集積と血中および尿中の単クローン性免疫グロブリン(M蛋白)を伴っている。一部に髄外腫瘤(形質細胞腫)で発症する場合もある。
 
骨髄腫細胞(骨髄塗抹標本、ライト・ギムザ染色)

標本中の骨髄腫細胞は大型で核が偏在し、クロマチンは粗造で豹紋状に分布し、細胞質は好塩基性で核周明庭がみられる。

出典

img1:  著者提供
 
 
 
  1. わが国における年間発症率はおよそ10万人あたり3人とされており、人口の高齢化に伴い増加傾向にある。推定罹病率は5歳ごとの年齢階層別で50歳以降、その前の年齢階層より約50%増加し、85歳以上では10万人あたりの推定罹病率は男性30.9、女性16.7である。診断時の年齢中央値は66歳、年齢階層別では60歳代が最も多い。わが国での死亡者数は年間4,000 人前後で、全悪性腫瘍の約1%、全造血器腫瘍の約10%を占めている。
  1. 発症初期には臓器病変はないが、骨髄微小環境と相互作用をしながら進行し、貧血を主とする造血障害、骨破壊性病変、高カルシウム血症、腎障害や感染症などの多彩な臨床症状を呈するようになる。
  1. 症候性骨髄腫の症状:図<図表>
  1. 臓器病変があれば症候性骨髄腫と診断し治療を開始する。近年プロテアソーム阻害薬や免疫調節薬(IMiDs)、抗体医薬などの新規薬剤が臨床応用され、多発性骨髄腫の治療成績が大きく改善している。
  1. 多発性骨髄腫は、骨髄腫細胞内で起こるゲノム不安定性や遺伝子プロモーターのメチル化などのepigeneticな異常制御により特定の癌遺伝子が活性化あるいは癌抑制遺伝子が不活性化し、骨髄腫は多段階の発癌ステップにより進行する。また、骨髄腫は骨髄微小環境に依存した進展を示し、骨破壊病変など本症に特徴的な症候を呈する。このような病態の形成や腫瘍進展・治療耐性の獲得に、骨髄腫細胞自身の細胞遺伝学的な異常に加え、骨髄腫細胞と骨髄微小環境との間の複雑な細胞間相互作用が重要な役割を演じている。
 
骨髄腫の進展と染色体異常

Hyperdiploidy:高二倍体、non-hyperdiploidy:非高二倍体
 
参考文献:
Palumbo A, Anderson K: Multiple myeloma. N Engl J Med. 2011 Mar 17;364(11):1046-60. を参考に作製

出典

img1:  著者提供
 
 
 
骨髄腫の病態

骨髄腫細胞が産生するM蛋白を介する病態と、骨髄腫細胞が直接もたらす病態がある。

出典

img1:  著者提供
 
 
 
  1. 骨髄腫の分子病態
  1. 骨髄腫細胞は症例ごとに形態的にも細胞遺伝学的にも不均一な性格を有しており、このような性格の違いが腫瘍進展や治療反応性の違いに影響を及ぼしている。骨髄腫細胞内で起こるゲノム不安定性や遺伝子プロモーターのメチル化などのepigeneticな異常制御により特定の癌遺伝子が活性化あるいは癌抑制遺伝子が不活性化し、骨髄腫は多段階の発癌ステップにより進行する(図<図表>)。
  1. また、このような骨髄腫細胞自身の細胞遺伝学的な異常に加え、本症に特徴的な病態の形成や腫瘍進展・治療耐性の獲得に骨髄腫細胞と骨髄微小環境との間の複雑な細胞間相互作用が注目されている。
  1. 骨髄腫細胞の起源と骨髄腫の発症:
  1. 胚中心B細胞は、抗原刺激により選択され、免疫グロブリン(Ig)重鎖遺伝子定常部のクラススイッチ再構成を起こした後、メモリーB細胞から形質芽細胞へと分化する。そして、骨髄へホーミングしlong-lived plasma cellに分化する。
  1. 骨髄腫細胞では、抗原特異的であるIg超可変部の遺伝子にアミノ酸置換を伴う体細胞変異を認め、クラススイッチ再構成を起こしていることより、骨髄腫細胞の起源は頻回の抗原刺激を受けた抗原依存性B細胞であるメモリーB細胞から形質芽球あたりの分化段階の細胞と考えられている。
  1. したがって、骨髄腫前駆細胞はリンパ濾胞で頻回の抗原刺激を受け、分化とともにVLA-4などの接着分子やケモカイン受容体を発現し血中に入り、骨髄へホーミングし、骨髄微小環境内で骨髄腫細胞に分化、増殖すると想定されている。遺伝的素因に慢性抗原刺激や種々の発癌要因が加わり骨髄腫は多段階のステップを経て発症すると思われる。
  1. 骨髄腫細胞の細胞遺伝学的異常:
  1. 骨髄腫細胞はゲノム不安定性を有し細胞遺伝学的に不均一である。染色体や遺伝子発現プロファイリング(gene expression profiling、GEP)より、骨髄腫細胞は層別化され、分子病態の解明が進んでいる。骨髄腫は大きく染色体の異数性により高二倍体と非高二倍体とに分けられる(図<図表>)。
  1. 非高二倍体では、IGH転座と染色体13/13q14欠失が高頻度にみられる。高二倍体では、染色体3、5、7、9、11、15、19や21などのトリソミー(3倍数体)が多いが、染色体13/13q14欠失やIGH転座の頻度は低い。経過を通じて高二倍体と非高二倍体との間の移行はない。IGH遺伝子座(14q32)またはIGL遺伝子λ座(22q11)に切断点を有する染色体転座が多く認められるが、IGL遺伝子κ座(2p12)との転座はまれである。IGH遺伝子とCCND1(11q13)、MMSET/FGFR3(4p16)、CCND3(6p21)、c-MAF(16q23)との転座は骨髄腫発症の初期よりみられ、その後の経過で2次性の転座としてMUM1/IRF4(6p25)、MAFB(20q11)、c-MYC(8q24)などとの転座が惹起される。
  1. 染色体17p欠失や1番染色体の異常(1pの欠失、1qの増幅)も腫瘍の増悪過程でみられ、このような2次性の異常は腫瘍増殖の悪化や薬剤耐性の獲得と関連がある。MGUSにはみられないが、MMではNRASKRASの活性型変異がみられる。また、FGFR3の活性型点突然変異やサイクリン依存性キナーゼ阻害因子CDKN2AやCDKN2Cの不活性化も2次性の異常である
問診・診察のポイント  
  1. 多発性骨髄腫の診断を確定するためには、まずM蛋白と形質細胞の増加により形質細胞の腫瘍性増殖を証明する。臓器障害を認めれば治療の対象となる症候性骨髄腫と診断する。診断基準として、国際骨髄腫ワーキンググループ(International Myeloma Working Group、IMWG)から発表された骨髄腫および関連疾患の診断基準が用いられる。次いで病期分類に必要な検査および治療に関連する検査を行う。

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文献 

著者: Robert A Kyle, Ellen D Remstein, Terry M Therneau, Angela Dispenzieri, Paul J Kurtin, Janice M Hodnefield, Dirk R Larson, Matthew F Plevak, Diane F Jelinek, Rafael Fonseca, Lee Joseph Melton, S Vincent Rajkumar
雑誌名: N Engl J Med. 2007 Jun 21;356(25):2582-90. doi: 10.1056/NEJMoa070389.
Abstract/Text BACKGROUND: Smoldering (asymptomatic) multiple myeloma is an asymptomatic plasma-cell proliferative disorder associated with a high risk of progression to symptomatic multiple myeloma or amyloidosis. Prognostic factors for the progression and outcome of this disease are unclear.
METHODS: We searched a computerized database and reviewed the medical records of all patients at Mayo Clinic who fulfilled the criteria of the International Myeloma Working Group for the diagnosis of smoldering multiple myeloma between 1970 and 1995. Bone marrow aspirate and biopsy specimens were studied, and patients were followed throughout the course of disease.
RESULTS: During the 26-year period, 276 patients fulfilled the criteria for smoldering multiple myeloma. During 2131 cumulative person-years of follow-up, symptomatic multiple myeloma or amyloidosis developed in 163 persons (59%). The overall risk of progression was 10% per year for the first 5 years, approximately 3% per year for the next 5 years, and 1% per year for the last 10 years; the cumulative probability of progression was 73% at 15 years. At diagnosis, significant risk factors for progression included the serum level and type of monoclonal protein, the presence of urinary light chain, the extent and pattern of bone marrow involvement, and the reduction in uninvolved immunoglobulins. The proportion of plasma cells in the bone marrow and the serum monoclonal protein level were combined to create a risk-stratification model with three distinct prognostic groups.
CONCLUSIONS: The risk of progression from smoldering multiple myeloma to symptomatic disease is related to the proportion of bone marrow plasma cells and the serum monoclonal protein level at diagnosis.

Copyright 2007 Massachusetts Medical Society.
PMID 17582068  N Engl J Med. 2007 Jun 21;356(25):2582-90. doi: 10.1056・・・
著者: Angela Dispenzieri, Robert A Kyle, Jerry A Katzmann, Terry M Therneau, Dirk Larson, Joanne Benson, Raynell J Clark, L Joseph Melton, Morie A Gertz, Shaji K Kumar, Rafael Fonseca, Diane F Jelinek, S Vincent Rajkumar
雑誌名: Blood. 2008 Jan 15;111(2):785-9. doi: 10.1182/blood-2007-08-108357. Epub 2007 Oct 17.
Abstract/Text We hypothesized that increased monoclonal free kappa or lambda immunoglobulin light chains in smoldering multiple myeloma (SMM), as detected by the serum free light chain (FLC) assay, indicates an increased risk of progression to active myeloma. Baseline serum samples obtained within 30 days of diagnosis were available in 273 patients with SMM seen from 1970 to 1995. At a median follow-up of surviving patients of 12.4 years, transformation to active disease has occurred in 59%. The best breakpoint for predicting risk of progression was an FLC ratio of 0.125 or less, or 8 or more (hazard ratio, 2.3; 95% CI, 1.6-3.2). The extent of abnormality of FLC ratio was independent of SMM risk categories defined by number of bone marrow plasma cells (BMPCs) and size of serum M proteins (BMPC>or=10% and serum M protein>or=3 g/dL; BMPC>or=10% but serum M protein<3 g/dL; and serum M protein>or=3 g/dL but BMPC<10%). Incorporating the FLC ratio into the risk model, the 5-year progression rates in high-, intermediate-, and low-risk groups were 76%, 51%, and 25%, respectively. The serum immunoglobulin FLC ratio is an important additional determinant of clinical outcome in patients with SMM.

PMID 17942755  Blood. 2008 Jan 15;111(2):785-9. doi: 10.1182/blood-200・・・
著者: M Hjorth, L Hellquist, E Holmberg, B Magnusson, S Rödjer, J Westin
雑誌名: Eur J Haematol. 1993 Feb;50(2):95-102.
Abstract/Text From October 1983 until December 1988, 50 patients with asymptomatic multiple myeloma stage I were included in a prospective randomized multi-centre study comparing melphalan-prednisone (MP) therapy started at the time of diagnosis with deferred therapy where MP was started at the time of disease progression. Twenty-five patients were randomized to each group. The median time from diagnosis to start of therapy in the group with deferred therapy was 12 months. The reasons for starting therapy were increasing M-protein in 8 cases, symptomatic bone disease in 9 and anaemia in 5. In 2 cases, disease progression was complicated by vertebral fractures necessitating radiotherapy. Two patients in the group in which MP was started at the time of diagnosis developed acute leukaemia. No differences in response rate, response duration or survival were observed between the treatment groups. We conclude that in asymptomatic myeloma deferral of chemotherapy is feasible in well-informed and well-controlled patients but conveys no advantage in survival. In clinical practice the benefits of treatment deferral are to some extent outweighed by disease progression before start of treatment.

PMID 8440364  Eur J Haematol. 1993 Feb;50(2):95-102.
著者: A Riccardi, O Mora, C Tinelli, D Valentini, S Brugnatelli, R Spanedda, A De Paoli, L Barbarano, M Di Stasi, M Giordano, C Delfini, G Nicoletti, C Bergonzi, E Rinaldi, L Piccinini, E Ascari
雑誌名: Br J Cancer. 2000 Apr;82(7):1254-60. doi: 10.1054/bjoc.1999.1087.
Abstract/Text We conducted a randomized trial to evaluate whether melphalan-prednisone (MPH-P) treatment administered just after diagnosis improves survival of stage I multiple myeloma (MM). Between January 1987 and March 1993, 145 consecutive previously untreated patients with stage I MM were randomized between treatment with MPH-P (administered for 4 days every 6 weeks) just after diagnosis and treatment only at disease progression. Survival was not influenced by MPH-P treatment either administered just after diagnosis or at disease progression (64 vs 71 months respectively). Comparing the first with the second group the odds ratio of death is 1.17 (95% confidence interval 0.57-2.42; P = 0.64). Disease progression occurred within a year in about 50% of patients who were initially untreated. Response rate was similar in both groups, but duration of response was shorter in patients who were treated at disease progression (48 vs 79 months, P = 0.044). Patients actually treated at disease progression (34/70) survived shorter than those who had neither disease progression nor treatment (56 vs > 92 months; P = 0.005). Starting MPH-P just after diagnosis does not improve survival and response rate in stage I MM, with respect to deferring therapy until disease progression. However, patients with stage I MM randomized to have treatment delayed and who actually progressed and were treated had shorter survival than those with stable disease and no treatment. Biologic or other disease features could identify these subgroups of patients.

