Treatment of relapsed and refractory multiple myeloma: recommendations from the International Myeloma Working Group

复发性和难治性多发性骨髓瘤的治疗：国际骨髓瘤工作组的建议 

This Policy Review presents the International Myeloma Working Group’s clinical practice recommendations for the treatment of relapsed and refractory multiple myeloma. Based on the results of phase 2 and phase 3 trials, these recommendations are proposed for the treatment of patients with relapsed and refractory disease who have received one previous line of therapy, and for patients with relapsed and refractory multiple myeloma who have received two or more previous lines of therapy. These recommendations integrate the issue of drug access in both low-income and middle-income countries and in high-income countries to help guide real-world practice and thus improve patient outcomes.

本政策综述介绍了国际骨髓瘤工作组关于治疗复发和难治性多发性骨髓瘤的临床实践建议。根据二期和三期试验的结果，这些建议适用于治疗既往接受过一线治疗的复发和难治性患者，以及既往接受过两线或更多线治疗的复发和难治性多发性骨髓瘤患者。这些建议综合考虑了中低收入国家和高收入国家的药物可及性问题，有助于指导现实世界的实践，从而改善患者的治疗效果。

Introduction 导言 

The   treatment   of   multiple   myeloma   has   changed drastically in the past decade with the incorporation of novel agents into therapeutic strategies. These new drugs, in various combinations, have been added to national and international  clinical  guidelines  and have transformed the approach to the treatment of patients with multiple myeloma,  resulting  in   substantial  improvements  in overall survival.

过去十年间，随着新型药物被纳入治疗策略，多发性骨髓瘤的治疗方法发生了翻天覆地的变化。这些新药的各种组合已被纳入国家和国际临床指南，并改变了多发性骨髓瘤患者的治疗方法，大大提高了患者的总生存率。

 With the availability of at least seven different classes of   approved   agents,   including   alkylators,   steroids, proteasome    inhibitors,    immunomodulatory    agents, histone  deacetylase  inhibitors,  monoclonal  antibodies, and selective inhibitors of nuclear export, which can be combined   in   doublet,   triplet,   or   even   quadruplet regimens and used with or without high-dose therapy and  autologous  stem-cell  transplantation   (ASCT),  or in  some  cases  as  continuous  treatment,  the  choice of  the  optimal  strategy  at  diagnosis  and  at  relapse represents  a  challenge for physicians.  Moreover, next- generation  immunotherapies  or  targeted  agents  will soon  improve  the  therapeutic  armamentarium.  Also somewhat problematic is the scarcity oftrials addressing important questions, such as the integration of the first salvage   regimen   into   the   assessment   of  front-line therapies   to   define   optimal   treatment    sequencing strategies  in  homogeneous  or  at  least  similar  patient populations. Furthermore, few data are available on the efficacy of the  different approved regimens in specific patient populations, such as those with refractory disease versus those being treated for relapse after a treatment- free interval, those with biochemical versus symptomatic relapse,  those with  relapse  after  one  previous  line  of therapy versus those with more advanced disease, those with high-risk versus standard-risk cytogenetic profiles, and those with extramedullary disease, among others.

目前至少有七种不同类别的药物获得批准，包括烷化剂、类固醇、蛋白酶体抑制剂、免疫调节剂、组蛋白去乙酰化酶抑制剂、单克隆抗体和核输出选择性抑制剂、 在诊断和复发时，如何选择最佳策略是医生面临的一项挑战。 此外，新一代免疫疗法或靶向药物将很快改善治疗手段。 同样存在一些问题的是，解决一些重要问题的试验很少，例如将首个挽救方案纳入一线疗法评估，以确定同质或至少相似患者群体的最佳治疗排序策略。此外，关于不同获批方案在特定患者群体中的疗效，如难治性疾病患者与无治疗间隔后复发患者、生化性复发患者与症状性复发患者、前一疗程治疗后复发患者与晚期疾病患者、高危细胞遗传学特征患者与标准风险细胞遗传学特征患者、髓外疾病患者等，目前几乎没有相关数据。 

Several phase  3 trials have  shown  improved  survival outcomes  (progression-free  survival, overall  survival, or both) with the use of triplet combinations, suggesting that at least two active drugs should be combined with steroids, if patients can safely tolerate this therapeutic regimen. However, combinations of the aforementioned agents are unfortunately associated with a high cost, which raises two important issues: drug access in both low-income and middle-income countries and in high-income countries, and the definition of value versus patient benefit.

几项三期试验显示，使用三联疗法可改善生存结果（无进展生存期、总生存期或两者兼有），这表明，如果患者能够安全耐受这种治疗方案，至少应将两种活性药物与类固醇药物联合使用。然而，令人遗憾的是，上述药物的联合用药成本较高，这就提出了两个重要问题：中低收入国家和高收入国家的药物可及性，以及价值与患者获益的定义。 

At the time of relapse, the treatment choice is affected by many patient-related and disease-related factors, such as patient preference, age, cytogenetic profile, pre-existing toxicities,   comorbidities,   and   aggressiveness   of  the relapse, but mostly by the type of, and the response to, previous therapies. The aim of this Policy Review is to discuss the currently available data for the treatment of relapsed and refractory multiple myeloma and to propose clear   recommendations   and   guidelines   for   routine practice,  recognising  the  challenges  of  clinical  trial complications and translating phase 2 and 3 study results to real-world practice.

多发性骨髓瘤复发时，治疗方法的选择受许多患者相关因素和疾病相关因素的影响，如患者的偏好、年龄、细胞遗传学特征、原有毒性、合并症和复发的侵袭性，但最主要的是受先前疗法的类型和反应的影响。本政策综述旨在讨论治疗复发和难治性多发性骨髓瘤的现有数据，并为常规治疗提出明确的建议和指南，同时认识到临床试验并发症以及将2期和3期研究结果转化为实际应用所面临的挑战。 

Treatment of relapsed and refractory disease in  patients who have received one previous line of therapy

治疗既往接受过一种疗法的复发和难治性疾病患者 

The most important question for most cases of myeloma relapse, or disease that is resistant to therapy, is whether a  patient  has  lenalidomide-refractory   disease  or  not (figure 1). A second consideration that will be increasingly important is whether the disease is progressing on front- line therapies that include daratumumab.

对于大多数骨髓瘤复发或耐药病例来说，最重要的问题是患者是否患有来那度胺难治性疾病（图1）。第二个越来越重要的考虑因素是，患者在接受包括达拉单抗在内的一线疗法后病情是否有所进展。 

On the basis of the overall  survival benefits  seen in randomised  trials  and  meta-analyses,  lenalidomide  is used as part of the front-line therapy for newly diagnosed multiple myeloma. Inpatients treated with upfront ASCT, lenalidomide  monotherapy  at  a  low  dose  is  approved as  a  maintenance  therapy  until  disease  progression.6,7  In patients with previously untreated, newly diagnosed multiple myeloma who are not eligible for ASCT, lenali- domide is also approved in combination with low-dose dexamethasone until disease progression, on the basis of the  results  of  the  FIRST  trial.8     Additionally,  in  the prospective SWOG0777 trial, which enrolled patients with newly   diagnosed   multiple   myeloma   who   were   not intended to undergo immediate ASCT, the regimen of bortezomib   plus   lenalidomide   plus   dexamethasone followed by lenalidomide plus dexamethasone until pro- gression resulted in significantly improved progression- free survival and overall survival.9,10   However, ultimately, a high number of patients taking continuous treatment including lenalidomide as front-line therapy have disease progression.

由于随机试验和荟萃分析显示来那度胺对患者的总生存期有好处，因此来那度胺被作为新诊断多发性骨髓瘤一线治疗的一部分。在接受前期ASCT治疗的患者中，小剂量来那度胺单药治疗被批准作为维持治疗，直至疾病进展。6,7 对于既往未接受过治疗、不符合ASCT条件的新诊断多发性骨髓瘤患者，根据FIRST试验的结果，来那度胺也被批准与小剂量地塞米松联合使用，直至疾病进展。 此外，前瞻性的SWOG0777试验招募了不打算立即进行ASCT的新诊断多发性骨髓瘤患者，采用硼替佐米+来那度胺+地塞米松，然后再用来那度胺+地塞米松直至疾病进展的方案，可显著改善无进展生存期和总生存期。 

First relapse inpatients with lenalidomide- refractory disease

来那度胺难治性疾病患者的首次复发 

Patients   with    lenalidomide-refractory   disease   were rightly excluded from randomised phase 3 trials testing lenalidomide plus dexamethasone versus lenalidomide plus   dexamethasone   plus   a   third   agent   (either   a proteasome  inhibitor  [carfilzomib or  ixazomib]  or  a monoclonal antibody [elotuzumab  or daratumumab]). The    precise    effect    of    lenalidomide-based    triplet combinations  in  patients  with  lenalidomide-refractory disease  is unknown, but  it would  most likely lead to suboptimal  results,  and  these  regimens  are  therefore rarely used in this setting. The only known study showing that the addition of a third agent to lenalidomide and steroids might rescue lenalidomide-refractory disease is the phase  1–2 trial  (n=67  patients) reported by  Nijhof and  colleagues, which  showed  that  the  addition  of continuous  low-dose  oral  cyclophosphamide  to  lenali- domide and prednisone induced a 67% response rate, with a median progression-free survival of 12.1 months and an overall survival of 29.0 months in lenalidomide- refractory patients.

来那度胺难治性疾病患者被排除在来那度胺加地塞米松与来那度胺加地塞米松加第三种药物（蛋白酶体抑制剂[卡非佐米或伊沙佐米]或单克隆抗体[埃洛珠单抗或达拉单抗]）的随机三期试验之外。基于来那度胺的三联疗法对来那度胺难治性疾病患者的确切疗效尚不清楚，但很可能会导致次优疗效，因此这些疗法很少用于这种情况。Nijhof及其同事报告的1-2期试验（67例患者）显示，在来那度胺和泼尼松的基础上加用持续小剂量口服环磷酰胺可诱导67%的应答率，来那度胺难治性患者的中位无进展生存期为12.1个月，总生存期为29.0个月。 

For a patient who has disease progression while taking lenalidomide as part of their front-line therapy, a reasonable approach would be to switch the class of agent, from an immunomodulatory   drug  to   a  proteasome   inhibitor. Bortezomib plus dexamethasone was the first combination used in this setting, resulting in progression-free survival ranging from 8 to 10 months.16 Cyclophosphamide can also be added to bortezomib plus dexamethasone to increase the  response  rate,  but  no  prospective  comparison  of bortezomib plus dexamethasone versus bortezomib plus cyclophosphamide   plus    dexamethasone    in   relapsed myeloma has been done yet.

对于在一线治疗中服用来那度胺而病情恶化的患者，合理的方法是更换药物种类，从免疫调节药物更换为蛋白酶体抑制剂。硼替佐米加地塞米松是第一种用于这种情况的联合用药，无进展生存期从 8 个月到 10 个月不等。16 环磷酰胺也可加入硼替佐米加地塞米松以提高应答率，但目前还没有对硼替佐米加地塞米松与硼替佐米加环磷酰胺加地塞米松治疗复发性骨髓瘤进行前瞻性比较。

 Several  phase  3  trials  have  evaluated  proteasome inhibitor-based  combinations  using  bortezomib  plus dexamethasone as the control regimen in relapsed and refractory multiple myeloma, but few patients with true lenalidomide-refractory  disease  were  included.  In  the randomised, phase  3  ENDEAVOR  trial, bortezomib plus dexamethasone was prospectively compared with carfilzomib plus dexamethasone inpatients with relapse after one to three previous lines of therapy, until disease progression  occurred.  This  trial,  a  head-to-head  com- parison  of  two  proteasome  inhibitors,  showed  that both progression-free survival (median 18.7 months vs 9.4 months; hazard ratio [HR] 0.53 [95% CI 0.44–0.65]; p<0.0001) and overall survival (median 47.6 months vs 40.0 months; HR 0.79 [95% CI 0.65–0.96]; p=0.01) were  superior  with  carfilzomib  plus  dexamethasone than with bortezomib plus dexamethasone across the whole   group   of  patients.  The   number   of  patients refractory  to  lenalidomide  (regardless  of the  number of previous  lines  of therapy)  in  this  trial  was  113  in the carfilzomib plus dexamethasone group and 122 in the bortezomib plus dexamethasone group, although the total number of patients who had progressed on front- line  lenalidomide  was  not   specified. The   median progression-free survival inpatients with lenalidomide- refractory  disease was  rather  short:  8.6  months with carfilzomib  plus  dexamethasone  versus  6.6  months with bortezomib plus dexamethasone. Overall survival was   numerically,   but   not   significantly,   longer   by 7.8 months with carfilzomib plus dexamethasone versus bortezomib plus dexamethasone (median 29.2 months vs 21.4 months; HR 0.857 [95% CI 0.623–1.178]; p value not available). These findings suggest that patients with lenalidomide-refractory  disease  might  not  benefit  as much  from  carfilzomib  plus  dexamethasone  combi- nation  therapy  as  those  with  a  previous  response  to lenalidomide.

