We estimate that in 2024, there were 66,434 diagnosed incident cases of multiple myeloma (MM) in the US, Japan, and five major European markets (France, Germany, Italy, Spain, and the UK). By 2043, we forecast that the number of diagnosed incident cases will increase to 84,214 cases. 
我们预估 2024 年，美国、日本及欧洲五大主要市场（法国、德国、意大利、西班牙和英国）的多发性骨髓瘤(MM)确诊新发病例数为 66,434 例。到 2043 年，我们预测确诊新发病例数将增至 84,214 例。

Revlimid (lenalidomide), an immunomodulatory drug (IMiD), and Velcade (bortezomib), a proteasome inhibitor (PI), play key roles as the backbone for combination regimens across various lines of therapy. These drugs have broad approvals in all markets, and the launches of lenalidomide and bortezomib generics in 2022 have exerted downward pressure on the MM market.  
⁠⁠瑞复美（来那度胺）作为一种免疫调节药物（IMiD），与万珂（硼替佐米）这款蛋白酶体抑制剂（PI），构成了多线联合治疗方案的核心支柱。⁠⁠这两款药物在所有市场均获得广泛批准，而 2022 年来那度胺和硼替佐米仿制药的上市对多发性骨髓瘤市场形成了降价压力。

Darzalex (daratumumab), the first monoclonal antibody (mAb) approved for MM, replaced Revlimid as the top-selling drug in MM during 2023. Darzalex has become a standard of care based on impressive trial results in both the newly diagnosed and relapsed/refractory MM (RRMM) settings. Key regimens in the newly diagnosed setting include the quadruplet regimen of Darzalex combined with Velcade, lenalidomide, and dexamethasone (VRd) for both transplant-ineligible (CEPHEUS trial) and transplant-eligible (PERSEUS trial) patients. While submissions based on PERSEUS were approved in 2024, submissions based on CEPHEUS were approved in the EU in 2025 with FDA approval expected in mid-2025. The MAIA regimen (Darzalex combined with Rd) is used for the majority of transplant-ineligible patients who are too frail for a quadruplet. In the RRMM setting, key regimens include triplets of Darzalex combined with dex and either a PI (bortezomib or Kyprolis/carfilzomib) or an IMiD (lenalidomide or Pomalyst/pomalidomide). The CD38-targeted Darzalex will experience continual commercial success due to additional label expansions as well as the approval of a more convenient subcutaneous (SC) formulation. Phase III trials are also evaluating Darzalex combined with bispecific antibodies in the newly diagnosed and RRMM settings (see below). 
⁠⁠达雷妥尤单抗（Darzalex）作为首个获批用于多发性骨髓瘤（MM）的单克隆抗体（mAb），在 2023 年取代来那度胺（Revlimid）成为 MM 领域最畅销药物。基于在新诊断和复发/难治性 MM（RRMM）患者中令人瞩目的临床试验结果，该药物已成为标准治疗方案。针对新诊断患者的关键方案包括：适用于不适合移植患者的 Darzalex 联合硼替佐米、来那度胺和地塞米松四联方案（CEPHEUS 试验），以及适合移植患者的相同四联方案（PERSEUS 试验）⁠⁠。基于 PERSEUS 试验的申请于 2024 年获批，而 CEPHEUS 试验的申请于 2025 年在欧盟获批，预计食品药品监督管理局将于 2025 年年中批准。MAIA 方案（Darzalex 联合 Rd）适用于大多数身体虚弱无法承受四联治疗的不适合移植患者。在 RRMM 治疗领域，关键方案包括 Darzalex 联合地塞米松与蛋白酶体抑制剂（硼替佐米或卡非佐米）或免疫调节剂（来那度胺或泊马度胺）组成的三联方案。由于适应症范围的持续扩大以及更便捷的皮下注射剂型的获批，靶向 CD38 的达雷妥尤单抗将持续获得商业成功。 三期临床试验也正在评估 Darzalex 联合双特异性抗体在新诊断和复发/难治性多发性骨髓瘤（RRMM）患者中的应用（详见下文）。