PMID 10755397  Br J Cancer. 2000 Apr;82(7):1254-60. doi: 10.1054/bjoc.・・・
著者: María-Victoria Mateos, Miguel-Teodoro Hernández, Pilar Giraldo, Javier de la Rubia, Felipe de Arriba, Lucía López Corral, Laura Rosiñol, Bruno Paiva, Luis Palomera, Joan Bargay, Albert Oriol, Felipe Prosper, Javier López, Eduardo Olavarría, Nuria Quintana, José-Luis García, Joan Bladé, Juan-José Lahuerta, Jesús-F San Miguel
雑誌名: N Engl J Med. 2013 Aug 1;369(5):438-47. doi: 10.1056/NEJMoa1300439.
Abstract/Text BACKGROUND: For patients with smoldering multiple myeloma, the standard of care is observation until symptoms develop. However, this approach does not identify high-risk patients who may benefit from early intervention.
METHODS: In this randomized, open-label, phase 3 trial, we randomly assigned 119 patients with high-risk smoldering myeloma to treatment or observation. Patients in the treatment group received an induction regimen (lenalidomide at a dose of 25 mg per day on days 1 to 21, plus dexamethasone at a dose of 20 mg per day on days 1 to 4 and days 12 to 15, at 4-week intervals for nine cycles), followed by a maintenance regimen (lenalidomide at a dose of 10 mg per day on days 1 to 21 of each 28-day cycle for 2 years). The primary end point was time to progression to symptomatic disease. Secondary end points were response rate, overall survival, and safety.
RESULTS: After a median follow-up of 40 months, the median time to progression was significantly longer in the treatment group than in the observation group (median not reached vs. 21 months; hazard ratio for progression, 0.18; 95% confidence interval [CI], 0.09 to 0.32; P<0.001). The 3-year survival rate was also higher in the treatment group (94% vs. 80%; hazard ratio for death, 0.31; 95% CI, 0.10 to 0.91; P=0.03). A partial response or better was achieved in 79% of patients in the treatment group after the induction phase and in 90% during the maintenance phase. Toxic effects were mainly grade 2 or lower.
CONCLUSIONS: Early treatment for patients with high-risk smoldering myeloma delays progression to active disease and increases overall survival. (Funded by Celgene; ClinicalTrials.gov number, NCT00480363.).

PMID 23902483  N Engl J Med. 2013 Aug 1;369(5):438-47. doi: 10.1056/NE・・・
著者: John Koreth, Corey S Cutler, Benjamin Djulbegovic, Rajesh Behl, Robert L Schlossman, Nikhil C Munshi, Paul G Richardson, Kenneth C Anderson, Robert J Soiffer, Edwin P Alyea
雑誌名: Biol Blood Marrow Transplant. 2007 Feb;13(2):183-96. doi: 10.1016/j.bbmt.2006.09.010.
Abstract/Text Myeloablative high-dose therapy and single autologous stem cell transplantation (HDT) is frequently performed early in the course of multiple myeloma, supported by some randomized controlled trials (RCTs) indicating overall survival (OS) and progression-free survival (PFS) benefit compared with nonmyeloablative standard-dose therapy (SDT). Other RCTs, however, suggest variable benefit. We therefore undertook a systematic review and meta-analysis of all RCTs evaluating upfront HDT versus SDT in myeloma. The primary objective was to quantify OS benefit with HDT, with PFS benefit a secondary objective. Anticipating heterogeneity, sensitivity and subgroup analyses were undertaken to assess robustness of results. Assessment of harms (treatment-related mortality) was also undertaken. We searched the PubMed, Embase, and Cochrane Collection of Controlled Trials databases using the terms myeloma combined with autologous or transplant or myeloablative or stem cell. In total, 3407 articles were accessed, and 10 RCTs prospectively comparing upfront HDT with SDT, with > or =2-year follow-up, and reporting OS benefit on an intent-to-treat basis were identified. Two reviewers independently extracted study characteristics, interventions, and outcomes. Hazard ratios (with 95% confidence interval) were determined. Nine studies comprising 2411 patients were fully analyzed. Significant heterogeneity was present. The combined hazard of death with HDT was 0.92 (95% confidence interval, 0.74-1.13). The combined hazard of progression with HDT was 0.75 (95% confidence interval, 0.59-0.96). The totality of the randomized data indicates PFS benefit but not OS benefit for HDT with single autologous transplantation performed early in multiple myeloma. Sensitivity and subgroup analyses supported the findings and indicated that, contrary to current reimbursement criteria, PFS benefit with upfront HDT is not restricted to chemoresponsive myeloma. However, the overall risk of developing treatment-related mortality with HDT was increased significantly (odds ratio, 3.01; 95% confidence interval, 1.64-5.50). Hence, evaluating alternative therapeutic options upfront may also be reasonable.

PMID 17241924  Biol Blood Marrow Transplant. 2007 Feb;13(2):183-96. do・・・
著者: Jean-Luc Harousseau, Michel Attal, Hervé Avet-Loiseau, Gerald Marit, Denis Caillot, Mohamad Mohty, Pascal Lenain, Cyrille Hulin, Thierry Facon, Philippe Casassus, Mauricette Michallet, Hervé Maisonneuve, Lotfi Benboubker, Frédéric Maloisel, Marie-Odile Petillon, Iain Webb, Claire Mathiot, Philippe Moreau
雑誌名: J Clin Oncol. 2010 Oct 20;28(30):4621-9. doi: 10.1200/JCO.2009.27.9158. Epub 2010 Sep 7.
Abstract/Text PURPOSE: To compare efficacy and safety of bortezomib plus dexamethasone and vincristine plus doxorubicin plus dexamethasone (VAD) as induction before stem-cell transplantation in previously untreated myeloma.
PATIENTS AND METHODS: Four hundred eighty-two patients were randomly assigned to VAD (n = 121), VAD plus dexamethasone, cyclophosphamide, etoposide, and cisplatin (DCEP) consolidation (n = 121), bortezomib plus dexamethasone (n = 121), or bortezomib plus dexamethasone plus DCEP (n = 119), followed by autologous stem-cell transplantation. Patients not achieving very good partial response (VGPR) required a second transplantation. The primary end point was postinduction complete response/near complete response (CR/nCR) rate.
RESULTS: Postinduction CR/nCR (14.8% v 6.4%), at least VGPR (37.7% v 15.1%), and overall response (78.5% v 62.8%) rates were significantly higher with bortezomib plus dexamethasone versus VAD; CR/nCR and at least VGPR rates were higher regardless of disease stage or adverse cytogenetic abnormalities. Response rates were similar in patients who did and did not receive DCEP. Post first transplantation, CR/nCR (35.0% v 18.4%) and at least VGPR (54.3% v 37.2%) rates remained significantly higher with bortezomib plus dexamethasone. Median progression-free survival (PFS) was 36.0 months versus 29.7 months (P = .064) with bortezomib plus dexamethasone versus VAD; respective 3-year survival rates were 81.4% and 77.4% (median follow-up, 32.2 months). The incidence of severe adverse events appeared similar between groups, but hematologic toxicity and deaths related to toxicity (zero v seven) were more frequent with VAD. Conversely, rates of grade 2 (20.5% v 10.5%) and grades 3 to 4 (9.2% v 2.5%) peripheral neuropathy during induction through first transplantation were significantly higher with bortezomib plus dexamethasone.
CONCLUSION: Bortezomib plus dexamethasone significantly improved postinduction and post-transplantation CR/nCR and at least VGPR rates compared with VAD and resulted in a trend for longer PFS. Bortezomib plus dexamethasone should therefore be considered a standard of care in this setting.

PMID 20823406  J Clin Oncol. 2010 Oct 20;28(30):4621-9. doi: 10.1200/J・・・
著者: Michele Cavo, Paola Tacchetti, Francesca Patriarca, Maria Teresa Petrucci, Lucia Pantani, Monica Galli, Francesco Di Raimondo, Claudia Crippa, Elena Zamagni, Antonio Palumbo, Massimo Offidani, Paolo Corradini, Franco Narni, Antonio Spadano, Norbert Pescosta, Giorgio Lambertenghi Deliliers, Antonio Ledda, Claudia Cellini, Tommaso Caravita, Patrizia Tosi, Michele Baccarani, GIMEMA Italian Myeloma Network
雑誌名: Lancet. 2010 Dec 18;376(9758):2075-85. doi: 10.1016/S0140-6736(10)61424-9. Epub 2010 Dec 9.
Abstract/Text BACKGROUND: Thalidomide plus dexamethasone (TD) is a standard induction therapy for myeloma. We aimed to assess the efficacy and safety of addition of bortezomib to TD (VTD) versus TD alone as induction therapy before, and consolidation therapy after, double autologous stem-cell transplantation in newly diagnosed multiple myeloma.
METHODS: Patients (aged 18-65 years) with previously untreated symptomatic myeloma were enrolled from 73 sites in Italy between May, 2006, and April, 2008, and data collection continued until June 30, 2010. Patients were randomly allocated (1:1 ratio) by a web-based system to receive three 21-day cycles of thalidomide (100 mg daily for the first 14 days and 200 mg daily thereafter) plus dexamethasone (40 mg daily on 8 of the first 12 days, but not consecutively; total of 320 mg per cycle), either alone or with bortezomib (1·3 mg/m(2) on days 1, 4, 8, and 11). The randomisation sequence was computer generated by the study coordinating team and was stratified by disease stage. After double autologous stem-cell transplantation, patients received two 35-day cycles of their assigned drug regimen, VTD or TD, as consolidation therapy. The primary endpoint was the rate of complete or near complete response to induction therapy. Analysis was by intention to treat. Patients and treating physicians were not masked to treatment allocation. This study is still underway but is not recruiting participants, and is registered with ClinicalTrials.gov, number NCT01134484, and with EudraCT, number 2005-003723-39.
FINDINGS: 480 patients were enrolled and randomly assigned to receive VTD (n=241 patients) or TD (n=239). Six patients withdrew consent before start of treatment, and 236 on VTD and 238 on TD were included in the intention-to-treat analysis. After induction therapy, complete or near complete response was achieved in 73 patients (31%, 95% CI 25·0-36·8) receiving VTD, and 27 (11%, 7·3-15·4) on TD (p<0·0001). Grade 3 or 4 adverse events were recorded in a significantly higher number of patients on VTD (n=132, 56%) than in those on TD (n=79, 33%; p<0·0001), with a higher occurrence of peripheral neuropathy in patients on VTD (n=23, 10%) than in those on TD (n=5, 2%; p=0·0004). Resolution or improvement of severe peripheral neuropathy was recorded in 18 of 23 patients on VTD, and in three of five patients on TD.
INTERPRETATION: VTD induction therapy before double autologous stem-cell transplantation significantly improves rate of complete or near complete response, and represents a new standard of care for patients with multiple myeloma who are eligible for transplant.
FUNDING: Seràgnoli Institute of Haematology at the University of Bologna, Bologna, Italy.

Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID 21146205  Lancet. 2010 Dec 18;376(9758):2075-85. doi: 10.1016/S01・・・
著者: Efstathios Kastritis, Athanasios Anagnostopoulos, Maria Roussou, Dimitra Gika, Charis Matsouka, Despina Barmparousi, Irini Grapsa, Erasmia Psimenou, Aristotle Bamias, Meletios Athanasios Dimopoulos
雑誌名: Haematologica. 2007 Apr;92(4):546-9.
Abstract/Text The impact of high dose dexamethasone containing regimens with or without the novel agents thalidomide and bortezomib on the reversal of renal failure (RF) was evaluated in 41 consecutive newly diagnosed patients with multiple myeloma (MM) treated in a single institution. RF was reversed in 73% of all patients within a median of 1.9 months. In patients treated with dexamethasone and novel agents (thalidomide and/or bortezomib) the reversibility rate was 80% within a median of 0.8 months. Severe RF and significant Bence Jones proteinuria were associated with a lower probability of RF reversal. Patients who responded to treatment achieved RF reversal more often than in those who did not (85% versus 56%, p=0.046). In conclusion, RF is reversible in the majority of newly diagnosed MM patients treated with high-dose dexamethasone containing regimens. The addition of novel agents induces a more rapid RF reversal.

PMID 17488666  Haematologica. 2007 Apr;92(4):546-9.
著者: Jesús F San Miguel, Rudolf Schlag, Nuriet K Khuageva, Meletios A Dimopoulos, Ofer Shpilberg, Martin Kropff, Ivan Spicka, Maria T Petrucci, Antonio Palumbo, Olga S Samoilova, Anna Dmoszynska, Kudrat M Abdulkadyrov, Rik Schots, Bin Jiang, Maria-Victoria Mateos, Kenneth C Anderson, Dixie L Esseltine, Kevin Liu, Andrew Cakana, Helgi van de Velde, Paul G Richardson, VISTA Trial Investigators
雑誌名: N Engl J Med. 2008 Aug 28;359(9):906-17. doi: 10.1056/NEJMoa0801479.
Abstract/Text BACKGROUND: The standard treatment for patients with multiple myeloma who are not candidates for high-dose therapy is melphalan and prednisone. This phase 3 study compared the use of melphalan and prednisone with or without bortezomib in previously untreated patients with multiple myeloma who were ineligible for high-dose therapy.
METHODS: We randomly assigned 682 patients to receive nine 6-week cycles of melphalan (at a dose of 9 mg per square meter of body-surface area) and prednisone (at a dose of 60 mg per square meter) on days 1 to 4, either alone or with bortezomib (at a dose of 1.3 mg per square meter) on days 1, 4, 8, 11, 22, 25, 29, and 32 during cycles 1 to 4 and on days 1, 8, 22, and 29 during cycles 5 to 9. The primary end point was the time to disease progression.
RESULTS: The time to progression among patients receiving bortezomib plus melphalan-prednisone (bortezomib group) was 24.0 months, as compared with 16.6 months among those receiving melphalan-prednisone alone (control group) (hazard ratio for the bortezomib group, 0.48; P<0.001). The proportions of patients with a partial response or better were 71% in the bortezomib group and 35% in the control group; complete-response rates were 30% and 4%, respectively (P<0.001). The median duration of the response was 19.9 months in the bortezomib group and 13.1 months in the control group. The hazard ratio for overall survival was 0.61 for the bortezomib group (P=0.008). Adverse events were consistent with established profiles of toxic events associated with bortezomib and melphalan-prednisone. Grade 3 events occurred in a higher proportion of patients in the bortezomib group than in the control group (53% vs. 44%, P=0.02), but there were no significant differences in grade 4 events (28% and 27%, respectively) or treatment-related deaths (1% and 2%).
CONCLUSIONS: Bortezomib plus melphalan-prednisone was superior to melphalan-prednisone alone in patients with newly diagnosed myeloma who were ineligible for high-dose therapy. (ClinicalTrials.gov number, NCT00111319.)