有几项三期试验评估了以蛋白酶体抑制剂为基础、硼替佐米加地塞米松为对照方案的复发性和难治性多发性骨髓瘤联合疗法，但很少纳入真正来那度胺难治性疾病患者。 在ENDEAVOR随机三期试验中，硼替佐米加地塞米松与卡非佐米加地塞米松对经过一至三线治疗后复发的患者进行了前瞻性比较，直到疾病出现进展。 该试验对两种蛋白酶体抑制剂进行了头对头比较，结果显示，无进展生存期（中位 18.7 个月 vs 9.4 个月；危险比 [HR] 0.53 [95% CI 0.44-0.65]; p<0.0001）和总生存期（中位47.6个月 vs 40.0个月；HR 0.79 [95% CI 0.65-0.96]；p=0.01）在整组患者中，卡非佐米加地塞米松优于硼替佐米加地塞米松。 在这项试验中，卡非佐米加地塞米松组和硼替佐米加地塞米松组对来那度胺治疗难治的患者人数分别为113人和122人（不考虑前线来那度胺治疗进展的患者总数），但未说明前线来那度胺治疗进展的患者总数。来那度胺难治性疾病患者的中位无进展生存期较短：卡非佐米加地塞米松组为8.6个月，硼替佐米加地塞米松组为6.6个月。卡非佐米加地塞米松与硼替佐米加地塞米松相比，总生存期延长了7.8个月（中位29.2个月对21.4个月；HR 0.857 [95% CI 0.623-1.178]；P值不详），但并不明显。这些研究结果表明，来那度胺难治性疾病患者从卡非佐米加地塞米松联合疗法中获益的程度可能不及那些既往对来那度胺有反应的患者。

 In the CASTOR trial, bortezomib plus dexamethasone was compared with daratumumab plus bortezomib plus dexamethasone   in   patients   with   relapsed   multiple myeloma who had received at least one previous line of therapy.  The  triplet  combination  was  associated  with significantly   longer   progression-free   survival   in   all patients (median not reached vs 7.2 months; HR 0.39 [95%  CI  0.28–0.53];  p<0.001), as  confirmed  by  an updated analysis in which, after a median follow-up of 47.0 months,the median progression-free survival with bortezomib plus dexamethasone plus daratumumab was longer than with bortezomib plus dexamethasone alone (16.7   months   vs   7.1   months,   HR   0.31   [95%   CI 0.25–0.39]; p<0.0001). As in the  ENDEAVOR  study, the  total  number  of patients  whose  disease  had  pro- gressed  during  front-line  lenalidomide  treatment  was not  specified. The only information available is based on   a   subgroup   analysis   showing   that,   in   patients with lenalidomide-refractory disease  (regardless  of the number of previous lines of therapy),  progression-free survival was longer with daratumumab plus bortezomib plus dexamethasone (median 7.8 months; n=60) versus bortezomib plus dexamethasone  (median 4.9 months; n=81).  These  results  are  similar  to  the  data  reported in  the  ENDEAVOR  study  for  a  similar  subgroup  of patients,  which suggests that daratumumab plus borte- zomib plus dexamethasone is also suboptimal for this patient population. Overall survival data for this subgroup of patients in the  CASTOR trial are not yet available. Importantly, the safety profile of the triplet combination seems to be acceptable, and daratumumab was not found to add any  substantial toxicity to the bortezomib plus dexamethasone combination.

在 CASTOR 试验中，硼替佐米加地塞米松与达拉土穆单抗加硼替佐米加地塞米松比较了既往接受过至少一种疗法的复发性多发性骨髓瘤患者。 三联疗法使所有患者的无进展生存期明显延长（中位数未达到 vs 7.2 个月；HR 0.39 [95% CI 0.28-0.53]；p<0.001），更新的分析证实了这一点。0个月后，硼替佐米加地塞米松加达拉单抗的中位无进展生存期长于硼替佐米加地塞米松单药（16.7个月 vs 7.1个月，HR 0.31 [95% CI 0.25-0.39]; p<0.0001）。与ENDEAVOR研究一样，在来那度胺一线治疗期间病情恶化的患者总数没有明确说明。唯一可用的信息基于一项亚组分析，该分析表明，在来那度胺难治性疾病患者中（无论既往接受过几种治疗），达拉单抗联合硼替佐米联合地塞米松（中位数7.8个月；n=60）与硼替佐米联合地塞米松（中位数4.9个月；n=81）相比，无进展生存期更长。 这些结果与ENDEAVOR研究中类似亚组患者的数据相似，表明达拉单抗联合硼替佐米联合地塞米松对这一患者群体也是次优方案。CASTOR试验中该亚组患者的总生存期数据尚未公布。重要的是，三联疗法的安全性似乎是可以接受的，达拉土单抗没有给硼替佐米加地塞米松疗法增加任何实质性毒性。

 The   phase    3   PANORAMA   1   study, comparing bortezomib  plus  dexamethasone with bortezomib  plus dexamethasone plus panobinostat, enrolled a subgroup of patients progressing on lenalidomide as front-line therapy, but the number of patients in this setting was very small (nnot specified) and previous treatment with lenalidomide was not a stratification factor. Overall, the study showed that the combination of bortezomib plus dexamethasone plus panobinostat improved progression-free survival by 4 months compared with the doublet regimen, but did not result in an overall survival benefit. The toxicity observed in the panobinostat group of the trial, especially the high frequency of fatigue, thrombocytopenia, and grade 3 or grade 4 gastrointestinal adverse events, does not support the  use  of  this  triplet  combination  in  patients  with lenalidomide-refractory disease.

PANORAMA 1三期研究比较了硼替佐米加地塞米松与硼替佐米加地塞米松加帕诺比诺司特，该研究招募了来那度胺作为一线疗法的进展患者亚组，但这种情况下的患者人数非常少（n未注明），而且既往接受过来那度胺治疗也不是分层因素。总之，研究表明，硼替佐米+地塞米松+帕诺比诺司特的联合疗法与双联疗法相比，无进展生存期提高了4个月，但并没有带来总生存期的获益。试验中帕诺比诺司他（panobinostat）组观察到的毒性，尤其是疲劳、血小板减少、3级或4级胃肠道不良事件的高发率，不支持来那度胺难治性疾病患者使用这种三联疗法。

 In the phase 3 OPTIMISMM trial, the combination of pomalidomide  plus  bortezomib  plus  dexamethasone (n=278)  was  prospectively  compared  with  bortezomib plus  dexamethasone  (n=270)  in  patients with  relapsed and refractory multiple myeloma who had received one to three previous lines of therapy that included lenalidomide. More  than   70%   of  the   patients   had   lenalidomide- refractory disease. After a median follow-up of 16 months, pomalidomide  plus  bortezomib  plus  dexamethasone resulted   in    an   improved    median   progression-free survival  versus  bortezomib  plus  dexamethasone  alone (11.2 months vs 7.1 months, HR 0.61 [95% CI 0.49–0.77]; p<0.0001).  The  median  progression-free  survival  was also  longer  with  pomalidomide  plus  bortezomib  plus dexamethasone than with bortezomib plus dexametha- sone   alone   in   patients   with   lenalidomide-refractory disease (9.5 months vs 5.6 months, HR 0.65 [95% CI 0.50–0.84]; p=0.0008), inpatients with one previous line of treatment  (20.7  months  vs  11.6  months,  HR  0.54 [95%   CI   0.36–0.82];   p=0.0027),   and,   of   particular interest, in patients who had received one previous line of treatment  and  had  lenalidomide-refractory  disease (17.8  months  vs  9.5  months,   HR  0.55   [0.33–0.94]; p=0.03). Overall survival data are not available due to the relatively short follow-up of this trial (16.4 months).

在OPTIMISMM三期试验中，对既往接受过一至三线治疗（包括来那度胺）的复发性和难治性多发性骨髓瘤患者进行了泊马度胺联合硼替佐米联合地塞米松（278例）与硼替佐米联合地塞米松（270例）的前瞻性比较。70%以上的患者患有来那度胺难治性疾病。中位随访16个月后，泊马度胺联合硼替佐米联合地塞米松与单用硼替佐米联合地塞米松相比，中位无进展生存期有所改善（11.2个月 vs 7.1个月，HR 0.61 [95% CI 0.49-0.77]；P<0.0001）。 在来那度胺难治性疾病患者（9.5个月 vs 5.6个月，HR 0.65 [95% CI 0.50-0.84]；P=0.0008）、既往接受过一线治疗的患者（20.7个月 vs 11.6个月，HR 0.61 [95% CI 0.49-0.77]；P<0.0001）中，泊马度胺联合硼替佐米联合地塞米松的中位无进展生存期也长于单独使用硼替佐米联合地塞米松。7个月 vs 11.6个月，HR 0.54 [95% CI 0.36-0.82]；P=0.0027），尤其值得注意的是，既往接受过一线治疗且患有来那度胺难治性疾病的患者（17.8个月 vs 9.5个月，HR 0.55 [0.33-0.94]；P=0.03）。由于该试验的随访时间较短（16.4个月），因此没有提供总生存期数据。

 Combinations of carfilzomib plus dexamethasone plus anti-CD38  antibodies have been  evaluated  in  phase  3 studies.   In   the   CANDOR   trial,  carfilzomib   plus dexamethasone  was  compared  with  carfilzomib  plus dexamethasone  plus  daratumumab  in  patients  with relapsed  and  refractory  multiple  myeloma  who  had received   one   to   three    previous   lines   of   therapy (446  patients,  of  whom  147   (33%)  had  lenalidomide- refractory disease). Median progression-free survival was not reached in the daratumumab plus carfilzomib plus dexamethasone   group   versus   15.8   months   in   the carfilzomib   plus   dexamethasone   group    (HR   0.63 [95%  CI  0.46–0.85];  p=0.0027).  Daratumumab  plus carfilzomib   plus   dexamethasone   was    superior    to carfilzomib plus dexamethasone in terms of progression- free survival, both inpatients with previous lenalidomide exposure  (HR  0.53  [95%  CI  0.34–0.82];  p  value  not available)    and    in    lenalidomide-refractory    patients (HR 0.47 [0.29–0.78]; p value not available). Furthermore, both the overall response rate  (84%  vs 75%, p=0.008) and  the  minimal  residual  disease  negative  rate  at 12 months  (13%  vs  1%, p<0.0001) were  superior with daratumumab  plus   carfilzomib  plus   dexamethasone than  with   carfilzomib   plus   dexamethasone.   In  the phase 3 IKEMA trial,29   302 patients with relapsed and refractory multiple myeloma and one to three previous lines of therapy were randomly assigned to receive either isatuximab    plus    carfilzomib    plus    dexamethasone (n=179)  or  carfilzomib  plus  dexamethasone  (n=123). After  a  median  follow-up  of  20.7  months,  median progression-free  survival  was  not  reached  for  isatuxi- mab  plus  carfilzomib  plus  dexamethasone  and  was 19.1   months   for   carfilzomib   plus   dexamethasone (HR 0.53  [95% CI 0.32–0.89); p=0.0007).  Isatuximab plus  carfilzomib  plus  dexamethasone was  superior  to carfilzomib plus dexamethasone in terms of progression- free survival, both inpatients with previous lenalidomide exposure  (HR  0.50  [95%  CI  0.29–0.87];  p  value  not available)    and    in    lenalidomide-refractory    patients (HR 0.60 [95% CI 0.34–1.06]; p value not available). On Aug 20, 2020, the daratumumab plus carfilzomib plus dexamethasone   combination   was   approved   by   the US  Food  and  Drug  Administration  for  adult  patients with relapsed or refractory multiple myeloma after one to three lines of therapy. Based on progression-free survival data and HRs, daratumumab plus carfilzomib plus and dexamethasone  and  isatuximab  plus  carfilzomib  plus dexamethasone  (approval  anticipated  soon)  might  be important treatment options for first relapse inpatients with lenalidomide-refractory disease in the near future.