Sarclisa (isatuximab), another CD38-directed mAb, faces intense in-class competition from Darzalex, which has the advantage of physician familiarity and approval of a SC formulation. A Sarclisa quadruplet (Sarclisa-VRd) is approved for transplant-ineligible patients (IMROZ trial) and a regulatory submission for transplant-eligible patients based on positive data from the GMMG HD7 trial was recently submitted to EU authorities with a submission to US authorities expected in H1 2025. The GMMG HD7 trial is also evaluating Sarclisa + lenalidomide as post-transplant maintenance therapy, however the maintenance results have not yet been released but are expected in 2025. Sarclisa + Kyprolis + dex is approved as a treatment for second-line or later patients, while the combination of Sarclisa + Pomalyst + dex is approved for third-line or later patients. Sanofi is developing a hands-free SC formulation of Sarclisa based on the enFUSE on-body delivery device. The IRAKLIA trial demonstrated non-inferiority of the drug device combination to IV Sarclisa and regulatory submissions are expected in H1 2025. 
⁠⁠Sarclisa（isatuximab）作为另一款靶向 CD38 的单抗药物，正面临来自 Darzalex 的激烈同类竞争——后者凭借内科医生对其皮下注射剂型的熟悉度和认可度占据优势⁠⁠。目前 Sarclisa 四联疗法（Sarclisa-VRd）已获批用于不适合移植的患者（基于 IMROZ 试验数据），而针对适合移植患者的上市申请也于近期提交至欧盟监管机构（基于 GMMG HD7 试验的积极数据），预计 2025 年上半年将向美国提交申请。GMMG HD7 试验同时评估了 Sarclisa 联合来那度胺作为移植后维持治疗的方案，但维持治疗结果尚未公布，预计 2025 年揭晓。Sarclisa 联合卡非佐米与地塞米松获批用于二线及以上患者的治疗，而 Sarclisa 联合泊马度胺与地塞米松则获批用于三线及以上患者。⁠⁠赛诺菲正在基于 enFUSE 体上给药装置开发 Sarclisa 的无针皮下制剂。IRAKLIA 试验证实该药物器械组合不劣于静脉注射 Sarclisa，相关监管申请预计于 2025 年上半年提交⁠⁠。

The launches of BCMA-targeted therapies will play a pivotal part in future market dynamics over the next decade. Key anti-BCMA agents include the CAR-T therapies Abecma (ide-cel) and Carvykti (cilta-cel). Abecma is approved for third-line or later patients in the US, EU, and Japan, while Carvykti is approved in the US and EU for a larger population of second-line or later patients. In Japan, Carvykti is approved for fourth-line or later patients. All approvals were for triple-class exposed patients (previously treated with an IMiD, a PI, and an anti-CD38 antibody). While the drugs are highly efficacious, the complicated logistics of administering CAR-T have slowed uptake of both Abecma and Carvykti. 
⁠⁠靶向 BCMA 疗法的推出将在未来十年对市场动态产生关键影响。主要抗 BCMA 药物包括 CAR-T 疗法 Abecma（ide-cel）和 Carvykti（cilta-cel）⁠⁠。Abecma 已在美国、欧盟和日本获批用于三线或后线治疗患者，而 Carvykti 则在美国和欧盟获批用于更广泛的二线或后线治疗人群。在日本，Carvykti 获批用于四线或后线患者。所有获批适应症均针对三重暴露患者（既往接受过免疫调节剂、蛋白酶体抑制剂和抗 CD38 抗体治疗）。尽管这些药物疗效显著，但 CAR-T 疗法的复杂给药流程延缓了 Abecma 和 Carvykti 的市场渗透速度。

Carvykti has been gaining market share at the expense of Abecma due to physicians regarding it as more efficacious. Long-term follow-up results for Carvykti in the fourth-line or later setting report a median OS of 61 months with 33% of patients remaining alive and progression-free for ≥5 years suggesting that Carvykti could be curative in the relapsed/refractory setting. Carvykti has two ongoing Phase III trials in the first-line setting, with CARTITUDE-5 evaluating Carvykti as a replacement for lenalidomide maintenance following induction therapy in patients not suited for transplant, and CARTITUDE-6 evaluating Carvykti as a replacement for transplant in transplant-eligible patients. 
⁠⁠由于医生普遍认为 Carvykti 疗效更佳，该药物正以牺牲 Abecma 市场份额为代价持续扩张。Carvykti 在四线及以上治疗中的长期随访数据显示，患者中位总生存期达 61 个月，33%的患者存活且 5 年内无进展，这表明 Carvykti 在复发/难治性治疗中可能具有治愈潜力。目前 Carvykti 有两项针对一线治疗的三期临床试验正在进行：CARTITUDE-5 研究评估其作为不适合移植患者诱导治疗后替代来那度胺维持治疗的方案，CARTITUDE-6 研究则评估其在适合移植患者中替代移植治疗的潜力。⁠⁠