2008 Massachusetts Medical Society
PMID 18753647  N Engl J Med. 2008 Aug 28;359(9):906-17. doi: 10.1056/N・・・
著者: S Vincent Rajkumar, Susanna Jacobus, Natalie S Callander, Rafael Fonseca, David H Vesole, Michael E Williams, Rafat Abonour, David S Siegel, Michael Katz, Philip R Greipp, Eastern Cooperative Oncology Group
雑誌名: Lancet Oncol. 2010 Jan;11(1):29-37. doi: 10.1016/S1470-2045(09)70284-0. Epub 2009 Oct 21.
Abstract/Text BACKGROUND: High-dose dexamethasone is a mainstay of therapy for multiple myeloma. We studied whether low-dose dexamethasone in combination with lenalidomide is non-inferior to and has lower toxicity than high-dose dexamethasone plus lenalidomide.
METHODS: Patients with untreated symptomatic myeloma were randomly assigned in this open-label non-inferiority trial to lenalidomide 25 mg on days 1-21 plus dexamethasone 40 mg on days 1-4, 9-12, and 17-20 of a 28-day cycle (high dose), or lenalidomide given on the same schedule with dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle (low dose). After four cycles, patients could discontinue therapy to pursue stem-cell transplantation or continue treatment until disease progression. The primary endpoint was response rate after four cycles assessed with European Group for Blood and Bone Marrow Transplant criteria. The non-inferiority margin was an absolute difference of 15% in response rate. Analysis was by modified intention to treat. This trial is registered with ClinicalTrials.gov, number NCT00098475.
FINDINGS: 445 patients were randomly assigned: 223 to high-dose and 222 to low-dose regimens. 169 (79%) of 214 patients receiving high-dose therapy and 142 (68%) of 205 patients on low-dose therapy had complete or partial response within four cycles (odds ratio 1.75, 80% CI 1.30-2.32; p=0.008). However, at the second interim analysis at 1 year, overall survival was 96% (95% CI 94-99) in the low-dose dexamethasone group compared with 87% (82-92) in the high-dose group (p=0.0002). As a result, the trial was stopped and patients on high-dose therapy were crossed over to low-dose therapy. 117 patients (52%) on the high-dose regimen had grade three or worse toxic effects in the first 4 months, compared with 76 (35%) of the 220 on the low-dose regimen for whom toxicity data were available (p=0.0001), 12 of 222 on high dose and one of 220 on low-dose dexamethasone died in the first 4 months (p=0.003). The three most common grade three or higher toxicities were deep-vein thrombosis, 57 (26%) of 223 versus 27 (12%) of 220 (p=0.0003); infections including pneumonia, 35 (16%) of 223 versus 20 (9%) of 220 (p=0.04), and fatigue 33 (15%) of 223 versus 20 (9%) of 220 (p=0.08), respectively.
INTERPRETATION: Lenalidomide plus low-dose dexamethasone is associated with better short-term overall survival and with lower toxicity than lenalidomide plus high-dose dexamethasone in patients with newly diagnosed myeloma.
FUNDING: National Cancer Institute, Rockville, MD, USA.

Copyright (c) 2010 Elsevier Ltd. All rights reserved.
PMID 19853510  Lancet Oncol. 2010 Jan;11(1):29-37. doi: 10.1016/S1470-・・・
著者: Peter M Fayers, Antonio Palumbo, Cyrille Hulin, Anders Waage, Pierre Wijermans, Meral Beksaç, Sara Bringhen, Jean-Yves Mary, Peter Gimsing, Fabian Termorshuizen, Rauf Haznedar, Tommaso Caravita, Philippe Moreau, Ingemar Turesson, Pellegrino Musto, Lotfi Benboubker, Martijn Schaafsma, Pieter Sonneveld, Thierry Facon, Nordic Myeloma Study Group, Italian Multiple Myeloma Network, Turkish Myeloma Study Group, Hemato-Oncologie voor Volwassenen Nederland, Intergroupe Francophone du Myélome, European Myeloma Network
雑誌名: Blood. 2011 Aug 4;118(5):1239-47. doi: 10.1182/blood-2011-03-341669. Epub 2011 Jun 13.
Abstract/Text The role of thalidomide for previously untreated elderly patients with multiple myeloma remains unclear. Six randomized controlled trials, launched in or after 2000, compared melphalan and prednisone alone (MP) and with thalidomide (MPT). The effect on overall survival (OS) varied across trials. We carried out a meta-analysis of the 1685 individual patients in these trials. The primary endpoint was OS, and progression-free survival (PFS) and 1-year response rates were secondary endpoints. There was a highly significant benefit to OS from adding thalidomide to MP (hazard ratio = 0.83; 95% confidence interval 0.73-0.94, P = .004), representing increased median OS time of 6.6 months, from 32.7 months (MP) to 39.3 months (MPT). The thalidomide regimen was also associated with superior PFS (hazard ratio = 0.68, 95% confidence interval 0.61-0.76, P < .0001) and better 1-year response rates (partial response or better was 59% on MPT and 37% on MP). Although the trials differed in terms of patient baseline characteristics and thalidomide regimens, there was no evidence that treatment affected OS differently according to levels of the prognostic factors. We conclude that thalidomide added to MP improves OS and PFS in previously untreated elderly patients with multiple myeloma, extending the median survival time by on average 20%.

PMID 21670471  Blood. 2011 Aug 4;118(5):1239-47. doi: 10.1182/blood-20・・・
著者: I C MacLennan, J Cusick
雑誌名: Br J Cancer. 1985 Aug;52(2):153-8.
Abstract/Text In the Medical Research Council's IVth trial in Myelomatosis the possible benefit of adding vincristine to first line treatment with intermittent melphalan and prednisone has been assessed. This was analysed in 530 patients who were randomly allocated to receive vincristine or not. Survival was not improved by the addition of vincristine. A total of 268 patients reached plateau phase on first line therapy. Of these 226 patients were rerandomised either to continue receiving first line therapy for a further year or to cease therapy. At the present time there is a slight but not significant survival advantage in the group which received no further treatment on reaching plateau.

PMID 3896288  Br J Cancer. 1985 Aug;52(2):153-8.
著者: A Belch, W Shelley, D Bergsagel, K Wilson, P Klimo, D White, A Willan
雑誌名: Br J Cancer. 1988 Jan;57(1):94-9.
Abstract/Text In order to assess the role of maintenance melphalan and prednisone (MP) in responding multiple myeloma patients, 185 eligible patients who responded to initial MP with stabilization for at least 4 months were randomized to either stop treatment and resume therapy at relapse or to continue MP until relapse. Time to first relapse was significantly shorter in the no maintenance group (P = 0.0011), however 57% of the no maintenance patients had a second response when MP was restarted and others had minor improvement. The time to final progression on MP, which reflects the duration of disease control by MP, was therefore longer for the no maintenance group (median = 39 months) compared to the maintenance group (median = 31 months) although the observed difference was not statistically significant (P = 0.086). Median survival from start of MP in the maintenance group (46 months) was also not significantly different than the no maintenance group (51 months) (P = 0.587). Multifactor analysis of the randomized patients demonstrated shorter total remission duration and shorter survival in patients who had an initially rapid response to therapy or a lesser reduction in serum M-protein concentration.

PMID 3279997  Br J Cancer. 1988 Jan;57(1):94-9.
著者: Antonio Palumbo, Michele Cavo, Sara Bringhen, Elena Zamagni, Alessandra Romano, Francesca Patriarca, Davide Rossi, Fabiana Gentilini, Claudia Crippa, Monica Galli, Chiara Nozzoli, Roberto Ria, Roberto Marasca, Vittorio Montefusco, Luca Baldini, Francesca Elice, Vincenzo Callea, Stefano Pulini, Angelo M Carella, Renato Zambello, Giulia Benevolo, Valeria Magarotto, Paola Tacchetti, Norbert Pescosta, Claudia Cellini, Claudia Polloni, Andrea Evangelista, Tommaso Caravita, Fortunato Morabito, Massimo Offidani, Patrizia Tosi, Mario Boccadoro
雑誌名: J Clin Oncol. 2011 Mar 10;29(8):986-93. doi: 10.1200/JCO.2010.31.6844. Epub 2011 Jan 31.
Abstract/Text PURPOSE: In patients with myeloma, thalidomide significantly improves outcomes but increases the risk of thromboembolic events. In this randomized, open-label, multicenter trial, we compared aspirin (ASA) or fixed low-dose warfarin (WAR) versus low molecular weight heparin (LMWH) for preventing thromboembolism in patients with myeloma treated with thalidomide-based regimens.
PATIENTS AND METHODS: A total of 667 patients with previously untreated myeloma who received thalidomide-containing regimens and had no clinical indication or contraindication for a specific antiplatelet or anticoagulant therapy were randomly assigned to receive ASA (100 mg/d), WAR (1.25 mg/d), or LMWH (enoxaparin 40 mg/d). A composite primary end point included serious thromboembolic events, acute cardiovascular events, or sudden deaths during the first 6 months of treatment.
RESULTS: Of 659 analyzed patients, 43 (6.5%) had serious thromboembolic events, acute cardiovascular events, or sudden death during the first 6 months (6.4% in the ASA group, 8.2% in the WAR group, and 5.0% in the LMWH group). Compared with LMWH, the absolute differences were +1.3% (95% CI, -3.0% to 5.7%; P = .544) in the ASA group and +3.2% (95% CI, -1.5% to 7.8%; P = .183) in the WAR group. The risk of thromboembolism was 1.38 times higher in patients treated with thalidomide without bortezomib. Three major (0.5%) and 10 minor (1.5%) bleeding episodes were recorded.
CONCLUSION: In patients with myeloma treated with thalidomide-based regimens, ASA and WAR showed similar efficacy in reducing serious thromboembolic events, acute cardiovascular events, and sudden deaths compared with LMWH, except in elderly patients where WAR showed less efficacy than LMWH.

PMID 21282540  J Clin Oncol. 2011 Mar 10;29(8):986-93. doi: 10.1200/JC・・・
著者: Maurizio Zangari, Guido Tricot, Latha Polavaram, Fenghuang Zhan, Ashlie Finlayson, Robert Knight, Tommy Fu, Donna Weber, Meletios A Dimopoulos, Ruben Niesvizky, Louis Fink
雑誌名: J Clin Oncol. 2010 Jan 1;28(1):132-5. doi: 10.1200/JCO.2009.23.0169. Epub 2009 Nov 9.
Abstract/Text PURPOSE We conducted a retrospective analysis of the survival effect of venous thromboembolism (VTE) development in patients with multiple myeloma (MM). METHODS Two identically designed, multicenter, double-blind, phase III clinical trials (MM-009 and MM-010) were conducted in Europe and the United States to assess the effect of lenalidomide in combination with dexamethasone versus dexamethasone plus placebo in patients with relapsed or refractory MM, after failing at least one prior line of treatment. In this retrospective analysis, we evaluated incidence and survival effect of thromboembolism in 353 patients randomly assigned to receive 25 mg of lenalidomide on days 1 through 21 of a 28-day cycle, plus 40 mg of oral dexamethasone on days 1 through 4, 9 through 12, and 17 through 20 for the first four cycles; after the fourth cycle, 40 mg of dexamethasone was administered on days 1 through 4 only. Results Seventeen percent of patients experienced a thromboembolic episode. The development of VTE did not significantly affect overall survival (P = .90) or time to progression (P = .34). No significant survival impact was observed in a subgroup of patients who received prophylactic anticoagulation (overall survival P = .7, time to progression P = .1). CONCLUSION Patients with MM treated with lenalidomide and high-dose dexamethasone who developed a VTE did not experience shorter overall survival or time to progression.

PMID 19901114  J Clin Oncol. 2010 Jan 1;28(1):132-5. doi: 10.1200/JCO.・・・
著者: A Keith Stewart, S Vincent Rajkumar, Meletios A Dimopoulos, Tamás Masszi, Ivan Špička, Albert Oriol, Roman Hájek, Laura Rosiñol, David S Siegel, Georgi G Mihaylov, Vesselina Goranova-Marinova, Péter Rajnics, Aleksandr Suvorov, Ruben Niesvizky, Andrzej J Jakubowiak, Jesus F San-Miguel, Heinz Ludwig, Michael Wang, Vladimír Maisnar, Jiri Minarik, William I Bensinger, Maria-Victoria Mateos, Dina Ben-Yehuda, Vishal Kukreti, Naseem Zojwalla, Margaret E Tonda, Xinqun Yang, Biao Xing, Philippe Moreau, Antonio Palumbo, ASPIRE Investigators
雑誌名: N Engl J Med. 2015 Jan 8;372(2):142-52. doi: 10.1056/NEJMoa1411321. Epub 2014 Dec 6.
Abstract/Text BACKGROUND: Lenalidomide plus dexamethasone is a reference treatment for relapsed multiple myeloma. The combination of the proteasome inhibitor carfilzomib with lenalidomide and dexamethasone has shown efficacy in a phase 1 and 2 study in relapsed multiple myeloma.
METHODS: We randomly assigned 792 patients with relapsed multiple myeloma to carfilzomib with lenalidomide and dexamethasone (carfilzomib group) or lenalidomide and dexamethasone alone (control group). The primary end point was progression-free survival.
RESULTS: Progression-free survival was significantly improved with carfilzomib (median, 26.3 months, vs. 17.6 months in the control group; hazard ratio for progression or death, 0.69; 95% confidence interval [CI], 0.57 to 0.83; P=0.0001). The median overall survival was not reached in either group at the interim analysis. The Kaplan-Meier 24-month overall survival rates were 73.3% and 65.0% in the carfilzomib and control groups, respectively (hazard ratio for death, 0.79; 95% CI, 0.63 to 0.99; P=0.04). The rates of overall response (partial response or better) were 87.1% and 66.7% in the carfilzomib and control groups, respectively (P<0.001; 31.8% and 9.3% of patients in the respective groups had a complete response or better; 14.1% and 4.3% had a stringent complete response). Adverse events of grade 3 or higher were reported in 83.7% and 80.7% of patients in the carfilzomib and control groups, respectively; 15.3% and 17.7% of patients discontinued treatment owing to adverse events. Patients in the carfilzomib group reported superior health-related quality of life.
CONCLUSIONS: In patients with relapsed multiple myeloma, the addition of carfilzomib to lenalidomide and dexamethasone resulted in significantly improved progression-free survival at the interim analysis and had a favorable risk-benefit profile. (Funded by Onyx Pharmaceuticals; ClinicalTrials.gov number, NCT01080391.).