卡非佐米加地塞米松加抗CD38抗体的组合已在3期研究中进行了评估。 在CANDOR试验中，卡非佐米加地塞米松与卡非佐米加地塞米松加达拉单抗对既往接受过一至三线治疗的复发性和难治性多发性骨髓瘤患者进行了比较（446例患者，其中147例（33%）患有来那度胺难治性疾病）。达拉单抗联合卡非佐米联合地塞米松组的中位无进展生存期为15.8个月，而卡非佐米联合地塞米松组为15.8个月（HR 0.63 [95% CI 0.46-0.85]；P=0.0027）。 在无进展生存期方面，达拉单抗联合卡非佐米联合地塞米松优于卡非佐米联合地塞米松，无论是既往服用过来那度胺的患者（HR 0.53 [95% CI 0.34-0.82]；P值不详）还是来那度胺难治性患者（HR 0.47 [0.29-0.78]；P值不详）。此外，达拉单抗联合卡非佐米联合地塞米松的总体应答率（84% vs 75%，p=0.008）和12个月时的最小残留病阴性率（13% vs 1%，p<0.0001）均优于卡非佐米联合地塞米松。 在3期IKEMA试验29中，302名复发和难治性多发性骨髓瘤患者被随机分配接受伊沙妥昔单抗联合卡非佐米联合地塞米松（n=179）或卡非佐米联合地塞米松（n=123）治疗。中位随访20.7个月后，伊沙妥昔单抗联合卡非佐米联合地塞米松的中位无进展生存期未达到，而卡非佐米联合地塞米松的中位无进展生存期为19.1个月（HR 0.53 [95% CI 0.32-0.89]；P=0.0007）。 就无进展生存期而言，伊沙妥昔单抗联合卡非佐米联合地塞米松优于卡非佐米联合地塞米松，无论是在既往接受过来那度胺治疗的患者中（HR 0.50 [95% CI 0.29-0.87]；P值不详），还是在来那度胺难治性患者中（HR 0.60 [95% CI 0.34-1.06]；P值不详）。2020年8月20日，美国食品和药物管理局批准了达拉单抗加卡非佐米加地塞米松的组合疗法，用于经过一至三线治疗的复发或难治性多发性骨髓瘤成年患者。 根据无进展生存期数据和HRs，达拉曲单抗联合卡非佐米联合地塞米松和伊沙妥昔单抗联合卡非佐米联合地塞米松（预计不久将获批）可能在不久的将来成为来那度胺难治性疾病首次复发患者的重要治疗选择。

 Lenalidomide-exposed patients have been studied in a small  number  of phase  1b/2 trials that  evaluated  new combinations  based  on  proteasome  inhibitors  with  or without pomalidomide and with or without monoclonal antibodies. Major limitations of these trials are the small number  of patients  enrolled,  the  short  follow-up,  and the  absence  of  overall  survival  data.  Jakubowiak  and colleagues did a phase  2 randomised trial comparing bortezomib plus dexamethasone versus elotuzumab plus bortezomib  plus  dexamethasone  in  152  patients  with relapsed   and   refractory   multiple   myeloma,   showing a   longer   progression-free   survival   with    the   triplet combination versus the doublet in the intention-to-treat population (9.7 months vs 6.9 months, HR 0.72 [95% CI 0.49–1.06]; p=0.09).  Of these  patients,  101  (66%)  were treated at the time of the first relapse, but the number of patients  with  disease  progression  while  taking  lenali- domide was  not  reported,  and  a  subgroup  analysis  of patients   previously   treated   with   immunomodulatory agents showed no progression-free survival benefit with the  addition  of  elotuzumab  to  bortezomib  plus  dexa- methasone  (HR  0.87  [95%  CI  0.56–1.34]; p value  not available). In the phase 1b MMY1001 trial (NCT01998971), the  combination  of daratumumab  plus  pomalidomide plus dexamethasone was tested in one treatment group. 92  (90%)  of 102  patients  enrolled  into this  group had lenalidomide-refractory disease. The overall response rate in this group of patients overall was 66%, and the median progression-free survival was 10.1 months after a median follow-up  of  28.1  months.   However,  the  number  of patients with disease progression while taking front-line lenalidomide  therapy  included  in  this  group  was  very small (n=3). The same combination, daratumumab plus pomalidomide plus dexamethasone, was investigated in the  POM  MM  014 phase  2  trial  (NCT01946477),  which included 112 patients who had disease progression after lenalidomide-based therapy (median two previous lines of treatment), 84 (75%) of which had lenalidomide-refractory disease. With  a  median  follow-up  of  8.2   months, the  overall  response  rate   (the  primary  endpoint)  was 75% inpatients with lenalidomide-refractory disease, and the   9   month   progression-free   survival   was   86.3% (95% CI 76.5–92.2%), whereas the median progression- free survival was not reached. Pomalidomide was  also combined with carfilzomib and dexamethasone twice per week,  in  the  prospective   EMN011/HO114  trial. This phase  2 trial was designed for patients with refractory disease  or  first  progression  after  front-line  therapy  as part of the EMN02 trial, in which patients were randomly assigned to front-line ASCT versus no front-line ASCT, followed by consolidation and lenalidomide maintenance until progression. After four 28 day cycles of reinduction with carfilzomib plus pomalidomide plus dexamethasone, patients were offered either  salvage ASCT, if they had not   received   it   as   front-line   intensive   therapy,   or four additional cycles of carfilzomib plus pomalidomide plus  dexamethasone  (a  total  of eight  carfilzomib  plus pomalidomide plus dexamethasone cycles). Subsequently, patients with  stable  disease  or  better  received  pomali- domide with or without dexamethasone in 28-day cycles until progression. The analysis of the first 60 patients, 57  (95%)  of  whom  had  progressed   on  lenalidomide maintenance, showed that responses to carfilzomib plus pomalidomide plus  dexamethasone were  rapid, with  a median time to best response of 2 months. The toxicity of carfilzomib plus pomalidomide plus dexamethasone was manageable and, at a median follow-up of 16.3 months, the median progression-free survival was 18 months, with a better outcome inpatients with standard-risk cytogenetic profiles (n=40) than inpatients with high-risk cytogenetic profile (HR 0.27 [95% CI 0.09–0.83]; p value not available) and   in   patients   who   had   not   received   front-line ASCT  (n=25;  HR  0.49  [95%  CI  0.21–1.16];  p  value not  available).  Pomalidomide  plus  dexamethasone  has also been combined with oral weekly ixazomiband tested in a phase 1/2 trial of patients with lenalidomide-refractory disease  (n=32),  aged  up  to  84  years,  with  one  to  five (median two) previous lines of therapy. The exact number of patients progressing  on front-line lenalidomide was unspecified.  This  triplet  all-oral  combination  was  well tolerated and the overall response rate was 48%, with a median progression-free survival of 8.6 months.

来那度胺暴露的患者已在少数 1b/2 期试验中接受了研究，这些试验评估了基于蛋白酶体抑制剂的新组合，以及是否使用泊马度胺、是否使用单克隆抗体。这些试验的主要局限性在于入组患者人数少、随访时间短以及缺乏总体生存数据。 Jakubowiak及其同事进行了一项2期随机试验，在152例复发和难治性多发性骨髓瘤患者中比较了硼替佐米加地塞米松与艾洛妥珠单抗加硼替佐米加地塞米松，结果显示在意向治疗人群中，三联疗法与双联疗法的无进展生存期更长（9.7个月 vs 6.9个月，HR 0.72 [95% CI 0.49-1.06]；P=0.09）。 在这些患者中，有101人（66%）在首次复发时接受了治疗，但在服用来那度胺期间疾病进展的患者人数未见报道，对既往接受过免疫调节剂治疗的患者进行的亚组分析显示，在硼替佐米加地塞米松治疗的基础上加用艾洛单抗，无进展生存期没有获益（HR 0.87 [95% CI 0.56-1.34]；P值不可用）。在 MMY1001 1b 期试验（NCT01998971）中，达拉曲单抗联合泊马度胺加地塞米松在一个治疗组中进行了测试。102名患者中有92名（90%）患有来那度胺难治性疾病。该组患者的总体反应率为66%，中位无进展生存期为10.1个月，中位随访时间为28.1个月。 不过，这组患者中，在接受来那度胺一线治疗期间出现疾病进展的人数很少（3 人）。POM MM 014 2 期试验（NCT01946477）也对达拉单抗+泊马度胺+地塞米松的相同组合进行了研究，该试验纳入了112名接受来那度胺治疗（中位两线治疗）后疾病进展的患者，其中84人（75%）患有来那度胺难治性疾病。中位随访时间为8.2个月，来那度胺难治性疾病患者的总反应率（主要终点）为75%，9个月无进展生存率为86.3%（95% CI 76.5-92.2%），而中位无进展生存率则未达标。在EMN011/HO114前瞻性试验中，泊马度胺还与卡非佐米和地塞米松联合使用，每周两次。 作为EMN02试验的一部分，这项2期试验是为难治性疾病患者或一线治疗后病情首次进展的患者设计的，在这项试验中，患者被随机分配到一线ASCT或不接受一线ASCT，然后接受巩固治疗和来那度胺维持治疗，直至病情进展。在使用卡非佐米+泊马度胺+地塞米松进行4个28天周期的再诱导治疗后，如果患者没有接受过一线强化治疗，则为其提供挽救性ASCT，或者再提供4个周期的卡非佐米+泊马度胺+地塞米松治疗（总共8个周期的卡非佐米+泊马度胺+地塞米松治疗）。随后，病情稳定或好转的患者接受泊马度胺加或不加地塞米松治疗，28 天为一个周期，直至病情进展。对首批60名患者（其中57人（95%）在来那度胺维持治疗期间病情进展）的分析表明，卡非佐米加泊马度胺加地塞米松治疗反应迅速，达到最佳反应的中位时间为2个月。卡非佐米联合泊马度胺联合地塞米松的毒性可控，中位随访时间为16.3个月，中位无进展生存期为18个月，标准风险细胞遗传学特征患者（40人）的疗效优于高风险细胞遗传学特征患者（HR 0.27[95%CI0.09-0.83]；P值不详），未接受一线ASCT的患者（n=25；HR0.49[95%CI0.21-1.16]；P值不详）也是如此。 泊马度胺加地塞米松还与每周口服一次的伊沙佐米联用，并在来那度胺难治性疾病患者的1/2期试验中进行了测试（n=32），这些患者年龄不超过84岁，既往接受过1至5种（中位数为2种）治疗。一线来那度胺治疗进展患者的确切人数不详。 这种三联全口服联合疗法耐受性良好，总体反应率为48%，中位无进展生存期为8.6个月。

 A summary of the results of phase 3 trials inpatients with lenalidomide-refractory disease, including subgroup analyses, is presented in table 1. The preferred primary options and secondary options (based on the results of phase  3  trials),  and  alternative  options  (based  on  the results of phase 2 trials) for the treatment of patients with lenalidomide-refractory disease are shown in figure 1.

来那度胺难治性疾病患者的三期试验结果摘要（包括亚组分析）见表1。治疗来那度胺难治性疾病患者的首选主要方案和次要方案（基于第3期试验结果）以及替代方案（基于第2期试验结果）见图1。

 First relapse inpatients with disease not refractory to lenalidomide

来那度胺治疗无效的首次复发患者

 In patients who have received bortezomib-based front- line  therapy  (ie,  bortezomib  plus  cyclophosphamide plus dexamethasone, bortezomib plus thalidomide plus dexamethasone,  or  bortezomib  plus  melphalan  plus prednisone)   without   lenalidomide   maintenance,   or patients treated with  a fixed  duration  of lenalidomide with progression occurring more than 6 months after cessation of therapy, second-line therapy should be based on lenalidomide and dexamethasone regimens, such as carfilzomib  plus  lenalidomide  plus  dexamethasone, daratumumab plus lenalidomide plus dexamethasone, ixazomib  plus  lenalidomide  plus  dexamethasone, or elotuzumab plus lenalidomide plus dexamethasone.  In pivotal phase 3 trials with progression-free survival as the primary endpoint, all of these combinations were found to  be  superior  to  lenalidomide  plus  dexamethasone. Carfilzomib plus lenalidomide plus dexamethasone  and elotuzumab  plus  lenalidomide  plus  dexamethasone,  investigated in the two trials with the longest follow-up (67.1  months  for  carfilzomib  plus  lenalidomide  plus dexamethasone,   70.6   months   for   elotuzumab   plus lenalidomide  plus  dexamethasone),  also   showed  an overall  survival  benefit  compared  with  lenalidomide plus  dexamethasone  for  the  intention-to-treat  patient population.