Arcellx’s anito-cel is positioned to be the third BCMA CAR-T to enter the market, but it significantly lags behind in development. While Abecma and Carvykti were first approved in 2021 and 2022, respectively, anito-cel only began its pivotal trial, iMMagine-1, in December 2022, and a commercial launch in the fourth-line or later setting is not expected until 2026. Early results suggest that anito-cel may have efficacy comparable to Carvykti, but with a better safety profile with no delayed neurotoxicity events seen to date. A confirmatory Phase III trial is enrolling second-line or later patients but, unlike CARTITUDE-4, will not require that patients have prior exposure to a PI and be refractory to lenalidomide, which may allow anito-cel to be used in more relapsed/refractory patients than Carvykti. 
⁠⁠Arcellx 公司的 anito-cel 有望成为第三个进入市场的 BCMA CAR-T 疗法⁠⁠，但其研发进度明显滞后。虽然 Abecma 和 Carvykti 分别于 2021 年和 2022 年首次获批，但 anito-cel 直到 2022 年 12 月才启动关键性试验 iMMagine-1，预计最早要到 2026 年才能在四线或后线治疗中实现商业化上市。⁠⁠早期数据显示 anito-cel 疗效可能与 Carvykti 相当，但安全性更优，迄今未观察到迟发性神经毒性事件。⁠⁠目前正在开展的验证性 III 期试验针对二线或后线患者，与 CARTITUDE-4 试验不同，该试验不要求患者既往接受过蛋白酶体抑制剂治疗且对来那度胺耐药，这意味着 anito-cel 可能比 Carvykti 适用于更多复发/难治性患者群体。

There are currently four BCMA x CD3 bispecific antibodies that are either approved or are in late-phase development. Tecvayli (teclistamab) and Elrexfio (elranatamab) are approved in the US (for fifth-line or later patients), EU (for fourth-line or later patients) and Japan (for second-line or later patients). Lynozyfic is currently approved in the EU for fourth-line or later MM with an FDA decision expected by July 2025. Tecvayli has the advantage of being first-to-market and currently leads in market share. Elrexfio is differentiated by its subcutaneous administration while Lynozyfic has reported the highest response rate (71% ORR vs 62% for Tecvayli and 58% for Elrexfio) and offers every-four-week dosing after 24 weeks. The bispecifics can also be differentiated by their hospitalization requirements after initial step-up dosing.  Tecvayli requires 48-hour hospitalizations after each of three step-up doses, while Elrexfio requires one 48-hour hospitalization after the first step-up dose and one 24-hour hospitalization after the second step-up dose. Lynozyfic requires two separate 24-hour hospitalizations.  Overall, the BCMA x CD3 bispecifics have efficacy comparable to Abecma but are not as efficacious as Carvykti. The final bispecific antibody, etentamig, initiated a Phase III trial in 2024 that is enrolling third-line or later patients. Entatamig is differentiated by its every four-week dosing regimen after the first month and low rate of grade 3/4 infections. Regulatory submissions are expected in 2028. 
⁠⁠目前有四款 BCMA x CD3 双特异性抗体已获批或处于研发后期阶段。Tecvayli（teclistamab）和 Elrexfio（elranatamab）已在美国（用于五线及以上患者）、欧盟（用于四线及以上患者）和日本（用于二线及以上患者）获批。Lynozyfic 目前获欧盟批准用于四线及以上多发性骨髓瘤治疗，美国食品药品监督管理局预计将于 2025 年 7 月前作出审批决定。Tecvayli 凭借先发优势目前市场份额领先。Elrexfio 的差异化优势在于皮下给药方式，而 Lynozyfic 则报告了最高应答率（71%客观缓解率，Tecvayli 为 62%，Elrexfio 为 58%），并在 24 周后采用四周一次给药方案。⁠⁠这三款双抗在初始阶梯给药后的住院要求也有所不同：Tecvayli 需在三次阶梯给药后各住院 48 小时，Elrexfio 在首次阶梯给药后住院 48 小时、第二次给药后住院 24 小时，Lynozyfic 则需进行两次 24 小时住院观察。  ⁠⁠总体而言，BCMA x CD3 双特异性抗体的疗效与 Abecma 相当，但不及 Carvykti。最后一种双抗药物 etentamig 于 2024 年启动 III 期临床试验，入组对象为三线及以上治疗患者。该药物的差异化优势在于首月治疗后采用四周一次的给药方案，且 3/4 级感染发生率较低。预计将于 2028 年提交上市申请。⁠⁠

⁠⁠Bispecific antibodies have the advantage of off-the-shelf availability, which is an important consideration given the complicated logistics of administering CAR-T.⁠⁠ However, there has been some concern over high levels of infections with prolonged treatment with BCMA-directed bispecifics. To address this, the Tecvayli and Elrexfio approvals allow switching from weekly to every-other-week dosing after six months. 
⁠⁠双特异性抗体具有即用型优势，考虑到 CAR-T 疗法复杂的给药流程，这一点尤为重要。但针对 BCMA 靶点的双抗长期治疗引发的高感染率问题也受到关注。⁠⁠为此，Tecvayli 和 Elrexfio 的获批方案允许在治疗六个月后，将给药频率从每周一次调整为隔周一次。