PMID 25482145  N Engl J Med. 2015 Jan 8;372(2):142-52. doi: 10.1056/NE・・・
著者: M A Dimopoulos, E Kastritis, C Bamia, I Melakopoulos, D Gika, M Roussou, M Migkou, E Eleftherakis-Papaiakovou, D Christoulas, E Terpos, A Bamias
雑誌名: Ann Oncol. 2009 Jan;20(1):117-20. doi: 10.1093/annonc/mdn554. Epub 2008 Aug 9.
Abstract/Text BACKGROUND: Osteonecrosis of the jaw (ONJ) is a well-described complication of bisphosphonates use in patients with multiple myeloma (MM). We investigated whether the occurrence of ONJ decreased after the implementation of preventive measures in 128 patients with MM who received zoledronic acid.
PATIENTS AND METHODS: Patients with MM who received zoledronic acid were included in this analysis. Patients with a previous use of other bisphosphonates were excluded; patients were stratified into group A (n=38) and group B (n=90) if treatment was started before or after the implementation of preventive measures.
RESULTS: One hundred and twenty-eight patients were included in this analysis. Sixteen patients (12.5%) developed ONJ--group A: 8 (26.3%), group B: 2 (6.7%) (P=0.002). The incidence rate (IR) was 0.671/100 person-months for group A and 0.230/100 person-months for group B [IR ratio 2.92, P=0.029, 95% confidence interval 1.06-8.03]. No patient in group B developed stage III ONJ.
CONCLUSION: In conclusion, the risk of developing ONJ after treatment of zoledronic acid is reduced (but not deleted) by the implementation of preventive measures.

PMID 18689864  Ann Oncol. 2009 Jan;20(1):117-20. doi: 10.1093/annonc/m・・・
著者: Gareth J Morgan, Faith E Davies, Walter M Gregory, Kim Cocks, Sue E Bell, Alex J Szubert, Nuria Navarro-Coy, Mark T Drayson, Roger G Owen, Sylvia Feyler, A John Ashcroft, Fiona Ross, Jennifer Byrne, Huw Roddie, Claudius Rudin, Gordon Cook, Graham H Jackson, J Anthony Child, National Cancer Research Institute Haematological Oncology Clinical Study Group
雑誌名: Lancet. 2010 Dec 11;376(9757):1989-99. doi: 10.1016/S0140-6736(10)62051-X. Epub 2010 Dec 3.
Abstract/Text BACKGROUND: Bisphosphonates reduce the risk of skeletal events in patients with malignant bone disease, and zoledronic acid has shown potential anticancer effects in preclinical and clinical studies. We aimed to establish whether bisphosphonates can affect clinical outcomes in patients with multiple myeloma.
METHODS: Patients of age 18 years or older with newly diagnosed multiple myeloma were enrolled from 120 centres in the UK. Computer-generated randomisation sequence was used to allocate patients equally, via an automated telephone service, to receive 4 mg zoledronic acid as an infusion every 3-4 weeks or 1600 mg oral clodronic acid daily. Patients also received intensive or non-intensive induction chemotherapy. No investigators, staff, or patients were masked to treatment allocation, and bisphosphonate and maintenance therapy continued at least until disease progression. The primary endpoints were overall survival, progression-free survival, and overall response rate. We assessed between-group differences with Cox proportional hazards models for progression-free survival and overall survival, and with logistic regression models for overall response rate. Analysis was by intention to treat. This trial is registered, number ISRCTN68454111.
FINDINGS: 1970 patients were enrolled between May, 2003, and November, 2007, of whom 1960 were eligible for intention-to-treat analysis: 981 in the zoledronic acid group (555 on intensive chemotherapy, 426 on non-intensive chemotherapy); and 979 on clodronic acid (556 on intensive chemotherapy, 423 on non-intensive chemotherapy). The treatment cutoff was Oct 5, 2009, with patients receiving bisphosphonates for a median of 350 days (IQR 137-632) before disease progression, with a median of 3·7 years' follow-up (IQR 2·9-4·7). Zoledronic acid reduced mortality by 16% (95% CI 4-26) versus clodronic acid (hazard ratio [HR] 0·84, 95% CI 0·74-0·96; p=0·0118), and extended median overall survival by 5·5 months (50·0 months, IQR 21·0 to not reached vs 44·5 months, IQR 16·5 to not reached; p=0·04). Zoledronic acid also significantly improved progression-free survival by 12% (95% CI 2-20) versus clodronic acid (HR 0·88, 95% CI 0·80-0·98; p=0·0179), and increased median progression-free survival by 2·0 months (19·5 months, IQR 9·0-38·0 vs 17·5 months, IQR 8·5-34·0; p=0·07). Rates of complete, very good partial, or partial response did not differ significantly between the zoledronic acid and clodronic acid groups for patients receiving intensive induction chemotherapy (432 patients [78%] vs 422 [76%]; p=0·43) or non-intensive induction chemotherapy (215 [50%] vs 195 [46%]; p=0·18). Both bisphosphonates were generally well tolerated, with similar occurrence of acute renal failure and treatment-emergent serious adverse events, but zoledronic acid was associated with higher rates of confirmed osteonecrosis of the jaw (35 [4%]) than was clodronic acid (3 [<1%]).
INTERPRETATION: Consistent with the potential anticancer activity of zoledronic acid, overall survival improved independently of prevention of skeletal-related events, showing that zoledronic acid has treatment benefits beyond bone health. These findings support immediate treatment with zoledronic acid in patients with newly diagnosed multiple myeloma, not only for prevention of skeletal-related events, but also for potential antimyeloma benefits.
FUNDING: Medical Research Council (London, UK), with unrestricted educational grants from Novartis, Schering Health Care, Chugai, Pharmion, Celgene, and Ortho Biotech.

Copyright © 2010 Elsevier Ltd. All rights reserved.
PMID 21131037  Lancet. 2010 Dec 11;376(9757):1989-99. doi: 10.1016/S01・・・
著者: Lee S Rosen, David Gordon, Mary Kaminski, Anthony Howell, Andrew Belch, John Mackey, Justus Apffelstaedt, Mohamad A Hussein, Robert E Coleman, Dirk J Reitsma, Bee-Lian Chen, John J Seaman
雑誌名: Cancer. 2003 Oct 15;98(8):1735-44. doi: 10.1002/cncr.11701.
Abstract/Text BACKGROUND: The goal of the current study was to compare the long-term (25-month) safety and efficacy of zoledronic acid with pamidronate in patients with bone lesions secondary to advanced breast carcinoma or multiple myeloma.
METHODS: Patients (n = 1648) were randomized to receive 4 mg or 8 mg (reduced to 4 mg) zoledronic acid as a 15-minute infusion or to receive 90 mg pamidronate as a 2-hour infusion every 3-4 weeks for 24 months. The primary endpoint was the proportion of patients with at least 1 skeletal-related event (SRE), defined as pathologic fracture, spinal cord compression, radiation therapy, or surgery to bone. Secondary analyses included time to first SRE, skeletal morbidity rate, and multiple-event analysis. Hypercalcemia of malignancy (HCM) was included as an SRE in some secondary analyses.
RESULTS: After 25 months of follow-up, zoledronic acid reduced the overall proportion of patients with an SRE and reduced the skeletal morbidity rate similar to pamidronate. Compared with pamidronate, zoledronic acid (4 mg) reduced the overall risk of developing skeletal complications (including HCM) by an additional 16% (P = 0.030). In patients with breast carcinoma, zoledronic acid (4 mg) was significantly more effective than pamidronate, reducing the risk of SREs by an additional 20% (P = 0.025) compared with pamidronate and by an additional 30% in patients receiving hormonal therapy (P = 0.009). Zoledronic acid (4 mg) and pamidronate were tolerated equally well. The most common adverse events included bone pain, nausea, and fatigue.
CONCLUSIONS: Long-term follow-up data confirm that zoledronic acid was more effective than pamidronate in reducing the risk of skeletal complications in patients with bone metastases from breast carcinoma and was of similar efficacy in patients with multiple myeloma.

Copyright 2003 American Cancer Society.
PMID 14534891  Cancer. 2003 Oct 15;98(8):1735-44. doi: 10.1002/cncr.11・・・
著者: David H Henry, Luis Costa, Francois Goldwasser, Vera Hirsh, Vania Hungria, Jana Prausova, Giorgio Vittorio Scagliotti, Harm Sleeboom, Andrew Spencer, Saroj Vadhan-Raj, Roger von Moos, Wolfgang Willenbacher, Penella J Woll, Jianming Wang, Qi Jiang, Susie Jun, Roger Dansey, Howard Yeh
雑誌名: J Clin Oncol. 2011 Mar 20;29(9):1125-32. doi: 10.1200/JCO.2010.31.3304. Epub 2011 Feb 22.
Abstract/Text PURPOSE: This study compared denosumab, a fully human monoclonal anti-receptor activator of nuclear factor kappa-B ligand antibody, with zoledronic acid (ZA) for delaying or preventing skeletal-related events (SRE) in patients with advanced cancer and bone metastases (excluding breast and prostate) or myeloma.
PATIENTS AND METHODS: Eligible patients were randomly assigned in a double-blind, double-dummy design to receive monthly subcutaneous denosumab 120 mg (n = 886) or intravenous ZA 4 mg (dose adjusted for renal impairment; n = 890). Daily supplemental calcium and vitamin D were strongly recommended. The primary end point was time to first on-study SRE (pathologic fracture, radiation or surgery to bone, or spinal cord compression).
RESULTS: Denosumab was noninferior to ZA in delaying time to first on-study SRE (hazard ratio, 0.84; 95% CI, 0.71 to 0.98; P = .0007). Although directionally favorable, denosumab was not statistically superior to ZA in delaying time to first on-study SRE (P = .03 unadjusted; P = .06 adjusted for multiplicity) or time to first-and-subsequent (multiple) SRE (rate ratio, 0.90; 95% CI, 0.77 to 1.04; P = .14). Overall survival and disease progression were similar between groups. Hypocalcemia occurred more frequently with denosumab. Osteonecrosis of the jaw occurred at similarly low rates in both groups. Acute-phase reactions after the first dose occurred more frequently with ZA, as did renal adverse events and elevations in serum creatinine based on National Cancer Institute Common Toxicity Criteria for Adverse Events grading.
CONCLUSION: Denosumab was noninferior (trending to superiority) to ZA in preventing or delaying first on-study SRE in patients with advanced cancer metastatic to bone or myeloma. Denosumab represents a potential novel treatment option with the convenience of subcutaneous administration and no requirement for renal monitoring or dose adjustment.