接受过以硼替佐米为基础的一线治疗（即硼替佐米加环磷酰胺加地塞米松、硼替佐米加沙利度胺加地塞米松或硼替佐米加美法仑加泼尼松）但未接受来那度胺维持治疗的患者，或接受过固定疗程来那度胺治疗但病情在停止治疗后6个月以上出现进展的患者、二线治疗应以来那度胺和地塞米松方案为基础，如卡非佐米（carfilzomib）加来那度胺加地塞米松、达拉曲单抗（daratumumab）加来那度胺加地塞米松、伊沙佐米（ixazomib）加来那度胺加地塞米松或艾洛妥珠单抗（elotuzumab）加来那度胺加地塞米松。 在以无进展生存期为主要终点的关键性三期试验中，所有这些组合都优于来那度胺加地塞米松。卡非佐米联合来那度胺联合地塞米松和艾洛珠单抗联合来那度胺联合地塞米松是随访时间最长的两项试验（卡非佐米联合来那度胺联合地塞米松的随访时间为67.1个月，艾洛珠单抗联合来那度胺联合地塞米松的随访时间为70.6个月），与来那度胺联合地塞米松相比，这两种药物在意向治疗患者群体中也显示出了总生存期优势。

 The most effective combination available in the setting of first relapse of myeloma not refractory to lenalidomide is daratumumab plus lenalidomide plus dexamethasone. In the POLLUX trial, daratumumab plus lenalidomide plus dexamethasone significantly prolonged progression-free    survival    in    the    intention-to-treat    population compared   with   lenalidomide   plus    dexamethasone (median 45.8 months vs 17.5 months; HR 0.43 [95% CI 0.35–0.54]; p<0.0001) after a median of 51.3 months of follow-up. In the subgroup of patients who had received one previous line of therapy, daratumumab plus lenali- domide plus  dexamethasone  (n=149)  also  significantly prolonged progression-free survival versus lenalidomide plus  dexamethasone  (n=146;  median  53.3  months  vs 19.6 months, HR 0.42 [95% CI 0.30–0.57]; p<0.0001). Median   second    objective   disease    progression   was 53.3 months with daratumumab plus lenalidomide plus dexamethasone versus 31.7 months with lenalidomide plus  dexamethasone  (HR  0.54  [95%  CI  0.43–0.68]; p<0.0001) in the intention-to-treat population. With a longer follow-up, these results are expected to translate into an overall survival benefit. The daratumumab plus lenalidomide plus dexamethasone triplet combination is well  tolerated,  and  the  forthcoming  availability  of  a subcutaneous mode of administration of daratumumab will   increase   convenience. In   the   ASPIRE   trial,  the  median  overall  survival  was  11.4  months  longer with  carfilzomib  plus  lenalidomide   plus  dexametha- sone  (n=184) versus lenalidomide plus dexamethasone (n=157) inpatients who had received one previous line of therapy (47.3 months vs 35.9 months, HR 0.81 [95% CI 0.62–1.06];  p  value  not   available).  Elotuzumab  plus lenalidomide  plus  dexamethasone  and  ixazomib  plus lenalidomide  plus  dexamethasone  are  well  tolerated, but less effective than daratumumab plus lenalidomide plus dexamethasone, and than carfilzomib plus lenali- domide  plus  dexamethasone.  The  overall  survival benefit  observed  with  elotuzumab  plus  lenalidomide plus  dexamethasone  versus  lenalidomide  plus  dexa- methasone is restricted to patients who have received two to three previous lines of therapy, and overall survival is similar between the two treatments in patients with one previous line of therapy (median 43.7 months with elotuzumab plus lenalidomide plus  dexamethasone  vs 44.1  months  with  lenalidomide  plus  dexamethasone alone,   HR   1.00   [95%   CI   0.77–1.32];   p   value   not available).

对于来那度胺不耐受的首次复发骨髓瘤患者，目前最有效的联合疗法是达拉单抗加来那度胺加地塞米松。在POLLUX试验中，与来那度胺加地塞米松相比，达拉土单抗加来那度胺加地塞米松可显著延长意向治疗人群的无进展生存期（中位45.8个月 vs 17.5个月；HR 0.43 [95% CI 0.35-0.54]；p<0.0001），中位随访时间为51.3个月。在既往接受过一线治疗的患者亚组中，达拉土单抗联合来那度胺联合地塞米松（149例）与来那度胺联合地塞米松（146例；中位53.3个月 vs 19.6个月，HR 0.42 [95% CI 0.30-0.57]；p<0.0001）相比，也显著延长了无进展生存期。在意向治疗人群中，达拉单抗加来那度胺加地塞米松治疗的中位第二次客观疾病进展时间为53.3个月，而来那度胺加地塞米松治疗的中位第二次客观疾病进展时间为31.7个月（HR为0.54 [95% CI 0.43-0.68]；p<0.0001）。随着随访时间的延长，这些结果有望转化为总生存期的获益。达拉土单抗加来那度胺加地塞米松的三联疗法耐受性良好，即将推出的达拉土单抗皮下给药模式将为患者带来更多便利。在ASPIRE试验中，对于既往接受过一线治疗的患者，卡非佐米+来那度胺+地塞米松（184人）与来那度胺+地塞米松（157人）的中位总生存期延长了11.4个月（47.3个月 vs 35.9个月，HR 0.81 [95% CI 0.62-1.06]；P值不详）。 伊洛珠单抗联合来那度胺联合地塞米松和伊沙佐米联合来那度胺联合地塞米松的耐受性良好，但疗效不如达拉单抗联合来那度胺联合地塞米松，也不如卡非佐米联合来那度胺联合地塞米松。 伊洛珠单抗加来那度胺加地塞米松与来那度胺加地塞米松相比，观察到的总生存期获益仅限于既往接受过两到三线治疗的患者，对于既往接受过一线治疗的患者，两种疗法的总生存期相似（伊洛珠单抗的中位生存期为43.7个月，来那度胺加地塞米松的中位生存期为43.7个月。埃洛珠单抗联合来那度胺联合地塞米松的中位生存期为43.7个月，来那度胺联合地塞米松单独治疗的中位生存期为44.1个月，HR为1.00 [95% CI 0.77-1.32]；P值不详）。

 After   front-line    therapy   based    on   combinations including a proteasome inhibitor, a retreatment including a proteasome inhibitor can also be considered. Four trials have shown a progression-free survival benefit of other regimens versus bortezomib plus dexamethasone alone: ENDEAVOR  (evaluating     carfilzomib    plus    dexa- methasone), CASTOR  (evaluating daratumumab plus bortezomib plus dexamethasone), BOSTON  (evaluating selinexor  plus  bortezomib  plus  dexamethasone),  and BELLINI (evaluating venetoclax plus bortezomib plus dexamethasone).  In  ENDEAVOR,  patients  previously exposed   to   front-line   bortezomib   were   enrolled   if they  were  not  refractory  to  bortezomib.  The  median progression-free survival for patients who had received one previous line of therapy was 22.2 months for the 231   patients   who   received   carfilzomib   plus   dexa- methasone versus 10.1 months for the 229 patients who received  bortezomib  plus  dexamethasone   (HR  0.45 [95% CI 0.33–0.61]; p<0.0001).19   For patients who had previously received bortezomib, the median progression- free  survival  for  carfilzomib  plus  dexamethasone  was 15.6 months, versus 8.1 months for bortezomib plus dexamethasone (HR 0.56 [95% CI 0.44–0.73]; p<0.0001). The  median  overall  survival  in  patients  treated  after one  previous  line  of  therapy  was  51.3  months  with carfilzomib  plus  dexamethasone  versus  43.7  months with bortezomib plus dexamethasone (HR 0.77 [95% CI 0.58–1.02]; p value not available). In  CASTOR, after 19.4 months of median follow-up, daratumumab plus bortezomib plus dexamethasone was found to prolong progression-free  survival  compared  with  bortezomib plus  dexamethasone  alone  (median  16.7  months  vs 7.1 months,  HR 0.31  [95% CI 0.24–0.39]; p<0.0001). The progression-free  survival benefit of daratumumab plus bortezomib plus dexamethasone was most apparent in patients with one previous line of therapy compared with patients with more than one previous line of therapy (median 27.0 months vs 7.9 months, HR 0.22 [95% CI 0.13–0.33];  p<0.0001). The  phase  3  BOSTON  trial compared   bortezomib    plus   dexamethasone   versus selinexor   plus   bortezomib   plus   dexamethasone   in 402  patients  who  had  received  one  to  three  previous lines of therapy.  Selinexor plus bortezomib plus dexamethasone significantly prolonged median progression- free  survival  versus  bortezomib  plus  dexamethasone (13.9   months   vs   9.4   months,   HR   0.70   [95%   CI 0.53–0.93]; p=0.0075), but this benefit was less apparent inpatients previously exposed to a proteasome inhibitor (HR 0.78 [95% CI 0.58–1.06] in exposed patients vs 0.26 [0.11–0.60]   in   non-exposed   patients;   p   value   not available).  On  Dec  18,  2020,  the  US  Food  and  Drug Administration approved selinexor in combination with bortezomib  plus  dexamethasone  for  the  treatment  of adult patients with multiple myeloma who have received at  least   one  previous  line   of  therapy.  The  phase   3 BELLINI  trial has  compared  bortezomib  plus  dexa- methasone versus bortezomib plus dexamethasone plus venetoclax,  a  selective  BCL2  inhibitor,  in  291  patients who had received one to three previous lines of therapy. A   significant   progression-free   survival   benefit   was reported  with  bortezomib  plus  dexamethasone  plus venetoclax   in   patients   with   a   t(11;14)   translocation (HR  0.11  [95%  CI  0.02–0.56];  p=0.0040)  and  those with   high    BCL2    expression    (HR   0.24   [95%   CI 0.12–0.48]; p<0.0001). Bortezomib plus dexamethasone plus venetoclax was  also  superior  to bortezomib  plus dexamethasone  in  terms  of  progression-free  survival (HR 0.21 [95% CI 0.11–0.41]; p<0.0001) and minimal residual  disease  negativity  rate   (19%  vs  0%)  for  the combined   group   of  patients   with   t(11;14)   or   high BCL2 expression. By contrast, inpatients without t(11;14) and with low BCL2 expression, median progression-free survival   did   not   differ   significantly   between    the two treatment groups, and increased mortality was seen in the bortezomib plus dexamethasone plus venetoclax group, mostly because of a higher rate of fatal infections (septic  shock  and  pneumonia).  Finally,  the  results  of the  CANDOR  trial,28    in  which  carfilzomib  plus  dexa- methasone     was     compared     with     daratumumab plus carfilzomib plus dexamethasone, showed no statisti- cally  significant difference in progression-free  survival between  the  treatment  groups  in  patients  with  one previous line of therapy (HR 0.68 [95% CI 0.40–1.14]; p=0.37)  or  in  patients  with  disease  not  refractory  to lenalidomide (HR 0.74 [95% CI 0.49–1.11]; p=0.15), but an improved progression-free survival with daratumumab plus  carfilzomib plus  dexamethasone in patients with previous proteasome inhibitor exposure (HR 0.61 [95% CI 0.45–0.84];  p=0.065).  The  preliminary  results  of the IKEMA trial, in which carfilzomib plus dexamethasone was  compared  with  isatuximab  plus  carfilzomib  plus dexamethasone, did not show a significant difference in progression-free  survival between treatment groups in patients who had received one previous line of therapy (HR 0.59 [95% CI 0.31–1.12]; p value not available), in patients  with  disease  not  refractory  to  lenalidomide (HR 0.45 [95% CI 0.15–1.35]; p value not available), and in  patients  with  previous  exposure  to  a  proteasome inhibitor  (HR  0.56  [95%  CI  0.31–1.04];  p  value  not available).

在使用包括蛋白酶体抑制剂在内的联合疗法进行一线治疗后，还可以考虑使用包括蛋白酶体抑制剂在内的再治疗方案。有四项试验显示，与硼替佐米加地塞米松单药相比，其他治疗方案具有无进展生存期优势：ENDEAVOR（评估卡非佐米加地塞米松）、CASTOR（评估daratumumab加硼替佐米加地塞米松）、BOSTON（评估selinexor加硼替佐米加地塞米松）和BELLINI（评估venetoclax加硼替佐米加地塞米松）。 在ENDEAVOR研究中，曾接受过一线硼替佐米治疗的患者如果对硼替佐米没有难治性，也会被纳入研究。 231名接受卡非佐米加地塞米松治疗的患者的中位无进展生存期为22.2个月，而229名接受硼替佐米加地塞米松治疗的患者的中位无进展生存期为10.1个月（HR 0.19 对于既往接受过硼替佐米治疗的患者，卡非佐米加地塞米松治疗的中位无进展生存期为 15.6 个月，而硼替佐米加地塞米松治疗的中位无进展生存期为 8.1 个月（HR 0.56 [95% CI 0.44-0.73]; p<0.0001）。卡非佐米加地塞米松治疗患者的中位总生存期为51.3个月，而硼替佐米加地塞米松为43.7个月（HR 0.77 [95% CI 0.58-1.02]；P值不详）。在CASTOR中，经过19.4个月的中位随访，发现达拉土单抗联合硼替佐米联合地塞米松与硼替佐米联合地塞米松单药相比延长了无进展生存期（中位16.7个月 vs 7.1个月，HR 0.31 [95% CI 0.24-0.39]；P<0.0001）。达拉土单抗联合硼替佐米联合地塞米松的无进展生存期获益在既往接受过一种疗法的患者中最为明显，而在既往接受过一种以上疗法的患者中则不尽相同（中位27.0个月 vs 7.9个月，HR 0.22 [95% CI 0.13-0.33]；P<0.0001）。BOSTON三期试验比较了硼替佐米加地塞米松与赛来昔单抗加硼替佐米加地塞米松对402例既往接受过一至三线治疗的患者的疗效。 与硼替佐米加地塞米松相比，西利奈索加硼替佐米加地塞米松显著延长了患者的中位无进展生存期（13.9个月对9.4个月，HR 0.70 [95% CI 0.53-0.93]；P=0.0075）。0075），但这一益处在曾暴露于蛋白酶体抑制剂的患者中不太明显（暴露患者的 HR 为 0.78 [95% CI 0.58-1.06]，未暴露患者的 HR 为 0.26 [0.11-0.60]；P 值不详）。 2020 年 12 月 18 日，美国食品和药物管理局批准赛来昔单抗联合硼替佐米加地塞米松用于治疗既往接受过至少一种疗法的成年多发性骨髓瘤患者。 BELLINI三期试验比较了硼替佐米加地塞米松与硼替佐米加地塞米松加选择性BCL2抑制剂venetoclax对291名既往接受过一至三线治疗的患者的治疗效果。在t(11;14)易位患者（HR 0.11 [95% CI 0.02-0.56]；P=0.0040）和BCL2高表达患者（HR 0.24 [95% CI 0.12-0.48]；P<0.0001）中，硼替佐米联合地塞米松联合venetoclax有明显的无进展生存期获益。就无进展生存期（HR 0.21 [95% CI 0.11-0.41]; p<0.0001）和t(11;14)或BCL2高表达患者的最小残留病阴性率（19% vs 0%）而言，硼替佐米加地塞米松加venetoclax也优于硼替佐米加地塞米松。相比之下，对于没有t(11;14)和BCL2低表达的患者，两个治疗组的中位无进展生存期没有显著差异，而硼替佐米+地塞米松+venetoclax组的死亡率有所增加，主要是因为致命感染（脓毒性休克和肺炎）发生率较高。 最后，CANDOR 试验28 将卡非佐米加地塞米松与达拉单抗加卡非佐米加地塞米松进行了比较，结果显示，在既往接受过一线治疗的患者中，治疗组之间的无进展生存期无统计学意义上的显著差异（HR 0.68[95%CI0.40-1.14]；P=0.37）或来那度胺不耐药患者（HR 0.74 [95% CI 0.49-1.11]；P=0.15）的无进展生存期，但在既往接受过蛋白酶体抑制剂治疗的患者中，达拉单抗联合卡非佐米联合地塞米松可改善无进展生存期（HR 0.61 [95% CI 0.45-0.84]；P=0.065）。 在IKEMA试验中，卡非佐米加地塞米松与伊沙妥昔单抗加卡非佐米加地塞米松进行了比较，初步结果显示，在既往接受过一线治疗的患者中，治疗组间的无进展生存期没有显著差异（HR 0.59[95%CI0.31-1.12]；P值不详）、来那度胺治疗不耐受的患者（HR 0.45 [95% CI 0.15-1.35]；P值不详）以及既往接受过蛋白酶体抑制剂治疗的患者（HR 0.56 [95% CI 0.31-1.35] ；P值不详）。04]；P 值不详）。

 A summary of the progression-free  survival results of phase  3  trials  in  patients  with  multiple  myeloma  not refractory to lenalidomide, including subgroup analysis in patients with one previous line of therapy, is presented in table 2. Recommendations for first relapse inpatients with disease not refractory to lenalidomide are shown in figure 1.

表2列出了来那度胺治疗非难治性多发性骨髓瘤患者的三期试验无进展生存期结果摘要，包括对既往接受过一线治疗的患者进行的亚组分析。来那度胺非难治性多发性骨髓瘤患者首次复发的建议见图1。

 First relapse inpatients progressing on front- line daratumumab-based combinations

使用达拉单抗前线复方制剂治疗进展中的首次复发患者

 The  approval  of  daratumumab-based  regimens  (dara- tumumab   plus   bortezomib   plus    melphalan   plus prednisone [ALCYONE trial] and daratumumab plus lenalidomide  plus  dexamethasone   [MAIA  trial])  as the  front-line  therapy  for  myeloma  is  making  treat- ment  decisions  challenging.  So  far,  no  data  exist  to support daratumumab retreatment at second line, and salvage therapy with isatuximabin patients progressing on  daratumumab  is  unlikely  to  be  a  suitable  option because both antibodies target the same antigen (CD38).   In the ALCYONE trial,  patients in the daratumumab plus bortezomib plus melphalan plus prednisone group received nine 6-week cycles of subcutaneous bortezomib, oral  melphalan,  and  oral  prednisone,  plus  intravenous daratumumab until disease progression or unacceptable toxicity.  At  a  median  follow-up  of  40.1  months,  the Kaplan-Meier estimate of 36 month overall survival was significantly longer in this group than in the bortezomib plus melphalan plus prednisone group (HR 0.60 [95% CI 0.46–0.80];  p=0.0003).  The   Kaplan-Meier  estimate  of 36 month overall survival was 78.0% (95% CI 73.2–82.0) in the daratumumab plus bortezomib plus melphalan plus prednisone group and 67.9% (95% CI 62.6–72.6) in the bortezomib plus melphalan plus prednisone group. No data are yet available regarding subsequent therapies after disease  progression  on  daratumumab  plus  bortezomib plus melphalan plus prednisone. Nevertheless, at the time of relapse, the logical approach is to use a lenalidomide- based  combination  without  daratumumab.  ALCYONE enrolled patients aged 65 years or older not eligible for ASCT.  A  suitable  option  would  be  carfilzomib  plus lenalidomide plus dexamethasone for fit patients above the age of 65 years in this setting, but for frail patients or those  older  than  75  years  of  age,  dexamethasone  in combination with ixazomib or elotuzumab might be the best approaches after progression on daratumumab plus bortezomib plus melphalan plus prednisone.

以达拉图单抗为基础的治疗方案（达拉图单抗+硼替佐米+美法仑+泼尼松[ALCYONE试验]和达拉图单抗+来那度胺+地塞米松[MAIA试验]）被批准作为骨髓瘤的一线治疗方案，这使得治疗决策面临挑战。 到目前为止，还没有数据支持达拉土单抗二线再治疗，使用伊沙西马滨对达拉土单抗治疗进展的患者进行挽救治疗不太可能是一个合适的选择，因为这两种抗体都针对相同的抗原（CD38）。 在ALCYONE试验中，达拉土单抗+硼替佐米+美法仑+泼尼松组患者接受了9个6周周期的皮下注射硼替佐米、口服美法仑和口服泼尼松，以及静脉注射达拉土单抗，直到疾病进展或出现不可接受的毒性。 中位随访时间为40.1个月，该组患者36个月总生存期的Kaplan-Meier估计值明显长于硼替佐米加美法仑加泼尼松组（HR 0.60 [95% CI 0.46-0.80]；P=0.0003）。 达拉曲单抗加硼替佐米加美法仑加泼尼松组的36个月总生存率的卡普兰-梅耶估计值为78.0%（95% CI 73.2-82.0 ），而硼替佐米加美法仑加泼尼松组为67.9%（95% CI 62.6-72.6）。目前还没有关于达拉曲单抗加硼替佐米加美法仑加泼尼松治疗疾病进展后后续治疗的数据。不过，在复发时，合理的方法是使用来那度胺为基础的联合疗法，而不使用达拉单抗。 ALCYONE招募了65岁或65岁以上不符合ASCT条件的患者。 在这种情况下，对于65岁以上的健康患者，卡非佐米加来那度胺加地塞米松是一个合适的选择，但对于体弱或75岁以上的患者，在达拉单抗加硼替佐米加美法仑加强的松治疗进展后，地塞米松联合伊沙佐米或埃洛珠单抗可能是最好的方法。

 In   the   MAIA   trial, patients   received    front-line daratumumab  plus  lenalidomide  plus  dexamethasone until  disease  progression.  This  combination  is  now approved by the US Food and Drug Administration and by the European Medicines Agency, and the impressive progression-free survival results will probably lead to a widespread  use  of  this  triplet  combination,  even  in patients older than 75 years. No data on salvage regimens at the time of progression in the MAIA trial are available. A   proteasome   inhibitor-based   combination   without daratumumab  is the logical  approach.  In  this  setting, carfilzomib    plus    dexamethasone,   bortezomib    plus cyclophosphamide plus  dexamethasone, pomalidomide plus bortezomib plus dexamethasone, bortezomib plus melphalan plus prednisone, or carfilzomib plus pomali- domide  plus  dexamethasone  are  reasonable  options. Alternatively,  elotuzumab  plus  bortezomib  plus  dexa- methasone, selinexor plus bortezomib plus dexametha- sone, or ixazomib plus pomalidomide plus dexamethasone could be considered.

在MAIA试验中，患者接受达拉土单抗加来那度胺加地塞米松的一线治疗，直至疾病进展。 这种三联疗法现已获得美国食品药品管理局和欧洲药品管理局的批准，令人印象深刻的无进展生存期结果很可能会促使这种三联疗法得到广泛应用，即使是 75 岁以上的患者也不例外。目前还没有关于 MAIA 试验中病情恶化时抢救方案的数据。以蛋白酶体抑制剂为基础、不使用达拉单抗的联合疗法是合理的方法。 在这种情况下，卡非佐米加地塞米松、硼替佐米加环磷酰胺加地塞米松、泊马度胺加硼替佐米加地塞米松、硼替佐米加美法仑加泼尼松或卡非佐米加泊马度胺加地塞米松都是合理的选择。另外，也可以考虑艾洛单抗加硼替佐米加地塞米松、赛来昔单抗加硼替佐米加地塞米松或伊沙佐米加泊马度胺加地塞米松。

 Salvage ASCT 抢救性 ASCT

 Front-line ASCT is the standard of care for fit patients younger  than  70  years   of  age  in  many  countries.1,2 Nevertheless,  given the  absence  of an  overall  survival benefit of front-line ASCT inpatients with standard-risk disease, compared with bortezomib plus lenalidomide plus  dexamethasone  followed  by  lenalidomide  main- tenance, for example, some investigators and patients prefer to delay ASCT to the time of the first relapse, after harvesting and storing stem cells during induction. In this  setting,  salvage  ASCT  should  be  systematically considered   in   patients   who   have   never   previously received a transplant.One issue is the selection of the optimal   reinduction   regimen   before   salvage   ASCT, especially for patients progressing  on front-line, long- term   lenalidomide   therapy.   Few   data   are   available regarding   reinduction   regimens.   Carfilzomib   plus pomalidomide  plus  dexamethasone  was  found  to  be active in this setting in the phase EMN011 2 trial.