PMID 21343556  J Clin Oncol. 2011 Mar 20;29(9):1125-32. doi: 10.1200/J・・・
著者: Noopur Raje, Evangelos Terpos, Wolfgang Willenbacher, Kazuyuki Shimizu, Ramón García-Sanz, Brian Durie, Wojciech Legieć, Marta Krejčí, Kamel Laribi, Li Zhu, Paul Cheng, Douglas Warner, G David Roodman
雑誌名: Lancet Oncol. 2018 Mar;19(3):370-381. doi: 10.1016/S1470-2045(18)30072-X. Epub 2018 Feb 9.
Abstract/Text BACKGROUND: Multiple myeloma is characterised by monoclonal paraprotein production and osteolytic lesions, commonly leading to skeletal-related events (spinal cord compression, pathological fracture, or surgery or radiotherapy to affected bone). Denosumab, a monoclonal antibody targeting RANKL, reduces skeletal-related events associated with bone lesions or metastases in patients with advanced solid tumours. This study aimed to assess the efficacy and safety of denosumab compared with zoledronic acid for the prevention of skeletal-related events in patients with newly diagnosed multiple myeloma.
METHODS: In this international, double-blind, double-dummy, randomised, active-controlled, phase 3 study, patients in 259 centres and 29 countries aged 18 years or older with symptomatic newly diagnosed multiple myeloma who had at least one documented lytic bone lesion were randomly assigned (1:1; centrally, by interactive voice response system using a fixed stratified permuted block randomisation list with a block size of four) to subcutaneous denosumab 120 mg plus intravenous placebo every 4 weeks or intravenous zoledronic acid 4 mg plus subcutaneous placebo every 4 weeks (both groups also received investigators' choice of first-line antimyeloma therapy). Stratification was by intent to undergo autologous transplantation, antimyeloma therapy, International Staging System stage, previous skeletal-related events, and region. The clinical study team and patients were masked to treatment assignments. The primary endpoint was non-inferiority of denosumab to zoledronic acid with respect to time to first skeletal-related event in the full analysis set (all randomly assigned patients). All safety endpoints were analysed in the safety analysis set, which includes all randomly assigned patients who received at least one dose of active study drug. This study is registered with ClinicalTrials.gov, number NCT01345019.
FINDINGS: From May 17, 2012, to March 29, 2016, we enrolled 1718 patients and randomly assigned 859 to each treatment group. The study met the primary endpoint; denosumab was non-inferior to zoledronic acid for time to first skeletal-related event (hazard ratio 0·98, 95% CI 0·85-1·14; pnon-inferiority=0·010). 1702 patients received at least one dose of the investigational drug and were included in the safety analysis (850 patients receiving denosumab and 852 receiving zoledronic acid). The most common grade 3 or worse treatment-emergent adverse events for denosumab and zoledronic acid were neutropenia (126 [15%] vs 125 [15%]), thrombocytopenia (120 [14%] vs 103 [12%]), anaemia (100 [12%] vs 85 [10%]), febrile neutropenia (96 [11%] vs 87 [10%]), and pneumonia (65 [8%] vs 70 [8%]). Renal toxicity was reported in 85 (10%) patients in the denosumab group versus 146 (17%) in the zoledronic acid group; hypocalcaemia adverse events were reported in 144 (17%) versus 106 (12%). Incidence of osteonecrosis of the jaw was not significantly different between the denosumab and zoledronic acid groups (35 [4%] vs 24 [3%]; p=0·147). The most common serious adverse event for both treatment groups was pneumonia (71 [8%] vs 69 [8%]). One patient in the zoledronic acid group died of cardiac arrest that was deemed treatment-related.
INTERPRETATION: In patients with newly diagnosed multiple myeloma, denosumab was non-inferior to zoledronic acid for time to skeletal-related events. The results from this study suggest denosumab could be an additional option for the standard of care for patients with multiple myeloma with bone disease.
FUNDING: Amgen.

Copyright © 2018 Elsevier Ltd. All rights reserved.
PMID 29429912  Lancet Oncol. 2018 Mar;19(3):370-381. doi: 10.1016/S147・・・
著者: Jesus San Miguel, Katja Weisel, Philippe Moreau, Martha Lacy, Kevin Song, Michel Delforge, Lionel Karlin, Hartmut Goldschmidt, Anne Banos, Albert Oriol, Adrian Alegre, Christine Chen, Michele Cavo, Laurent Garderet, Valentina Ivanova, Joaquin Martinez-Lopez, Andrew Belch, Antonio Palumbo, Stephen Schey, Pieter Sonneveld, Xin Yu, Lars Sternas, Christian Jacques, Mohamed Zaki, Meletios Dimopoulos
雑誌名: Lancet Oncol. 2013 Oct;14(11):1055-66. doi: 10.1016/S1470-2045(13)70380-2. Epub 2013 Sep 3.
Abstract/Text BACKGROUND: Few effective treatments exist for patients with refractory or relapsed and refractory multiple myeloma not responding to treatment with bortezomib and lenalidomide. Pomalidomide alone has shown limited efficacy in patients with relapsed multiple myeloma, but synergistic effects have been noted when combined with dexamethasone. We compared the efficacy and safety of pomalidomide plus low-dose dexamethasone with high-dose dexamethasone alone in these patients.
METHODS: This multicentre, open-label, randomised phase 3 trial was undertaken in Australia, Canada, Europe, Russia, and the USA. Patients were eligible if they had been diagnosed with refractory or relapsed and refractory multiple myeloma, and had failed at least two previous treatments of bortezomib and lenalidomide. They were assigned in a 2:1 ratio with a validated interactive voice and internet response system to either 28 day cycles of pomalidomide (4 mg/day on days 1-21, orally) plus low-dose dexamethasone (40 mg/day on days 1, 8, 15, and 22, orally) or high-dose dexamethasone (40 mg/day on days 1-4, 9-12, and 17-20, orally) until disease progression or unacceptable toxicity. Stratification factors were age (≤75 years vs >75 years), disease population (refractory vs relapsed and refractory vs bortezomib intolerant), and number of previous treatments (two vs more than two). The primary endpoint was progression-free survival (PFS). Analysis was by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01311687, and with EudraCT, number 2010-019820-30.
FINDINGS: The accrual for the study has been completed and the analyses are presented. 302 patients were randomly assigned to receive pomalidomide plus low-dose dexamethasone and 153 high-dose dexamethasone. After a median follow-up of 10·0 months (IQR 7·2-13·2), median PFS with pomalidomide plus low-dose dexamethasone was 4·0 months (95% CI 3·6-4·7) versus 1·9 months (1·9-2·2) with high-dose dexamethasone (hazard ratio 0·48 [95% CI 0·39-0·60]; p<0·0001). The most common grade 3-4 haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups were neutropenia (143 [48%] of 300 vs 24 [16%] of 150, respectively), anaemia (99 [33%] vs 55 [37%], respectively), and thrombocytopenia (67 [22%] vs 39 [26%], respectively). Grade 3-4 non-haematological adverse events in the pomalidomide plus low-dose dexamethasone and high-dose dexamethasone groups included pneumonia (38 [13%] vs 12 [8%], respectively), bone pain (21 [7%] vs seven [5%], respectively), and fatigue (16 [5%] vs nine [6%], respectively). There were 11 (4%) treatment-related adverse events leading to death in the pomalidomide plus low-dose dexamethasone group and seven (5%) in the high-dose dexamethasone group.
INTERPRETATION: Pomalidomide plus low-dose dexamethasone, an oral regimen, could be considered a new treatment option in patients with refractory or relapsed and refractory multiple myeloma.
FUNDING: Celgene Corporation.

Copyright © 2013 Elsevier Ltd. All rights reserved.
PMID 24007748  Lancet Oncol. 2013 Oct;14(11):1055-66. doi: 10.1016/S14・・・
著者: Meletios A Dimopoulos, Katja C Weisel, Kevin W Song, Michel Delforge, Lionel Karlin, Hartmut Goldschmidt, Philippe Moreau, Anne Banos, Albert Oriol, Laurent Garderet, Michele Cavo, Valentina Ivanova, Adrian Alegre, Joaquin Martinez-Lopez, Christine Chen, Andrew Spencer, Stefan Knop, Nizar J Bahlis, Christoph Renner, Xin Yu, Kevin Hong, Lars Sternas, Christian Jacques, Mohamed H Zaki, Jesus F San Miguel
雑誌名: Haematologica. 2015 Oct;100(10):1327-33. doi: 10.3324/haematol.2014.117077. Epub 2015 Aug 6.
Abstract/Text Patients with refractory or relapsed and refractory multiple myeloma who no longer receive benefit from novel agents have limited treatment options and short expected survival. del(17p) and t(4;14) are correlated with shortened survival. The phase 3 MM-003 trial demonstrated significant progression-free and overall survival benefits from treatment with pomalidomide plus low-dose dexamethasone compared to high-dose dexamethasone among patients in whom bortezomib and lenalidomide treatment had failed. At an updated median follow-up of 15.4 months, the progression-free survival was 4.0 versus 1.9 months (HR, 0.50; P<0.001), and median overall survival was 13.1 versus 8.1 months (HR, 0.72; P=0.009). Pomalidomide plus low-dose dexamethasone, compared with high-dose dexamethasone, improved progression-free survival in patients with del(17p) (4.6 versus 1.1 months; HR, 0.34; P <0.001), t(4;14) (2.8 versus 1.9 months; HR, 0.49; P=0.028), and in standard-risk patients (4.2 versus 2.3 months; HR, 0.55; P<0.001). Although the majority of patients treated with high-dose dexamethasone took pomalidomide after discontinuation, the overall survival of patients treated with pomalidomide plus low-dose dexamethasone or high-dose dexamethasone was 12.6 versus 7.7 months (HR, 0.45; P=0.008) in patients with del(17p), 7.5 versus 4.9 months (HR, 1.12; P=0.761) in those with t(4;14), and 14.0 versus 9.0 months (HR, 0.85; P=0.380) in standard-risk subjects. The overall response rate was higher in patients treated with pomalidomide plus low-dose dexamethasone than in those treated with high-dose dexamethasone both among standard-risk patients (35.2% versus 9.7%) and those with del(17p) (31.8% versus 4.3%), whereas it was similar in patients with t(4;14) (15.9% versus 13.3%). The safety of pomalidomide plus low-dose dexamethasone was consistent with initial reports. In conclusion, pomalidomide plus low-dose dexamethasone is efficacious in patients with relapsed/refractory multiple myeloma and del(17p) and/or t(4;14). This study is registered at ClinicalTrials.gov as NCT01311687 and with EudraCT as 2010-019820-30.

Copyright© Ferrata Storti Foundation.
PMID 26250580  Haematologica. 2015 Oct;100(10):1327-33. doi: 10.3324/h・・・
著者: Meletios A Dimopoulos, Hartmut Goldschmidt, Ruben Niesvizky, Douglas Joshua, Wee-Joo Chng, Albert Oriol, Robert Z Orlowski, Heinz Ludwig, Thierry Facon, Roman Hajek, Katja Weisel, Vania Hungria, Leonard Minuk, Shibao Feng, Anita Zahlten-Kumeli, Amy S Kimball, Philippe Moreau
雑誌名: Lancet Oncol. 2017 Oct;18(10):1327-1337. doi: 10.1016/S1470-2045(17)30578-8. Epub 2017 Aug 23.
Abstract/Text BACKGROUND: The phase 3 ENDEAVOR trial was a head-to-head comparison of two proteasome inhibitors in patients with relapsed or refractory multiple myeloma. Progression-free survival was previously reported to be significantly longer with carfilzomib administered in combination with dexamethasone than with bortezomib and dexamethasone in an interim analysis. The aim of this second interim analysis was to compare overall survival between the two treatment groups.
METHODS: ENDEAVOR was a phase 3, open-label, randomised controlled trial in patients with relapsed or refractory multiple myeloma. Patients were recruited from 198 hospitals and outpatient clinics in 27 countries in Europe, North America, South America, and the Asia-Pacific region. Patients were aged 18 years or older, had relapsed or refractory multiple myeloma, and had received between one and three previous lines of therapy. Patients were randomly assigned (1:1) to receive carfilzomib and dexamethasone (carfilzomib group) or bortezomib and dexamethasone (bortezomib group) through a blocked randomisation scheme (block size of four), stratified by International Staging System stage, previous lines of treatment, previous proteasome inhibitor therapy, and planned route of bortezomib delivery if assigned to the bortezomib group. Carfilzomib (20 mg/m2 on days 1 and 2 of cycle 1; 56 mg/m2 thereafter) was given as a 30-min intravenous infusion on days 1, 2, 8, 9, 15, and 16 of 28-day cycles; bortezomib (1·3 mg/m2) was given as an intravenous bolus or subcutaneous injection on days 1, 4, 8, and 11 of 21-day cycles. Dexamethasone (20 mg oral or intravenous infusion) was given on days 1, 2, 8, 9, 15, 16, 22, and 23 in the carfilzomib group and on days 1, 2, 4, 5, 8, 9, 11, and 12 in the bortezomib group. The primary endpoint of ENDEAVOR, progression-free survival, has been previously reported. A stratified log-rank test was used to compare overall survival between treatment groups for this prospectively planned second interim analysis. Efficacy assessments were done in all randomly assigned patients (the intention-to-treat population) and the safety analysis included patients who received at least one dose of study treatment. This trial is registered with ClinicalTrials.gov, number NCT01568866, and is no longer enrolling patients.
FINDINGS: Between June 20, 2012, and June 30, 2014, 1096 patients were assessed for eligibility, of whom 929 were randomly assigned (464 to the carfilzomib group and 465 to the bortezomib group). The cutoff date for this prespecified interim analysis was Jan 3, 2017. Median overall survival was 47·6 months (95% CI 42·5-not evaluable) in the carfilzomib group versus 40·0 months (32·6-42·3) in the bortezomib group (hazard ratio 0·791 [95% CI 0·648-0·964], one-sided p=0·010). Grade 3 or worse adverse events were reported in 377 (81%) of 463 patients in the carfilzomib group and 324 (71%) of 456 patients in the bortezomib group, and serious adverse events in 273 (59%) patients in the carfilzomib group and 182 (40%) in the bortezomib group. The most frequent grade 3 or worse adverse events were anaemia (76 [16%] of 463 patients in the carfilzomib group vs 46 [10%] of 456 patients in the bortezomib group), hypertension (67 [15%] vs 15 [3%]), pneumonia (42 [9%] vs 39 [9%]), thrombocytopenia (41 [9%] vs 43 [9%]), fatigue (31 [7%] vs 35 [8%]), dyspnoea (29 [6%] vs ten [2%]), decreased lymphocyte count (29 [6%] vs nine [2%]), diarrhoea (18 [4%] vs 39 [9%]), and peripheral neuropathy (six [1%] vs 28 [6%]). Treatment-related deaths occurred in five (1%) of 463 patients in the carfilzomib group (pneumonia [n=2], interstitial lung disease [n=1], septic shock [n=1], and unknown [n=1]) and two (<1%) of 456 patients in the bortezomib group (cardiac arrest [n=1] and pneumonia [n=1]).
INTERPRETATION: Carfilzomib provided a significant and clinically meaningful reduction in the risk of death compared with bortezomib. To our knowledge, carfilzomib is the first and only multiple myeloma treatment that extends overall survival in the relapsed setting over the current standard of care. This study is informative for deciding which proteasome inhibitor to use for treating this disease.
FUNDING: Onyx Pharmaceuticals Inc, an Amgen Inc subsidiary.