尽管如此，与硼替佐米+来那度胺+地塞米松，然后再用来那度胺维持治疗等方法相比，一线ASCT对标准风险疾病患者的总体生存并无益处，因此一些研究者和患者更倾向于在诱导期间收获并储存干细胞后，将ASCT推迟到首次复发时进行。在这种情况下，对于从未接受过移植的患者，应系统地考虑挽救性ASCT。一个问题是在挽救性ASCT前选择最佳的再诱导方案，尤其是对于接受一线长期来那度胺治疗后病情进展的患者。 有关恢复方案的数据很少。 在EMN011 2期试验中，发现卡非佐米加泊马度胺加地塞米松在这种情况下具有活性。

 Salvage  ASCT  can  also  be  considered  in  patients progressing after front-line ASCT. The only randomised, controlled trial to  show the  role  of salvage ASCT  in patients with myeloma at first relapse or progression at least  12 months after ASCT was the  UK  Myeloma X study. In this trial,  patients with relapsed multiple myeloma   who   had   at   least   stable   disease   after reinduction  with  bortezomib  plus  doxorubicin  plus dexamethasone had a longer time to disease progression (19 months vs 11 months; HR 0.45 [95% CI 0.25–0.53]; p<0.0001) and    overall    survival    (67    months    vs 52 months; HR 0.56 [95% CI 0.35–0.90]; p=0.022)46 with salvage ASCT (n=89) versus weekly oral cyclophos- phamide (n=85) as consolidation (probably a suboptimal scheme because oral cyclophosphamide is not normally used  as  consolidation  therapy).  Another  prospective phase 3 study compared continuous lenalidomide plus dexamethasone  versus  continuous  lenalidomide  plus dexamethasone  reinduction  followed  by  ASCT  and maintenance  with  lenalidomide  in  277  patients  with first   to   third   relapse,   of   which   260   (94%)   had one previous line of therapy at the time of study entry, and   259   (94%)  received  front-line  ASCT.  Median progression-free survival was 20.7 months in the ASCT group     and     18.8    months    in    the     continuous dexamethasone  arm   (HR  0.87  [95%  CI  0.65–1.16]; p=0.34). Median overall survival was not reached in the ASCT group and was 62.7 months in the control group (HR 0.81 [95% CI 0.52–1.28]; p=0.37).

前线ASCT治疗后病情进展的患者也可考虑挽救性ASCT治疗。英国骨髓瘤X研究是唯一一项显示挽救性ASCT在ASCT后至少12个月首次复发或进展的骨髓瘤患者中的作用的随机对照试验。在这项试验中，复发的多发性骨髓瘤患者在重新接受硼替佐米加多柔比星加地塞米松治疗后病情至少稳定，其疾病进展时间（19 个月 vs 11 个月；HR 0.45 [95% CI 0.25-0.53]; p<0.0001）和总生存期（67 个月 vs 52 个月；HR 0.56 [95% CI 0.35-0.90]; p=0.022）46。 另一项前瞻性三期研究比较了持续来那度胺加地塞米松与持续来那度胺加地塞米松再诱导，然后进行ASCT并用来那度胺维持治疗277例首次至第三次复发的患者，其中260例（94%）在进入研究时已接受过一种治疗，259例（94%）接受了一线ASCT。 ASCT组的中位无进展生存期为20.7个月，持续地塞米松组为18.8个月（HR 0.87 [95% CI 0.65-1.16]；P=0.34）。ASCT组未达到中位总生存期，对照组为62.7个月（HR 0.81 [95% CI 0.52-1.28]；P=0.37）。

 The most important prognostic factor for progression- free  survival  after  salvage  ASCT   is  the   duration  of remission after the first ASCT procedure. Because front- line  ASCT  followed  by  lenalidomide  maintenance  is associated  with  a  median  duration  of  response   of 50 months,  salvage ASCT should not be recommended for patients with a response duration of less than 3 years after the first ASCT, but this cutoff is arbitrary and could be  reduced to  2 years  if the  patient has  not  received maintenance therapy (grade 2A recommendation).

挽救性 ASCT 后无进展生存期的最重要预后因素是首次 ASCT 后的缓解持续时间。由于前线ASCT后再接受来那度胺维持治疗的中位反应持续时间为50个月，因此对于首次ASCT后反应持续时间少于3年的患者，不应推荐进行挽救性ASCT，但这一分界线是任意的，如果患者未接受过维持治疗，则可缩短至2年（2A级推荐）。

 Treatment of relapsed and refractory disease after two or more previous lines of therapy

治疗既往接受过两种或两种以上疗法的复发和难治性疾病

 The treatment  of patients with relapsed  and  refractory multiple myeloma who have received two or more previous lines  of  therapy  is  becoming  particularly  challenging. Lenalidomide and bortezomib are often used as part of front-line therapy or at first relapse. Monoclonal antibodies (eg, daratumumab and elotuzumab) and carfilzomib are also being increasingly used during the first two lines of treatment. Therefore, at the time of the second relapse, allagents considered but not used for first relapse can be considered again. Enrolling the patient in a clinical trial, when available, should always be considered.

复发性和难治性多发性骨髓瘤患者曾接受过两种或两种以上的治疗，对他们的治疗正变得越来越具有挑战性。来那度胺和硼替佐米通常作为一线疗法的一部分或在首次复发时使用。单克隆抗体（如达拉单抗和埃洛珠单抗）和卡非佐米也越来越多地用于前两线治疗。因此，在第二次复发时，可以再次考虑在第一次复发时考虑但未使用的试剂。在有条件的情况下，应始终考虑让患者参加临床试验。

 Few phase 3 trials have focused on patients who have received  two  or  more  previous  lines  of  therapy.   In patients whose disease has progressed after treatment with   bortezomib    and   lenalidomide,    pomalidomide plus dexamethasone has been considered as standard of care, on the basis of the results of the MM-003 randomised study.  This  combination  (pomalidomide  plus  dexa- methasone) has been  compared with  isatuximab  plus pomalidomide plus dexamethasone in the ICARIA trial49  in patients previously treated with two or more lines of therapy   including   lenalidomide   and   a   proteasome inhibitor.   Notably,   284   (92%)   of   307   patients   had lenalidomide-refractory  disease,  and  301  (98%)  of  307 were refractory to their last line of therapy. At a median follow-up of 11.6 months, the median progression-free survival (the primary endpoint) was 11.5 months in the 154 patients in the isatuximab plus pomalidomide plus dexamethasone   group   versus   6.5   months   in   the 153 patients in the pomalidomide plus dexamethasone group   (HR   0.59   [95%   CI   0.44–0.81];   p=0.0010). Isatuximab plus pomalidomide plus dexamethasone was approved by the US Food and Drug Administration on March 2, 2020, and by the European Medicines Agency on June  2,  2020, for adult patients with relapsed and refractory   multiple   myeloma  who   received   at  least two previous lines of therapies including lenalidomide and a proteasome inhibitor and demonstrated disease progression on the last therapy. The CANDOR study, in which  carfilzomib plus  dexamethasone was  compared with daratumumab plus carfilzomib plus dexamethasone, also included a prespecified analysis of the outcome of 266 patients who had received two or more previous lines of  therapy;  this  analysis   showed  a  progression-free survival benefit with the triplet combination (HR 0.61 [95% CI 0.45–0.84]; p value not available). Similarly, the IKEMA trial,  in which carfilzomib plus dexamethasone was  compared  with  isatuximab  plus  carfilzomib  plus dexamethasone,  analysed the  outcome  of 167  patients who had received two or more previous lines of therapy, and   found    a   progression-free    survival   benefit    of isatuximab    plus    carfilzomib    plus    dexamethasone (HR 0.48 [95% CI 0.29–0.78]; p value not available).

很少有三期试验是针对接受过两种或两种以上治疗的患者。 对于接受硼替佐米和来那度胺治疗后病情恶化的患者，根据MM-003随机研究的结果，泊马度胺加地塞米松被认为是标准疗法。 在 ICARIA 试验49 中，这种联合疗法（泊马度胺加地塞米松）与伊沙妥昔单抗加泊马度胺加地塞米松进行了比较。 值得注意的是，307 例患者中有 284 例（92%）为来那度胺难治性疾病，307 例患者中有 301 例（98%）为最后一种疗法难治性疾病。在中位随访11.6个月时，伊沙妥昔单抗联合泊马度胺联合地塞米松组154名患者的中位无进展生存期（主要终点）为11.5个月，而泊马度胺联合地塞米松组153名患者的中位无进展生存期为6.5个月（HR 0.59 [95% CI 0.44-0.81]；P=0.0010）。伊沙妥昔单抗联合泊马度胺加地塞米松于2020年3月2日获得美国食品药品管理局批准，并于2020年6月2日获得欧洲药品管理局批准，用于治疗复发和难治性多发性骨髓瘤成人患者，这些患者之前至少接受过两线治疗，包括来那度胺和蛋白酶体抑制剂，并在最后一次治疗中出现疾病进展。CANDOR研究将卡非佐米加地塞米松与达拉单抗加卡非佐米加地塞米松进行了比较，该研究还对266名既往接受过两种或两种以上疗法的患者的预设结果进行了分析；分析结果显示，三联疗法可使患者获得无进展生存期（HR 0.61 [95% CI 0.45-0.84]；P值不详）。同样，IKEMA 试验将卡非佐米加地塞米松与伊沙妥昔单抗加卡非佐米加地塞米松进行了比较，分析了 167 名接受过两种或两种以上既往疗法的患者的结果，发现伊沙妥昔单抗加卡非佐米加地塞米松的无进展生存期获益（HR 0.48 [95% CI 0.29-0.78]；P 值暂缺）。

 Two  other  antibody-based  combinations  that  can  be considered for patients with advanced disease have been approved on the basis of the results from phase 2 trials. In the  randomised  phase  2  ELOQUENT-3  trial,  patients who had received at least two previous lines of therapy were randomly assigned to receive either elotuzumab plus pomalidomide  plus  dexamethasone   (n=60)  or  poma- lidomide plus dexamethasone (n=57).  After 9 months of follow-up,   the   median   progression-free   survival   was 10.3 months in the elotuzumab plus pomalidomide plus dexamethasone   group   versus    4.7   months   in   the pomalidomide  plus  dexamethasone  group   (HR  0.54[95%  CI  0.34–0.86];  p=0.0080).  On  June  16,  2017,  the combination  of daratumumab plus pomalidomide plus dexamethasone was also licensed by the  US  Food  and Drug Administration for patients whose disease has not responded  to  at  least   two  previous  lines   of  therapy, including lenalidomide and a proteasome inhibitor. This approval was granted on the basis of the results of a phase 2 non-randomised study, the EQUULEUS trial, in which daratumumab  plus  pomalidomide  plus  dexamethasone was  given to  103  patients  with  relapsed  and  refractory multiple myeloma. At a median follow-up of 13 months, the median progression-free survival was 8.8 months and the median overall survival was 17.5 months. The phase 3 APOLLO     study     (NCT03180736;      EMN14)     enrolled 304 patients and was designed to compare pomalidomide plus dexamethasone  (n=153) versus  daratumumab plus pomalidomide  plus  dexamethasone   (n=151;  randomly assigned)  in  patients  refractory  to  lenalidomide  and proteasome inhibitors. 33 (11%) patients had received at least one previous line of therapy (median 2, range 1–5), and 242 (80%) patients were refractory to lenalidomide. The results, presented for the first time at the American Society of Hematology 2020 meeting, showed a median progression-free survival benefit with daratumumab plus pomalidomide plus dexamethasone versus pomalidomide plus dexamethasone (12.4 months vs 6.9 months; HR 0.63 [95% CI 0.47–0.85]; p=0.0018).

根据二期临床试验的结果，另外两种可考虑用于晚期患者的抗体疗法组合已获得批准。在ELOQUENT-3随机2期试验中，既往接受过至少两线治疗的患者被随机分配接受艾洛单抗加泊马度胺加地塞米松（60人）或泊马度胺加地塞米松（57人）治疗。 随访9个月后，埃洛珠单抗联合泊马度胺联合地塞米松组的中位无进展生存期为10.3个月，而泊马度胺联合地塞米松组为4.7个月（HR 0.54[95% CI 0.34-0.86]；P=0.0080）。 2017年6月16日，达拉单抗加泊马度胺加地塞米松的组合疗法也获得了美国食品和药物管理局的许可，可用于对既往至少两种疗法（包括来那度胺和蛋白酶体抑制剂）无效的患者。这项批准的依据是一项二期非随机研究--EQUULEUS试验的结果，在这项试验中，103名复发和难治性多发性骨髓瘤患者接受了达拉土单抗+泊马度胺+地塞米松治疗。中位随访时间为13个月，无进展生存期中位数为8.8个月，总生存期中位数为17.5个月。3期APOLLO研究（NCT03180736；EMN14）共招募了304名患者，旨在比较泊马度胺加地塞米松（153人）与达拉单抗加泊马度胺加地塞米松（151人；随机分配）治疗来那度胺和蛋白酶体抑制剂难治性患者的疗效。33名（11%）患者之前至少接受过一次治疗（中位数为2次，范围为1-5次），242名（80%）患者对来那度胺难治。在美国血液学会2020年会议上首次公布的结果显示，达拉单抗联合泊马度胺联合地塞米松与泊马度胺联合地塞米松相比，中位无进展生存期获益（12.4个月 vs 6.9个月；HR 0.63 [95% CI 0.47-0.85]；P=0.0018）。

 A simple and inexpensive option to improve the results of pomalidomide plus dexamethasone when other agents are not available is the addition of cyclophosphamide to this  treatment  combination.  Although  no  direct  comparisons  are  available  from  phase  3  studies,  several phase 2 trials have shown that the median progression- free  survival of pomalidomide plus cyclophosphamide plus   dexamethasone   is   approximately   7–9   months, compared with 4–6 months for the same subgroup of patients treated with pomalidomide plus dexamethasone alone (table 3).

在没有其他药物的情况下，要想改善泊马度胺加地塞米松的治疗效果，一个简单而廉价的选择就是在这种治疗组合中加入环磷酰胺。 虽然没有三期研究的直接比较，但几项二期试验显示，泊马度胺加环磷酰胺加地塞米松的中位无进展生存期约为7-9个月，而单用泊马度胺加地塞米松的同一亚组患者的中位无进展生存期为4-6个月（表3）。

 Additional options for patients with relapsed and refractory disease after two or more previous lines of therapy

为接受过两种或两种以上疗法的复发和难治性疾病患者提供更多选择

 The outcome is very poor for patients whose multiple myeloma has become refractory to proteasome inhibitors, immunomodulatory agents, and anti-CD38 antibodies, with one study showing that these patients have a median overall  survival  of only  5.6  months.  In  this  setting, intensive   chemotherapeutic   combinations,   such   as bortezomib plus dexamethasone plus thalidomide plus cisplatin plus doxorubicin plus cyclophosphamide plus etoposide, can be used,  although prospective data are not available for these combinations.

对蛋白酶体抑制剂、免疫调节剂和抗CD38抗体产生耐药性的多发性骨髓瘤患者的治疗效果很差，一项研究显示，这些患者的中位总生存期仅为5.6个月。 在这种情况下，可以使用强化化疗组合，如硼替佐米加地塞米松加沙利度胺加顺铂加多柔比星加环磷酰胺加依托泊苷，但目前还没有这些组合的前瞻性数据。

 Selinexor,   a    selective   inhibitor    of   nuclear   export compound that blocks exportin 1 and forces nuclear accu- mulation and activation of tumour suppressor proteins, has been evaluated in combination with dexamethasone in patients previously exposed to (individually or in combi- nation)  bortezomib,  carfilzomib,  lenalidomide,  pomali- domide, daratumumab, or an alkylating agent and had disease  refractory to  at least  one  proteasome  inhibitor, one immunomodulatory agent, and daratumumab (triple- class refractory) in the phase 2  STORM study. A  total of 122 patients were included,  65  (53%)  of which  had high-risk cytogenetic abnormalities, such as del(17p)/p53, t(4;14), t(14;16), and gain(1q). A partial response or better was observed in  32  (26%)  of 122  patients,  the  median progression-free survival was 3.7 months, and the median overall survival was 8.6 months. A prespecified subgroup analysis of 83 patients whose disease was refractory to (individually or in combination) bortezomib, carfilzomib, lenalidomide, pomalidomide, and daratumumab showed an overall response rate of 25.3%, with a median response duration  of  3.8  months.  Based  on  these  results,  the US  Food  and  Drug Administration  granted  accelerated approval to selinexor for the treatment of this subgroup of patients in July, 2019. One problem with selinexor is its safety  profile:  about  25%  of  the  patients  experienced grade  3  fatigue,  gastrointestinal  toxicity,  and  thrombo- cytopenia, but these side-effects are more manageable with less frequent doses and supportive care.

Selinexor是一种核输出选择性抑制剂，可阻断输出蛋白1，迫使肿瘤抑制蛋白在核内聚集和激活、 硼替佐米、卡非佐米、来那度胺、泊马利多米、达拉单抗或一种烷化剂，并对至少一种蛋白酶体抑制剂、一种免疫调节剂和达拉单抗（三类难治性）难治的患者进行了 STORM 2 期研究。研究共纳入了122例患者，其中65例（53%）有高危细胞遗传学异常，如del(17p)/p53、t(4;14)、t(14;16)和gain(1q)。122例患者中有32例（26%）观察到部分反应或更好的反应，中位无进展生存期为3.7个月，中位总生存期为8.6个月。对83例对硼替佐米、卡非佐米、来那度胺、泊马度胺和达拉单抗（单独或联合使用）难治的患者进行的预设亚组分析显示，总反应率为25.3%，中位反应持续时间为3.8个月。 基于这些结果，美国食品和药物管理局于2019年7月加速批准selinexor用于治疗该亚组患者。selinexor的一个问题是其安全性：约25%的患者出现3级疲劳、胃肠道毒性和血栓性全血细胞减少症，但这些副作用通过减少用药次数和支持性护理可以得到较好的控制。

 As   discussed   previously,   the   oral   pan-deacetylase inhibitor panobinostat was approved in combination with bortezomib  plus  dexamethasone  on  the  basis  of  the results of the phase 3 PANORAMA 1 trial,  but is less commonly used  due to  a previously  challenging toler- ability  profile,   and  little   evidence  of  clinical  benefit. Nevertheless, the phase 2 PANORAMA 2 trial showed that panobinostat was able to revert bortezomib resistance

如前所述，根据 3 期 PANORAMA 1 试验的结果，口服泛去乙酰化酶抑制剂泛比诺司特（panobinostat）获准与硼替佐米加地塞米松（dexamethasone）联用，但由于其耐受性较差，且几乎没有临床获益的证据，因此并不常用。然而，PANORAMA 2 的二期试验表明，帕诺比诺司他能够逆转硼替佐米的耐药性。

 in about  25% of the cases progressing on bortezomib plus  dexamethasone. Therefore,  when   patients  are progressing on proteasome inhibitors and few therapeutic options  are  available,  the  addition  of panobinostat  in combination can be tested, with careful dose adaptation.

在使用硼替佐米加地塞米松治疗的病例中，约有 25% 的患者病情有所进展。因此，当患者使用蛋白酶体抑制剂后病情出现进展，可供选择的治疗方案不多时，可以在谨慎调整剂量的情况下，试验联合使用帕诺比诺司特。

 Melflufen  (melphalan  flufenamide)  is  a  first-in-class anti-cancer peptide-drug conjugate that rapidly delivers an alkylating payload into tumour cells. This agent has been tested in combination with dexamethasone in the phase 1/2 O-12-M1 trial  in patients with relapsed and refractory multiple myeloma who had received two or more previous lines of therapy (including lenalidomide and bortezomib) and were refractory to their last line of therapy. In the phase 2 part of the study, 31% of patients treated with melflufen plus dexamethasone achieved an overall response. The most common grade 3 or 4 adverse events were thrombocytopenia (in 62% of patients) and neutropenia (in 58% of patients), and non-haematological toxicity was infrequent. Melflufen is not yet approved, but the HORIZON trial, testing melflufen plus dexa- methasone   in   patients   refractory   to   pomalidomide, daratumumab,  or  both,  has  been  recently  completed. Of 157 patients  (with  a  median  of five  previous lines of therapy)  enrolled  and  treated,   119  patients   (76%) had triple-class refractory disease, 55  (35%) had extra- medullary  disease,  and  92  (59%)  were  refractory  to previous alkylator therapy. The overall response rate was 29% in the all-treated population, with 26% in the triple- class refractory population. In the all-treated population, median duration of response was 5.5 months, median progression-free survival was 4.2 months, and median overall survival was 11.6 months at a median follow-up of 14 months.

Melflufen（美法仑氟酰胺）是一种首创的抗癌多肽药物共轭物，能将烷化有效载荷快速送入肿瘤细胞。在O-12-M1的1/2期试验中，该药物与地塞米松联合用于复发和难治性多发性骨髓瘤患者，这些患者此前接受过两种或两种以上的治疗（包括来那度胺和硼替佐米），但对最后一种治疗方法难治。在该研究的第二阶段中，31%接受过美氟芬加地塞米松治疗的患者获得了总体应答。最常见的3级或4级不良反应是血小板减少（62%的患者）和中性粒细胞减少（58%的患者），非血液学毒性不常见。美氟芬尚未获得批准，但HORIZON试验已于近期完成，该试验测试了美氟芬加地塞米松治疗泊马度胺、达拉单抗或两者均难治的患者。在入组并接受治疗的157名患者（中位数为既往接受过五种疗法）中，119名患者（76%）患有三类难治性疾病，55名患者（35%）患有髓外疾病，92名患者（59%）对既往的烷化剂疗法难治。在所有接受过治疗的人群中，总反应率为29%，其中三类难治性人群的反应率为26%。在所有治疗人群中，中位应答持续时间为5.5个月，中位无进展生存期为4.2个月，中位总生存期为11.6个月，中位随访时间为14个月。

 B-cell  maturation  antigen   (BCMA;  also  known  as TNFSRS17) promotes multiple myeloma pathogenesis in the bone marrow microenvironment and is a very specific multiple myeloma target antigen. Immunologically based therapies targeting BCMA show promise independent of genetic heterogeneity and genetic risk, even in patients with multiple myeloma with no other treatment options. These  agents  include  antibody–drug  conjugates,  auto- logous  chimeric  antigen  receptor  engineered  T  cells (CAR T cells), and bispecific T cell or NK engagers. Little data  are  yet  available  for  bispecific  agents,  and  early clinical trials are ongoing.

B细胞成熟抗原（BCMA，又称TNFSRS17）在骨髓微环境中促进多发性骨髓瘤的发病，是一种非常特异的多发性骨髓瘤靶抗原。针对 BCMA 的免疫疗法显示出良好的前景，不受遗传异质性和遗传风险的影响，即使是在没有其他治疗选择的多发性骨髓瘤患者中也是如此。这些药物包括抗体-药物共轭物、自动嵌合抗原受体工程 T 细胞（CAR T 细胞）以及双特异性 T 细胞或 NK 吸引剂。目前双特异性药物的数据还很少，早期临床试验正在进行中。

 Belantamab  mafodotin  is  an  anti-BCMA  antibody– drug conjugate containing monomethyl auristatin F. In the phase 2 DREAMM-2 trial, 196 patients with triple- class-refractory multiple myeloma received two different doses  of belantamab mafodotin  (2.5  mg/kg  [n=97]  or 3.4 mg/kg [n=99]). Overall response rates were 31% for the 2.5 mg/kg dose and 34% for the 3.4 mg/kg dose. The median progression-free survival was 2.9 months in the 2.5 mg/kg group, and 4.9 months in the 3.4 mg/kg group,  but  overall  survival  data  were  not  available  at the   time   of  publication   in   December,   2019.  The most  common  grade  3  or  4  adverse  events  included  keratopathy, thrombocytopenia, and anaemia. Of note, in  the  phase  1  study  (DREAMM-1),  at  the  dose  of 3.4  mg/kg,  the  median  progression-free  survival  was longer   (12  months,  compared  with  4.9  months  in the  phase   2   study),  and  the  overall  response  rate was 60%, but fewer patients had disease refractory to anti-CD38   antibodies   than   in   the   phase   2   study. Belantamab mafodotin was approved by the  US  Food and Drug Administration (on Aug 6, 2020) and by the European  Medicines  Agency  (on  Aug  26,  2020)  as  a monotherapy treatment for patients with relapsed and refractory multiple myeloma who have received at least four   previous   lines   of  therapy   including   an   anti- CD38 monoclonal antibody, a proteasome inhibitor, and an immunomodulatory agent.