Copyright © 2017 Elsevier Ltd. All rights reserved.
PMID 28843768  Lancet Oncol. 2017 Oct;18(10):1327-1337. doi: 10.1016/S・・・
著者: Philippe Moreau, Tamás Masszi, Norbert Grzasko, Nizar J Bahlis, Markus Hansson, Ludek Pour, Irwindeep Sandhu, Peter Ganly, Bartrum W Baker, Sharon R Jackson, Anne-Marie Stoppa, David R Simpson, Peter Gimsing, Antonio Palumbo, Laurent Garderet, Michele Cavo, Shaji Kumar, Cyrille Touzeau, Francis K Buadi, Jacob P Laubach, Deborah T Berg, Jianchang Lin, Alessandra Di Bacco, Ai-Min Hui, Helgi van de Velde, Paul G Richardson, TOURMALINE-MM1 Study Group
雑誌名: N Engl J Med. 2016 Apr 28;374(17):1621-34. doi: 10.1056/NEJMoa1516282.
Abstract/Text BACKGROUND: Ixazomib is an oral proteasome inhibitor that is currently being studied for the treatment of multiple myeloma.
METHODS: In this double-blind, placebo-controlled, phase 3 trial, we randomly assigned 722 patients who had relapsed, refractory, or relapsed and refractory multiple myeloma to receive ixazomib plus lenalidomide-dexamethasone (ixazomib group) or placebo plus lenalidomide-dexamethasone (placebo group). The primary end point was progression-free survival.
RESULTS: Progression-free survival was significantly longer in the ixazomib group than in the placebo group at a median follow-up of 14.7 months (median progression-free survival, 20.6 months vs. 14.7 months; hazard ratio for disease progression or death in the ixazomib group, 0.74; P=0.01); a benefit with respect to progression-free survival was observed with the ixazomib regimen, as compared with the placebo regimen, in all prespecified patient subgroups, including in patients with high-risk cytogenetic abnormalities. The overall rates of response were 78% in the ixazomib group and 72% in the placebo group, and the corresponding rates of complete response plus very good partial response were 48% and 39%. The median time to response was 1.1 months in the ixazomib group and 1.9 months in the placebo group, and the corresponding median duration of response was 20.5 months and 15.0 months. At a median follow-up of approximately 23 months, the median overall survival has not been reached in either study group, and follow-up is ongoing. The rates of serious adverse events were similar in the two study groups (47% in the ixazomib group and 49% in the placebo group), as were the rates of death during the study period (4% and 6%, respectively); adverse events of at least grade 3 severity occurred in 74% and 69% of the patients, respectively. Thrombocytopenia of grade 3 and grade 4 severity occurred more frequently in the ixazomib group (12% and 7% of the patients, respectively) than in the placebo group (5% and 4% of the patients, respectively). Rash occurred more frequently in the ixazomib group than in the placebo group (36% vs. 23% of the patients), as did gastrointestinal adverse events, which were predominantly low grade. The incidence of peripheral neuropathy was 27% in the ixazomib group and 22% in the placebo group (grade 3 events occurred in 2% of the patients in each study group). Patient-reported quality of life was similar in the two study groups.
CONCLUSIONS: The addition of ixazomib to a regimen of lenalidomide and dexamethasone was associated with significantly longer progression-free survival; the additional toxic effects with this all-oral regimen were limited. (Funded by Millennium Pharmaceuticals; TOURMALINE-MM1 ClinicalTrials.gov number, NCT01564537.).

PMID 27119237  N Engl J Med. 2016 Apr 28;374(17):1621-34. doi: 10.1056・・・
著者: María-Victoria Mateos, Tamas Masszi, Norbert Grzasko, Markus Hansson, Irwindeep Sandhu, Ludek Pour, Luísa Viterbo, Sharon R Jackson, Anne-Marie Stoppa, Peter Gimsing, Mehdi Hamadani, Gabriela Borsaru, Deborah Berg, Jianchang Lin, Alessandra Di Bacco, Helgi van de Velde, Paul G Richardson, Philippe Moreau
雑誌名: Haematologica. 2017 Oct;102(10):1767-1775. doi: 10.3324/haematol.2017.170118. Epub 2017 Jul 27.
Abstract/Text Prior treatment exposure in patients with relapsed/refractory multiple myeloma may affect outcomes with subsequent therapies. We analyzed efficacy and safety according to prior treatment in the phase 3 TOURMALINE-MM1 study of ixazomib-lenalidomide-dexamethasone (ixazomib-Rd) versus placebo-Rd. Patients with relapsed/refractory multiple myeloma received ixazomib-Rd or placebo-Rd. Efficacy and safety were evaluated in subgroups defined according to type (proteasome inhibitor [PI] and immunomodulatory drug) and number (1 vs. 2 or 3) of prior therapies received. Of 722 patients, 503 (70%) had received a prior PI, and 397 (55%) prior lenalidomide/thalidomide; 425 patients had received 1 prior therapy, and 297 received 2 or 3 prior therapies. At a median follow up of ~15 months, PFS was prolonged with ixazomib-Rd vs. placebo-Rd regardless of type of prior therapy received; HR 0.739 and 0.749 in PI-exposed and -naïve patients, HR 0.744 and 0.700 in immunomodulatory-drug-exposed and -naïve patients, respectively. PFS benefit with ixazomib-Rd vs. placebo-Rd appeared greater in patients with 2 or 3 prior therapies (HR 0.58) and in those with 1 prior therapy without prior transplant (HR 0.60) versus those with 1 prior therapy and transplant (HR 1.23). Across all subgroups, toxicity was consistent with that seen in the intent-to-treat population. In patients with relapsed/refractory multiple myeloma, ixazomib-Rd was associated with a consistent clinical benefit vs. placebo-Rd regardless of prior treatment with bortezomib or immunomodulatory drugs. Patients with 2 or 3 prior therapies, or 1 prior therapy without transplant seemed to have greater benefit than patients with 1 prior therapy and transplant. TOURMALINE-MM1 registered at clinicaltrials.gov identifier: 01564537.

Copyright© 2017 Ferrata Storti Foundation.
PMID 28751562  Haematologica. 2017 Oct;102(10):1767-1775. doi: 10.3324・・・
著者: Jesús F San-Miguel, Vânia T M Hungria, Sung-Soo Yoon, Meral Beksac, Meletios Athanasios Dimopoulos, Ashraf Elghandour, Wieslaw Wiktor Jedrzejczak, Andreas Günther, Thanyaphong Na Nakorn, Noppadol Siritanaratkul, Paolo Corradini, Suporn Chuncharunee, Je-Jung Lee, Robert L Schlossman, Tatiana Shelekhova, Kwee Yong, Daryl Tan, Tontanai Numbenjapon, Jamie D Cavenagh, Jian Hou, Richard LeBlanc, Hareth Nahi, Lugui Qiu, Hans Salwender, Stefano Pulini, Philippe Moreau, Krzysztof Warzocha, Darrell White, Joan Bladé, WenMing Chen, Javier de la Rubia, Peter Gimsing, Sagar Lonial, Jonathan L Kaufman, Enrique M Ocio, Ljupco Veskovski, Sang Kyun Sohn, Ming-Chung Wang, Jae Hoon Lee, Hermann Einsele, Monika Sopala, Claudia Corrado, Bourras-Rezki Bengoudifa, Florence Binlich, Paul G Richardson
雑誌名: Lancet Oncol. 2014 Oct;15(11):1195-206. doi: 10.1016/S1470-2045(14)70440-1. Epub 2014 Sep 18.
Abstract/Text BACKGROUND: Panobinostat is a potent oral pan-deacetylase inhibitor that in preclinical studies has synergistic anti-myeloma activity when combined with bortezomib and dexamethasone. We aimed to compare panobinostat, bortezomib, and dexamethasone with placebo, bortezomib, and dexamethasone in patients with relapsed or relapsed and refractory multiple myeloma.
METHODS: PANORAMA1 is a multicentre, randomised, placebo-controlled, double-blind phase 3 trial of patients with relapsed or relapsed and refractory multiple myeloma who have received between one and three previous treatment regimens. Patients were randomly assigned (1:1) via an interactive web-based and voice response system, stratified by number of previous treatment lines and by previous use of bortezomib, to receive 21 day cycles of placebo or panobinostat (20 mg; on days 1, 3, 5, 8, 10, 12, orally), both in combination with bortezomib (1·3 mg/m(2) on days 1, 4, 8, 11, intravenously) and dexamethasone (20 mg on days 1, 2, 4, 5, 8, 9, 11, 12, orally). Patients, physicians, and the investigators who did the data analysis were masked to treatment allocation; crossover was not permitted. The primary endpoint was progression-free survival (in accordance with modified European Group for Blood and Marrow Transplantation criteria and based on investigators' assessment) and was analysed by intention to treat. The study is ongoing, but no longer recruiting, and is registered at ClinicalTrials.gov, number NCT01023308.
FINDINGS: 768 patients were enrolled between Jan 21, 2010, and Feb 29, 2012, with 387 randomly assigned to panobinostat, bortezomib, and dexamethasone and 381 to placebo, bortezomib, and dexamethasone. Median follow-up was 6·47 months (IQR 1·81-13·47) in the panobinostat group and 5·59 months (2·14-11·30) in the placebo group. Median progression-free survival was significantly longer in the panobinostat group than in the placebo group (11·99 months [95% CI 10·33-12·94] vs 8·08 months [7·56-9·23]; hazard ratio [HR] 0·63, 95% CI 0·52-0·76; p<0·0001). Overall survival data are not yet mature, although at the time of this analysis, median overall survival was 33·64 months (95% CI 31·34-not estimable) for the panobinostat group and 30·39 months (26·87-not estimable) for the placebo group (HR 0·87, 95% CI 0·69-1·10; p=0·26). The proportion of patients achieving an overall response did not differ between treatment groups (235 [60·7%, 95% CI 55·7-65·6] for panobinostat vs 208 [54·6%, 49·4-59·7] for placebo; p=0·09); however, the proportion of patients with a complete or near complete response was significantly higher in the panobinostat group than in the placebo group (107 [27·6%, 95% CI 23·2-32·4] vs 60 [15·7%, 12·2-19·8]; p=0·00006). Minimal responses were noted in 23 (6%) patients in the panobinostat group and in 42 (11%) in the placebo group. Median duration of response (partial response or better) was 13·14 months (95% CI 11·76-14·92) in the panobinostat group and 10·87 months (9·23-11·76) in the placebo group, and median time to response (partial response or better) was 1·51 months (1·41-1·64) in the panobinostat group and 2·00 months (1·61-2·79) in the placebo group. Serious adverse events were reported in 228 (60%) of 381 patients in the panobinostat group and 157 (42%) of 377 patients in the placebo group. Common grade 3-4 laboratory abnormalities and adverse events (irrespective of association with study drug) included thrombocytopenia (256 [67%] in the panobinostat group vs 118 [31%] in the placebo group), lymphopenia (202 [53%] vs 150 [40%]), diarrhoea (97 [26%] vs 30 [8%]), asthenia or fatigue (91 [24%] vs 45 [12%]), and peripheral neuropathy (67 [18%] vs 55 [15%]).
INTERPRETATION: Our results suggest that panobinostat could be a useful addition to the treatment armamentarium for patients with relapsed or relapsed and refractory multiple myeloma. Longer follow up will be necessary to determine whether there is any effect on overall survival.
FUNDING: Novartis Pharmaceuticals.

Copyright © 2014 Elsevier Ltd. All rights reserved.
PMID 25242045  Lancet Oncol. 2014 Oct;15(11):1195-206. doi: 10.1016/S1・・・
著者: Jeffrey A Zonder, Ann F Mohrbacher, Seema Singhal, Frits van Rhee, William I Bensinger, Han Ding, John Fry, Daniel E H Afar, Anil K Singhal
雑誌名: Blood. 2012 Jul 19;120(3):552-9. doi: 10.1182/blood-2011-06-360552. Epub 2011 Dec 19.
Abstract/Text This multicenter, first-in-human study evaluated the safety, tolerability, and pharmacokinetic and pharmacodynamic properties of the anti-CS1 monoclonal antibody elotuzumab. A standard 3 + 3 design was used to determine maximum tolerated dose; dose-limiting toxicities were assessed during cycle 1. Thirty-five patients with relapsed/refractory multiple myeloma were treated with intravenous elotuzumab at doses ranging from 0.5 to 20 mg/kg every 2 weeks. Patients who achieved at least stable disease after 4 treatments could receive another 4 treatments. No maximum tolerated dose was identified up to the maximum planned dose of 20 mg/kg. The most common adverse events, regardless of attribution, were cough, headache, back pain, fever, and chills. Adverse events were generally mild to moderate in severity, and adverse events attributed to study medication were primarily infusion-related. Plasma elotuzumab levels and terminal half-life increased with dose whereas clearance decreased, suggesting target-mediated clearance. CS1 on bone marrow-derived plasma cells was reliably saturated (≥ 95%) at the 10-mg/kg and 20-mg/kg dose levels. Using the European Group for Bone and Marrow Transplantation myeloma response criteria, 9 patients (26.5%) had stable disease. In summary, elotuzumab was generally well tolerated in this population, justifying further exploration of this agent in combination regimens.