在二期DREAMM-2试验中，196名三类难治性多发性骨髓瘤患者接受了两种不同剂量的贝仑单抗mafodotin（2.5毫克/千克[n=97]或3.4毫克/千克[n=99]）。2.5毫克/千克剂量的总体反应率为31%，3.4毫克/千克剂量的总体反应率为34%。2.5毫克/千克组的中位无进展生存期为2.9个月，3.4毫克/千克组为4.9个月，但在2019年12月发表论文时尚未获得总生存期数据。 最常见的3级或4级不良事件包括角膜病、血小板减少和贫血。值得注意的是，在剂量为3.4 mg/kg的1期研究（DREAMM-1）中，中位无进展生存期更长（12个月，而2期研究中为4.9个月），总反应率为60%，但与2期研究相比，抗CD38抗体难治性疾病患者更少。Belantamab mafodotin于2020年8月6日获得美国食品药品管理局批准，并于2020年8月26日获得欧洲药品管理局批准，作为复发和难治性多发性骨髓瘤患者的单药治疗，这些患者此前至少接受过四种疗法，包括抗CD38单克隆抗体、蛋白酶体抑制剂和免疫调节剂。

 Early clinical trials of CAR T-cell therapy have shown encouraging results in multiple myeloma. In a phase 1 study  of idecaptagene  cicleucel  (previously  known  as bb2121), a BCMA-targeting CAR T-cell construct, 33 of the  36  enrolled  patients  received   CAR  T   cells  after lymphodepleting  chemotherapy. Three  patients  pro- gressed  during  CAR T-cell manufacturing, which was successful in all patients. A total of 26  (79%) patients receiving CAR T-cell therapy were refractory to both a proteasome inhibitor and an immunomodulatory agent; six (18%) patients were refractory to (individually or in combination)   bortezomib,   carfilzomib,   lenalidomide, pomalidomide,and daratumumab. The overall response rate was 85%, including a complete response rate of45%. Of the 16 patients with a haematological response and who were evaluated for minimal residual disease, 15 had no minimal residual disease. For patients who received at least 150 × 10⁶ CAR T cells, the median progression- free   survival   was   11.8   months. Cytokine   release syndrome  occurred  in  25  (76%)  of  33  patients,  and grade 3 or grade 4 neurotoxicity in 1 (3%) of 33 patients. The   initial   results   of  the   phase   2   trial   study   of idecabtagene vicleucel  (KarMMa) were reported  at the American  Society  of  Clinical  Oncology  Annual  2020 meeting. 140 patients were enrolled, of whom 128 (91%) were treated with idecabtagenevicleucel across the target dose  levels  of  150–450 × 10⁶  CAR  T  cells.  All  treated patients had been exposed to at least three previous lines of therapy,  including  an  immunomodulatory  agent,  a proteasome inhibitor, and an anti-CD38 antibody, and all were refractory to their last regimen.  107  (84%)  of 128  patients  were  triple-refractory   (refractory  to   an immunomodulatory  agent,  proteasome  inhibitor,  and an  anti-CD38  antibody).  With  a  median  follow-up  of 13.3  months  and  across  the  target  dose  levels   (150, 300, and 450 × 10⁶ CAR T cells), the overall response rate was 73.4% (including 33% complete response) and the median  progression-free  survival  was  8.8  months.63  These   promising   results   have   not   yet   been   fully published, and idecabtagenevicleucel is not yet approved by regulatory authorities. In the results from a phase 1 study of LCAR-B38M CAR T cells (LEGEND-2, n=57), 88% of less heavily pretreated patients (with a median of three  previous  lines  of  therapy)  achieved  an  overall response, and the median progression-free survival was 15   months.   LCAR-B38M   is   a   dual   epitope-binding CAR T-cell therapy directed against two distinct BCMA epitopes. The biepitope BCMA-binding moieties confer high-avidity binding and distinguish LCAR-B38M from other BCMA CAR constructs. Ongoing trials in Europe and the USA are using LCAR-B38M; an example is the phase   1b/2   CARTITUDE1   trial, reported   at   the American  Society  of  Clinical  Oncology  Annual  2020 meeting,  in which  25  of 29  patients  were  triple-class refractory. The overall response rate was 100%, including 86%  stringent  complete  response,  with   a  9  month progression-free   survival   of   86%.   Cytokine   release syndrome occurred in 27 (93%) of 29 patients (7% with grade ≥3), and grade 3 or grade 4 neurotoxicity occurred in 1 (4%) of 29 patients. Albeit promising, these results require confirmation in a larger number of patients, and LCAR-B38M/JNJ-4528 is not yet approved by regulatory authorities. Many other CAR T-cell therapies targeting BCMA  or  other  molecules   such  as   SLAMF7,  CD38, NKG2D (KLRK1) ligands, or CD138 (SYND1), are under evaluation. The use of CAR T cells raises several issues, especially   in   patients   with   very   advanced   disease: progression of the disease during product manufacturing, mechanisms  of resistance  (no plateau  of progression- free survival curves) related to antigen escape or absence of long-term persistence of CAR T cells, and the safety profile  of  this  therapy  (eg,  risk  of  cytokine  release syndrome and neurotoxicity).

CAR T 细胞疗法的早期临床试验在多发性骨髓瘤中取得了令人鼓舞的结果。在idecaptagene cicleucel（以前称为bb2121）（一种BCMA靶向CAR T细胞构建体）的一期研究中，36名入组患者中有33人在接受淋巴清除化疗后接受了CAR T细胞治疗。3 名患者在 CAR T 细胞制造过程中出现进展，所有患者均成功制造出 CAR T 细胞。接受CAR T细胞治疗的患者中，共有26人（79%）对蛋白酶体抑制剂和免疫调节剂难治；6人（18%）对硼替佐米、卡非佐米、来那度胺、泊马度胺和达拉曲单抗（单独或联合使用）难治。总反应率为85%，其中完全反应率为45%。在16例有血液学应答并接受了最小残留病评估的患者中，15例无最小残留病。接受至少 150 × 10⁶ CAR T 细胞治疗的患者的中位无进展生存期为 11.8 个月。33例患者中有25例（76%）出现细胞因子释放综合征，33例患者中有1例（3%）出现3级或4级神经毒性。美国临床肿瘤学会2020年年会上报告了idecabtagene vicleucel（KarMMa）2期试验研究的初步结果。140名患者入组，其中128人（91%）接受了idecabtagenevicleucel治疗，目标剂量为150-450×10⁶ CAR T细胞。所有接受治疗的患者之前至少接受过三种疗法，包括一种免疫调节剂、一种蛋白酶体抑制剂和一种抗CD38抗体，而且所有患者都对上一种疗法难治。128名患者中有107名（84%）是三线疗法难治患者（对免疫调节剂、蛋白酶体抑制剂和抗CD38抗体难治）。中位随访时间为 13.3 个月，在不同的目标剂量水平（150、300 和 450 × 10⁶ CAR T 细胞）下，总反应率为 73.4%（包括 33% 的完全反应），中位无进展生存期为 8.8 个月。LCAR-B38M CAR T 细胞的 1 期研究（LEGEND-2，n=57）结果显示，88% 预后较差的患者（中位数曾接受过三线治疗）获得了总体应答，中位无进展生存期为 15 个月。LCAR-B38M 是一种针对两种不同 BCMA 表位的双表位结合 CAR T 细胞疗法。双表位 BCMA 结合分子具有高活性结合，使 LCAR-B38M 有别于其他 BCMA CAR 构建物。 欧洲和美国正在进行的试验都使用了 LCAR-B38M；美国临床肿瘤学会 2020 年年会上报告的 1b/2 期 CARTITUDE1 试验就是一例。总反应率为 100%，包括 86% 的严格完全反应，9 个月无进展生存率为 86%。29例患者中有27例（93%）出现细胞因子释放综合征（7%≥3级），29例患者中有1例（4%）出现3级或4级神经毒性。尽管这些结果很有希望，但还需要更多患者的证实，而且LCAR-B38M/JNJ-4528尚未获得监管机构的批准。许多其他靶向 BCMA 或其他分子（如 SLAMF7、CD38、NKG2D (KLRK1) 配体或 CD138 (SYND1)）的 CAR T 细胞疗法正在接受评估。CAR T 细胞的使用引发了几个问题，尤其是在晚期患者中：产品生产过程中的疾病进展、与抗原逸出或 CAR T 细胞缺乏长期持久性有关的耐药机制（无进展生存曲线无高原）以及这种疗法的安全性（如细胞因子释放综合征和神经毒性风险）。

 Treatment recommendations for patients with relapsed and refractory disease who have received two or more previous lines of therapy are shown in figure 2.

图 2 列出了针对既往接受过两种或两种以上疗法的复发和难治性疾病患者的治疗建议。 

图 1：来那度胺难治性骨髓瘤患者首次复发的建议

DKd=达拉单抗加卡非佐米加地塞米松。

DPd=达拉单抗加泊马度胺加地塞米松。

DRd=达拉单抗加来那度胺加地塞米松。

DVd=达拉单抗加硼替佐米加地塞米松。

Elo-Rd=elotuzumab 加来那度胺加地塞米松。

IPd=伊沙佐米+泊马度胺+地塞米松。

IRd=ixazomib 加来那度胺加地塞米松。

Isa-Kd=isatuximab 加卡非佐米加地塞米松。

Kd=carfilzomib 加地塞米松。

KPd=卡非佐米+泊马度胺+地塞米松。

KRd=卡非佐米加来那度胺加地塞米松。

PVd=泊马度胺+硼替佐米+地塞米松。

Rd=来那度胺加地塞米松。

SVd=selinexor 加硼替佐米加地塞米松。

VCd=硼替佐米加环磷酰胺加地塞米松。

Vd=硼替佐米加地塞米松。

VMP=硼替佐米+美法仑+泼尼松。

VTd=硼替佐米+沙利度胺+地塞米松。

*考虑对不符合自体移植条件的患者进行抢救。 

†推荐等级：1A.

‡推荐等级：1B.

§推荐等级：1C.

图 2：针对第二次或第二次以上复发的建议

BCMA=B细胞成熟抗原。

CAR=嵌合抗原受体。

DKd=达拉单抗加卡非佐米加地塞米松。

DPd=达拉单抗加泊马度胺加地塞米松。

Elo-Pd=elotuzumab plus 泊马度胺 plus地塞米松。

Isa-Kd=isatuximab 加卡非佐米加地塞米松。

Isa-Pd=伊沙妥昔单抗加泊马度胺加地塞米松。

KPd=卡非佐米+泊马度胺+地塞米松。

PCd=泊马度胺加环磷酰胺加地塞米松。

Pd=泊马度胺加地塞米松。

VdT-PACE=硼替佐米+地塞米松+沙利度胺+顺铂+多柔比星+环磷酰胺+依托泊苷。 

**推荐等级：1A. 

†推荐等级：1B.

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A PubMed search was done using the terms “myeloma”, “relapsed”, and “trial” to identify clinical trials on relapsed myeloma published in English (exclusively) between Jan 1, 2013,and Sept 30, 2020. Published data were analysed by an interdisciplinary panel of experts representing all cooperative groups worldwide on behalf of the International Myeloma Working Group. Levels of evidence and grades of    recommendations were assigned using established criteria in line with the Grading of Recommendations, Assessment, Development and Evaluation (GRADE) system. The initial draft was circulated to each panel member for critical evaluation and to provide feedback on the levels of evidence and grading of recommendations. The manuscript  subsequently underwent two rounds of revision between the panel members and final consensus between all authors was  reached. The guidelines were developed for worldwide applicability, and therefore needed to accommodate the substantial disparity in drug availability in different parts of the world.

我们使用“myeloma”, “relapsed”, 和“trial”等词在PubMed上进行了搜索，以确定2013年1月1日至2020年9月30日期间发表的关于复发骨髓瘤的英文临床试验（仅限英文）。代表全球所有合作团体的跨学科专家小组代表国际骨髓瘤工作组对发表的数据进行了分析。根据 "建议、评估、发展和评价分级"（GRADE）系统，采用既定标准划分证据等级和建议等级。初稿分发给每位专家组成员进行严格评估，并就证据等级和建议分级提供反馈意见。随后，专家组成员对初稿进行了两轮修改，最后所有作者达成共识。该指南是为全球适用性而制定的，因此需要考虑到世界不同地区在药物供应方面的巨大差异。