PMID 22184404  Blood. 2012 Jul 19;120(3):552-9. doi: 10.1182/blood-201・・・
著者: Sagar Lonial, Meletios Dimopoulos, Antonio Palumbo, Darrell White, Sebastian Grosicki, Ivan Spicka, Adam Walter-Croneck, Philippe Moreau, Maria-Victoria Mateos, Hila Magen, Andrew Belch, Donna Reece, Meral Beksac, Andrew Spencer, Heather Oakervee, Robert Z Orlowski, Masafumi Taniwaki, Christoph Röllig, Hermann Einsele, Ka Lung Wu, Anil Singhal, Jesus San-Miguel, Morio Matsumoto, Jessica Katz, Eric Bleickardt, Valerie Poulart, Kenneth C Anderson, Paul Richardson, ELOQUENT-2 Investigators
雑誌名: N Engl J Med. 2015 Aug 13;373(7):621-31. doi: 10.1056/NEJMoa1505654. Epub 2015 Jun 2.
Abstract/Text BACKGROUND: Elotuzumab, an immunostimulatory monoclonal antibody targeting signaling lymphocytic activation molecule F7 (SLAMF7), showed activity in combination with lenalidomide and dexamethasone in a phase 1b-2 study in patients with relapsed or refractory multiple myeloma.
METHODS: In this phase 3 study, we randomly assigned patients to receive either elotuzumab plus lenalidomide and dexamethasone (elotuzumab group) or lenalidomide and dexamethasone alone (control group). Coprimary end points were progression-free survival and the overall response rate. Final results for the coprimary end points are reported on the basis of a planned interim analysis of progression-free survival.
RESULTS: Overall, 321 patients were assigned to the elotuzumab group and 325 to the control group. After a median follow-up of 24.5 months, the rate of progression-free survival at 1 year in the elotuzumab group was 68%, as compared with 57% in the control group; at 2 years, the rates were 41% and 27%, respectively. Median progression-free survival in the elotuzumab group was 19.4 months, versus 14.9 months in the control group (hazard ratio for progression or death in the elotuzumab group, 0.70; 95% confidence interval, 0.57 to 0.85; P<0.001). The overall response rate in the elotuzumab group was 79%, versus 66% in the control group (P<0.001). Common grade 3 or 4 adverse events in the two groups were lymphocytopenia, neutropenia, fatigue, and pneumonia. Infusion reactions occurred in 33 patients (10%) in the elotuzumab group and were grade 1 or 2 in 29 patients.
CONCLUSIONS: Patients with relapsed or refractory multiple myeloma who received a combination of elotuzumab, lenalidomide, and dexamethasone had a significant relative reduction of 30% in the risk of disease progression or death. (Funded by Bristol-Myers Squibb and AbbVie Biotherapeutics; ELOQUENT-2 ClinicalTrials.gov number, NCT01239797.).

PMID 26035255  N Engl J Med. 2015 Aug 13;373(7):621-31. doi: 10.1056/N・・・
著者: Meletios A Dimopoulos, Sagar Lonial, Darrell White, Philippe Moreau, Antonio Palumbo, Jesus San-Miguel, Ofer Shpilberg, Kenneth Anderson, Sebastian Grosicki, Ivan Spicka, Adam Walter-Croneck, Hila Magen, Maria-Victoria Mateos, Andrew Belch, Donna Reece, Meral Beksac, Eric Bleickardt, Valerie Poulart, Jennifer Sheng, Oumar Sy, Jessica Katz, Anil Singhal, Paul Richardson
雑誌名: Br J Haematol. 2017 Sep;178(6):896-905. doi: 10.1111/bjh.14787. Epub 2017 Jul 5.
Abstract/Text The randomized phase III ELOQUENT-2 study (NCT01239797) evaluated the efficacy and safety of elotuzumab + lenalidomide/dexamethasone (ELd) versus lenalidomide/dexamethasone (Ld) in relapsed/refractory multiple myeloma. ELd reduced the risk of disease progression/death by 30% versus Ld (hazard ratio [HR] 0·70). Median time from diagnosis was 3·5 years. We present extended 3-year follow-up data. Endpoints included progression-free survival (PFS), overall response rate (ORR) and interim overall survival (OS). Exploratory post-hoc analyses included impact of time from diagnosis and prior lines of therapy on PFS, and serum M-protein dynamic modelling. ORR was 79% (ELd) and 66% (Ld) (P = 0·0002). ELd reduced the risk of disease progression/death by 27% versus Ld (HR 0·73; P = 0·0014). Interim OS demonstrated a trend in favour of ELd (P = 0·0257); 1-, 2- and 3-year rates with ELd versus Ld were: 91% versus 83%, 73% versus 69% and 60% versus 53%. In patients with ≥ median time from diagnosis and one prior therapy, ELd resulted in a 53% reduction in the risk of progression/death versus Ld (HR 0·47). Serum M-protein dynamic modelling showed slower tumour regrowth with ELd. Adverse events were comparable between arms. ELd provided a durable and clinically relevant improvement in efficacy, with minimal incremental toxicity.

© 2017 John Wiley & Sons Ltd.
PMID 28677826  Br J Haematol. 2017 Sep;178(6):896-905. doi: 10.1111/bj・・・
著者: Sagar Lonial, Brendan M Weiss, Saad Z Usmani, Seema Singhal, Ajai Chari, Nizar J Bahlis, Andrew Belch, Amrita Krishnan, Robert A Vescio, Maria Victoria Mateos, Amitabha Mazumder, Robert Z Orlowski, Heather J Sutherland, Joan Bladé, Emma C Scott, Albert Oriol, Jesus Berdeja, Mecide Gharibo, Don A Stevens, Richard LeBlanc, Michael Sebag, Natalie Callander, Andrzej Jakubowiak, Darrell White, Javier de la Rubia, Paul G Richardson, Steen Lisby, Huaibao Feng, Clarissa M Uhlar, Imran Khan, Tahamtan Ahmadi, Peter M Voorhees
雑誌名: Lancet. 2016 Apr 9;387(10027):1551-1560. doi: 10.1016/S0140-6736(15)01120-4. Epub 2016 Jan 7.
Abstract/Text BACKGROUND: New treatment options are needed for patients with multiple myeloma that is refractory to proteasome inhibitors and immunomodulatory drugs. We assessed daratumumab, a novel CD38-targeted monoclonal antibody, in patients with refractory multiple myeloma.
METHODS: In this open-label, multicentre, phase 2 trial done in Canada, Spain, and the USA, patients (age ≥18 years) with multiple myeloma who were previously treated with at least three lines of therapy (including proteasome inhibitors and immunomodulatory drugs), or were refractory to both proteasome inhibitors and immunomodulatory drugs, were randomly allocated in a 1:1 ratio to receive intravenous daratumumab 8 mg/kg or 16 mg/kg in part 1 stage 1 of the study, to decide the dose for further assessment in part 2. Patients received 8 mg/kg every 4 weeks, or 16 mg/kg per week for 8 weeks (cycles 1 and 2), then every 2 weeks for 16 weeks (cycles 3-6), and then every 4 weeks thereafter (cycle 7 and higher). The allocation schedule was computer-generated and randomisation, with permuted blocks, was done centrally with an interactive web response system. In part 1 stage 2 and part 2, patients received 16 mg/kg dosed as in part 1 stage 1. The primary endpoint was overall response rate (partial response [PR] + very good PR + complete response [CR] + stringent CR). All patients who received at least one dose of daratumumab were included in the analysis. The trial is registered with ClinicalTrials.gov, number NCT01985126.
FINDINGS: The study is ongoing. In part 1 stage 1 of the study, 18 patients were randomly allocated to the 8 mg/kg group and 16 to the 16 mg/kg group. Findings are reported for the 106 patients who received daratumumab 16 mg/kg in parts 1 and 2. Patients received a median of five previous lines of therapy (range 2-14). 85 (80%) patients had previously received autologous stem cell transplantation, 101 (95%) were refractory to the most recent proteasome inhibitors and immunomodulatory drugs used, and 103 (97%) were refractory to the last line of therapy. Overall responses were noted in 31 patients (29.2%, 95% CI 20.8-38.9)-three (2.8%, 0.6-8.0) had a stringent CR, ten (9.4%, 4.6-16.7) had a very good PR, and 18 (17.0%, 10.4-25.5) had a PR. The median time to first response was 1.0 month (range 0.9-5.6). Median duration of response was 7.4 months (95% CI 5.5-not estimable) and progression-free survival was 3.7 months (95% CI 2.8-4.6). The 12-month overall survival was 64.8% (95% CI 51.2-75.5) and, at a subsequent cutoff, median overall survival was 17.5 months (95% CI 13.7-not estimable). Daratumumab was well tolerated; fatigue (42 [40%] patients) and anaemia (35 [33%]) of any grade were the most common adverse events. No drug-related adverse events led to treatment discontinuation.
INTERPRETATION: Daratumumab monotherapy showed encouraging efficacy in heavily pretreated and refractory patients with multiple myeloma, with a favourable safety profile in this population of patients.
FUNDING: Janssen Research & Development.

Copyright © 2016 Elsevier Ltd. All rights reserved.
PMID 26778538  Lancet. 2016 Apr 9;387(10027):1551-1560. doi: 10.1016/S・・・
著者: Meletios A Dimopoulos, Albert Oriol, Hareth Nahi, Jesus San-Miguel, Nizar J Bahlis, Saad Z Usmani, Neil Rabin, Robert Z Orlowski, Mieczyslaw Komarnicki, Kenshi Suzuki, Torben Plesner, Sung-Soo Yoon, Dina Ben Yehuda, Paul G Richardson, Hartmut Goldschmidt, Donna Reece, Steen Lisby, Nushmia Z Khokhar, Lisa O'Rourke, Christopher Chiu, Xiang Qin, Mary Guckert, Tahamtan Ahmadi, Philippe Moreau, POLLUX Investigators
雑誌名: N Engl J Med. 2016 Oct 6;375(14):1319-1331. doi: 10.1056/NEJMoa1607751.
Abstract/Text BACKGROUND: Daratumumab showed promising efficacy alone and with lenalidomide and dexamethasone in a phase 1-2 study involving patients with relapsed or refractory multiple myeloma.
METHODS: In this phase 3 trial, we randomly assigned 569 patients with multiple myeloma who had received one or more previous lines of therapy to receive lenalidomide and dexamethasone either alone (control group) or in combination with daratumumab (daratumumab group). The primary end point was progression-free survival.
RESULTS: At a median follow-up of 13.5 months in a protocol-specified interim analysis, 169 events of disease progression or death were observed (in 53 of 286 patients [18.5%] in the daratumumab group vs. 116 of 283 [41.0%] in the control group; hazard ratio, 0.37; 95% confidence interval [CI], 0.27 to 0.52; P<0.001 by stratified log-rank test). The Kaplan-Meier rate of progression-free survival at 12 months was 83.2% (95% CI, 78.3 to 87.2) in the daratumumab group, as compared with 60.1% (95% CI, 54.0 to 65.7) in the control group. A significantly higher rate of overall response was observed in the daratumumab group than in the control group (92.9% vs. 76.4%, P<0.001), as was a higher rate of complete response or better (43.1% vs. 19.2%, P<0.001). In the daratumumab group, 22.4% of the patients had results below the threshold for minimal residual disease (1 tumor cell per 105 white cells), as compared with 4.6% of those in the control group (P<0.001); results below the threshold for minimal residual disease were associated with improved outcomes. The most common adverse events of grade 3 or 4 during treatment were neutropenia (in 51.9% of the patients in the daratumumab group vs. 37.0% of those in the control group), thrombocytopenia (in 12.7% vs. 13.5%), and anemia (in 12.4% vs. 19.6%). Daratumumab-associated infusion-related reactions occurred in 47.7% of the patients and were mostly of grade 1 or 2.
CONCLUSIONS: The addition of daratumumab to lenalidomide and dexamethasone significantly lengthened progression-free survival among patients with relapsed or refractory multiple myeloma. Daratumumab was associated with infusion-related reactions and a higher rate of neutropenia than the control therapy. (Funded by Janssen Research and Development; POLLUX ClinicalTrials.gov number, NCT02076009 .).

PMID 27705267  N Engl J Med. 2016 Oct 6;375(14):1319-1331. doi: 10.105・・・
著者: Meletios A Dimopoulos, Jesus San-Miguel, Andrew Belch, Darrell White, Lotfi Benboubker, Gordon Cook, Merav Leiba, James Morton, P Joy Ho, Kihyun Kim, Naoki Takezako, Philippe Moreau, Jonathan L Kaufman, Heather J Sutherland, Marc Lalancette, Hila Magen, Shinsuke Iida, Jin Seok Kim, H Miles Prince, Tara Cochrane, Albert Oriol, Nizar J Bahlis, Ajai Chari, Lisa O'Rourke, Kaida Wu, Jordan M Schecter, Tineke Casneuf, Christopher Chiu, David Soong, A Kate Sasser, Nushmia Z Khokhar, Hervé Avet-Loiseau, Saad Z Usmani
雑誌名: Haematologica. 2018 Dec;103(12):2088-2096. doi: 10.3324/haematol.2018.194282. Epub 2018 Sep 20.
Abstract/Text In the POLLUX study, daratumumab plus lenalidomide/dexamethasone significantly reduced risk of progression/death versus lenalidomide/dexamethasone alone in relapsed/refractory multiple myeloma. We provide one additional year of follow up and include the effect on minimal residual disease and in clinically relevant subgroups. After 25.4 months of follow up, daratumumab plus lenalidomide/dexamethasone prolonged progression-free survival versus lenalidomide/dexamethasone alone (median not reached vs 17.5 months; hazard ratio, 0.41; 95% confidence interval, 0.31-0.53; P<0.0001). The overall response rate was 92.9% versus 76.4%, and 51.2% versus 21.0% achieved a complete response or better, respectively (both P<0.0001). At the 10-5 sensitivity threshold, 26.2% versus 6.4% were minimal residual disease-negative, respectively (P<0.0001). Post hoc analyses of clinically relevant patient subgroups demonstrated that progression-free survival was significantly prolonged for daratumumab plus lenalidomide/dexamethasone versus lenalidomide/dexamethasone regardless of number of prior lines of therapy. Patients previously treated with lenalidomide or thalidomide and those refractory to bortezomib received similar benefits (all P<0.01). Treatment benefit with daratumumab plus lenalidomide/dexamethasone was maintained in high-risk patients (median progression-free survival 22.6 vs 10.2 months; hazard ratio, 0.53; 95% confidence interval, 0.25-1.13; P=0.0921) and patients with treatment-free intervals of >12 and ≤12 months and >6 and ≤6 months. No new safety signals were observed. In relapsed/refractory multiple myeloma patients, daratumumab plus lenalidomide/dexamethasone continued to improve progression-free survival and deepen responses versus lenalidomide/dexamethasone. Trial Registration: clinicaltrials.gov identifier: 02076009.

Copyright© 2018 Ferrata Storti Foundation.
PMID 30237262  Haematologica. 2018 Dec;103(12):2088-2096. doi: 10.3324・・・
著者: Antonio Palumbo, Asher Chanan-Khan, Katja Weisel, Ajay K Nooka, Tamas Masszi, Meral Beksac, Ivan Spicka, Vania Hungria, Markus Munder, Maria V Mateos, Tomer M Mark, Ming Qi, Jordan Schecter, Himal Amin, Xiang Qin, William Deraedt, Tahamtan Ahmadi, Andrew Spencer, Pieter Sonneveld, CASTOR Investigators
雑誌名: N Engl J Med. 2016 Aug 25;375(8):754-66. doi: 10.1056/NEJMoa1606038.
Abstract/Text BACKGROUND: Daratumumab, a human IgGκ monoclonal antibody that targets CD38, induces direct and indirect antimyeloma activity and has shown substantial efficacy as monotherapy in heavily pretreated patients with multiple myeloma, as well as in combination with bortezomib in patients with newly diagnosed multiple myeloma.
METHODS: In this phase 3 trial, we randomly assigned 498 patients with relapsed or relapsed and refractory multiple myeloma to receive bortezomib (1.3 mg per square meter of body-surface area) and dexamethasone (20 mg) alone (control group) or in combination with daratumumab (16 mg per kilogram of body weight) (daratumumab group). The primary end point was progression-free survival.
RESULTS: A prespecified interim analysis showed that the rate of progression-free survival was significantly higher in the daratumumab group than in the control group; the 12-month rate of progression-free survival was 60.7% in the daratumumab group versus 26.9% in the control group. After a median follow-up period of 7.4 months, the median progression-free survival was not reached in the daratumumab group and was 7.2 months in the control group (hazard ratio for progression or death with daratumumab vs. control, 0.39; 95% confidence interval, 0.28 to 0.53; P<0.001). The rate of overall response was higher in the daratumumab group than in the control group (82.9% vs. 63.2%, P<0.001), as were the rates of very good partial response or better (59.2% vs. 29.1%, P<0.001) and complete response or better (19.2% vs. 9.0%, P=0.001). Three of the most common grade 3 or 4 adverse events reported in the daratumumab group and the control group were thrombocytopenia (45.3% and 32.9%, respectively), anemia (14.4% and 16.0%, respectively), and neutropenia (12.8% and 4.2%, respectively). Infusion-related reactions that were associated with daratumumab treatment were reported in 45.3% of the patients in the daratumumab group; these reactions were mostly grade 1 or 2 (grade 3 in 8.6% of the patients), and in 98.2% of these patients, they occurred during the first infusion.
CONCLUSIONS: Among patients with relapsed or relapsed and refractory multiple myeloma, daratumumab in combination with bortezomib and dexamethasone resulted in significantly longer progression-free survival than bortezomib and dexamethasone alone and was associated with infusion-related reactions and higher rates of thrombocytopenia and neutropenia than bortezomib and dexamethasone alone. (Funded by Janssen Research and Development; ClinicalTrials.gov number, NCT02136134.).

PMID 27557302  N Engl J Med. 2016 Aug 25;375(8):754-66. doi: 10.1056/N・・・
著者: Andrew Spencer, Suzanne Lentzsch, Katja Weisel, Hervé Avet-Loiseau, Tomer M Mark, Ivan Spicka, Tamas Masszi, Birgitta Lauri, Mark-David Levin, Alberto Bosi, Vania Hungria, Michele Cavo, Je-Jung Lee, Ajay K Nooka, Hang Quach, Cindy Lee, Wolney Barreto, Paolo Corradini, Chang-Ki Min, Emma C Scott, Asher A Chanan-Khan, Noemi Horvath, Marcelo Capra, Meral Beksac, Roberto Ovilla, Jae-Cheol Jo, Ho-Jin Shin, Pieter Sonneveld, David Soong, Tineke Casneuf, Christopher Chiu, Himal Amin, Ming Qi, Piruntha Thiyagarajah, A Kate Sasser, Jordan M Schecter, Maria-Victoria Mateos
雑誌名: Haematologica. 2018 Dec;103(12):2079-2087. doi: 10.3324/haematol.2018.194118. Epub 2018 Sep 20.
Abstract/Text Daratumumab, a CD38 human monoclonal antibody, demonstrated significant clinical activity in combination with bortezomib and dexamethasone versus bortezomib and dexamethasone alone in the primary analysis of CASTOR, a phase 3 study in relapsed and/or refractory multiple myeloma. A post hoc analysis based on treatment history and longer follow up is presented. After 19.4 (range: 0-27.7) months of median follow up, daratumumab plus bortezomib and dexamethasone prolonged progression-free survival (median: 16.7 versus 7.1 months; hazard ratio, 0.31; 95% confidence interval, 0.24-0.39; P<0.0001) and improved the overall response rate (83.8% versus 63.2%; P<0.0001) compared with bortezomib and dexamethasone alone. The progression-free survival benefit of daratumumab plus bortezomib and dexamethasone was most apparent in patients with 1 prior line of therapy (median: not reached versus 7.9 months; hazard ratio, 0.19; 95% con fidence interval, 0.12-0.29; P<0.0001). Daratumumab plus bortezomib and dexamethasone was also superior to bortezomib and dexamethasone alone in subgroups based on prior treatment exposure (bortezomib, thalidomide, or lenalidomide), lenalidomide-refractory status, time since last therapy (≤12, >12, ≤6, or >6 months), or cytogenetic risk. Minimal residual disease-negative rates were >2.5-fold higher with daratumumab across subgroups. The safety profile of daratumumab plus bortezomib and dexamethasone remained consistent with longer follow up. Daratumumab plus bortezomib and dexamethasone demonstrated significant clinical activity across clinically relevant subgroups and provided the greatest benefit to patients treated at first relapse. Trial registration: clinicaltrials.gov identifier: 02136134.

Copyright© 2018 Ferrata Storti Foundation.
PMID 30237264  Haematologica. 2018 Dec;103(12):2079-2087. doi: 10.3324・・・
著者: Meletios Dimopoulos, Hang Quach, Maria-Victoria Mateos, Ola Landgren, Xavier Leleu, David Siegel, Katja Weisel, Hui Yang, Zandra Klippel, Anita Zahlten-Kumeli, Saad Z Usmani
雑誌名: Lancet. 2020 Jul 18;396(10245):186-197. doi: 10.1016/S0140-6736(20)30734-0.
Abstract/Text BACKGROUND: Lenalidomide and bortezomib frontline exposure has raised a growing need for novel treatments for patients with relapsed or refractory multiple myeloma. Carfilzomib in combination with daratumumab has shown substantial efficacy with tolerable safety in relapsed or refractory multiple myeloma in a phase 1 study. In this study, we aimed to compare the efficacy and safety of carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone in patients with relapsed or refractory multiple myeloma.
METHODS: In this randomised, multicentre, open-label, phase 3 study, 466 patients recruited from 102 sites across North America, Europe, Australia, and Asia with relapsed or refractory multiple myeloma were randomly assigned 2:1 to carfilzomib, dexamethasone, and daratumumab (KdD) or carfilzomib and dexamethasone (Kd). All patients received twice per week carfilzomib at 56 mg/m2 (20 mg/m2; days 1 and 2 during cycle 1). Daratumumab (8 mg/kg) was administered intravenously on days 1 and 2 of cycle 1 and at 16 mg/kg weekly for the remaining doses of the first two cycles, then every 2 weeks for four cycles (cycles 3-6), and every 4 weeks thereafter. Patients received 40 mg dexamethasone weekly (20 mg for patients ≥75 years old starting on the second week). The primary endpoint was progression-free survival assessed by intention to treat. Adverse events were assessed in the safety population. This trial (NCT03158688) is registered with ClinicalTrials.gov, and is active but not recruiting.
FINDINGS: Between June 13, 2017, and June 25, 2018, 466 patients of 569 assessed for eligibility were enrolled. After median follow-up of approximately 17 months, median progression-free survival was not reached in the KdD group versus 15·8 months in the Kd group (hazard ratio 0·63; 95% CI 0·46-0·85; p=0·0027). Median treatment duration was longer in the KdD versus the Kd group (70·1 vs 40·3 weeks). Grade 3 or higher adverse events were reported in 253 (82%) patients in the KdD group and 113 (74%) patients in the Kd group. The frequency of adverse events leading to treatment discontinuation was similar in both groups (KdD, 69 [22%]; Kd, 38 [25%]).
INTERPRETATION: KdD significantly prolonged progression-free survival versus Kd in patients with relapsed or refractory multiple myeloma and was associated with a favourable benefit-risk profile.
FUNDING: Amgen.

Copyright © 2020 Elsevier Ltd. All rights reserved.
PMID 32682484  Lancet. 2020 Jul 18;396(10245):186-197. doi: 10.1016/S0・・・
著者: Michel Attal, Paul G Richardson, S Vincent Rajkumar, Jesus San-Miguel, Meral Beksac, Ivan Spicka, Xavier Leleu, Fredrik Schjesvold, Philippe Moreau, Meletios A Dimopoulos, Jeffrey Shang-Yi Huang, Jiri Minarik, Michele Cavo, H Miles Prince, Sandrine Macé, Kathryn P Corzo, Frank Campana, Solenn Le-Guennec, Franck Dubin, Kenneth C Anderson, ICARIA-MM study group
雑誌名: Lancet. 2019 Dec 7;394(10214):2096-2107. doi: 10.1016/S0140-6736(19)32556-5. Epub 2019 Nov 14.
Abstract/Text BACKGROUND: Isatuximab is a monoclonal antibody that binds a specific epitope on the human CD38 receptor and has antitumour activity via multiple mechanisms of action. In a previous phase 1b study, around 65% of patients with relapsed and refractory multiple myeloma achieved an overall response with a combination of isatuximab with pomalidomide and low-dose dexamethasone. The aim of this study was to determine the progression-free survival benefit of isatuximab plus pomalidomide and dexamethasone compared with pomalidomide and dexamethasone in patients with relapsed and refractory multiple myeloma.
METHODS: We did a randomised, multicentre, open-label, phase 3 study at 102 hospitals in 24 countries in Europe, North America, and the Asia-Pacific regions. Eligible participants were adult patients with relapsed and refractory multiple myeloma who had received at least two previous lines of treatment, including lenalidomide and a proteasome inhibitor. Patients were excluded if they were refractory to previous treatment with an anti-CD38 monoclonal antibody. We randomly assigned patients (1:1) to either isatuximab 10 mg/kg plus pomalidomide 4 mg plus dexamethasone 40 mg (20 mg for patients aged ≥75 years), or pomalidomide 4 mg plus dexamethasone 40 mg. Randomisation was done using interactive response technology and stratified according to the number of previous lines of treatment (2-3 vs >3) and age (<75 years vs ≥75 years). Treatments were assigned based on a permuted blocked randomisation scheme with a block size of four. The isatuximab-pomalidomide-dexamethasone group received isatuximab intravenously on days 1, 8, 15, and 22 in the first 28-day cycle, then on days 1 and 15 in subsequent cycles. Both groups received oral pomalidomide on days 1 to 21 in each cycle, and oral or intravenous dexamethasone on days 1, 8, 15, and 22 of each cycle. Treatment continued until disease progression, unacceptable toxicity, or consent withdrawal. Dose reductions for adverse reactions were permitted for pomalidomide and dexamethasone, but not for isatuximab. The primary endpoint was progression-free survival, determined by an independent response committee and assessed in the intention-to-treat population. Safety was assessed in all participants who received at least one dose of study drug. This study is registered at ClinicalTrials.gov, number NCT02990338.
FINDINGS: Between Jan 10, 2017, and Feb 2, 2018, we randomly assigned 307 patients to treatment: 154 to isatuximab-pomalidomide-dexamethasone, and 153 to pomalidomide-dexamethasone. At a median follow-up of 11·6 months (IQR 10·1-13·9), median progression-free survival was 11·5 months (95% CI 8·9-13·9) in the isatuximab-pomalidomide-dexamethasone group versus 6·5 months (4·5-8·3) in the pomalidomide-dexamethasone group; hazard ratio 0·596, 95% CI 0·44-0·81; p=0·001 by stratified log-rank test. The most frequent treatment-emergent adverse events (any grade; isatuximab-pomalidomide-dexamethasone vs pomalidomide-dexamethasone) were infusion reactions (56 [38%] vs 0), upper respiratory tract infections (43 [28%] vs 26 [17%]), and diarrhoea (39 [26%] vs 29 [20%]). Adverse events with a fatal outcome were reported in 12 patients (8%) in the isatuximab-pomalidomide-dexamethasone group and 14 (9%) in the pomalidomide-dexamethasone group. Deaths due to treatment-related adverse events were reported for one patient (<1%) in the isatuximab-pomalidomide-dexamethasone group (sepsis) and two (1%) in the pomalidomide-dexamethasone group (pneumonia and urinary tract infection).
INTERPRETATION: The addition of isatuximab to pomalidomide-dexamethasone significantly improves progression-free survival in patients with relapsed and refractory multiple myeloma. Isatuximab is an important new treatment option for the management of relapsed and refractory myeloma, particularly for patients who become refractory to lenalidomide and a proteasome inhibitor.
FUNDING: Sanofi. VIDEO ABSTRACT.

Copyright © 2019 Elsevier Ltd. All rights reserved.
PMID 31735560  Lancet. 2019 Dec 7;394(10214):2096-2107. doi: 10.1016/S・・・

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