The Tecvayli and Elrexfio confirmatory Phase III trials (MajesTEC-3 and MagnetisMM-5, respectively) are evaluating the bispecifics in combination with Darzalex, with the comparator being a Darzalex + PI + dex triplet. Lynozyfic’s confirmatory trial, LINKER-MM3, is comparing Lynozyfic monotherapy to Empliciti + Pomalyst + dex. All three trials are enrolling second-line or later patients. 
Tecvayli 和 Elrexfio 的确证性 III 期试验（分别为 MajesTEC-3 和 MagnetisMM-5）正在评估这两种双抗药物与 Darzalex 的联合疗法，对照组采用 Darzalex+蛋白酶体抑制剂+地塞米松三联方案。Lynozyfic 的确证性试验 LINKER-MM3 则将 Lynozyfic 单药与 Empliciti+泊马度胺+地塞米松方案进行对比。这三项试验均招募二线及以上治疗患者。

In the newly diagnosed setting, MajesTEC-7 and MagnetisMM-6 are evaluating Tecvayli and Elrexfio, respectively, both in combination with Darzalex and lenalidomide. The trials are enrolling transplant-ineligible patients, and the comparator is Darzalex + lenalidomide + dex. MagnetisMM-7 is evaluating Elrexfio as maintenance therapy in newly diagnosed patients after transplant, and the comparator is lenalidomide. 
在新诊断患者群体中，MajesTEC-7 和 MagnetisMM-6 试验分别评估 Tecvayli 和 Elrexfio 与 Darzalex 及来那度胺的联合用药方案。试验对象为不适合移植的患者，对照组采用 Darzalex+来那度胺+地塞米松方案。MagnetisMM-7 则评估 Elrexfio 作为新诊断患者移植后的维持治疗，对照组采用来那度胺单药。

Talvey (talquetamab), a bispecific antibody targeting CD3 and the novel target GPRC5D has been granted accelerated approval in the US and EU and is under regulatory review in Japan. Talvey will likely be a preferred option for patients who progress on an anti-BCMA agent. Talvey is associated with GPRC5D-related oral toxicity including dysgeusia (altered sense of taste). The oral toxicity can be difficult to manage and did not resolve in 65% of patients. A confirmatory Phase III trial, MonumenTAL-3, is evaluating Talvey + Darzalex +/- Pomalyst and is enrolling second-line or later patients. Another Phase III trial, MonumentTAL-6, is enrolling relapsed/refractory patients who were treated with an anti-CD38 antibody in the first line and is evaluating Talvey + Tecvayli. The Tecvayli MajesTEC-7 trial, enrolling newly diagnosed transplant-ineligible patients, will also have a cohort evaluating Talvey + Darzalex + lenalidomide. 
⁠⁠靶向 CD3 和新型靶点 GPRC5D 的双特异性抗体 Talvey（talquetamab）已在美国和欧盟获得加速批准，目前正在日本接受监管审查。对于抗 BCMA 药物治疗后病情进展的患者，Talvey 很可能成为优选方案。该药物存在与 GPRC5D 相关的口腔毒性，包括味觉障碍（味觉改变）。这种口腔毒性较难控制，且 65%的患者症状未缓解⁠⁠。确证性 III 期试验 MonumenTAL-3 正在评估 Talvey 联合 Darzalex（达雷妥尤单抗）±Pomalyst（泊马度胺）的疗效，入组对象为二线及以上治疗患者。另一项 III 期试验 MonumentTAL-6 则针对一线接受过抗 CD38 抗体治疗的复发/难治性患者，评估 Talvey 联合 Tecvayli（teclistamab）的疗效。针对新诊断不适合移植患者的 Tecvayli MajesTEC-7 试验也将设立一个队列评估 Talvey 联合 Darzalex 和来那度胺的联合方案。

BMS-986393 is a potentially first-in-class GPRC5D CAR-T product. QUINTESSENTIAL, a pivotal Phase II trial, is enrolling fourth-line or later patients previously exposed to at least four classes of MM treatments, namely an IMiD, a PI, an anti-CD38 antibody, and an anti-BCMA therapy. A confirmatory Phase III trial, QUINTESSENTIAL-2, is comparing BMS-986393 to standard regimens (Dara-Pd or Kd) in lenalidomide refractory, second-line or later patients. On-target/off-tumor toxicity such as skin, nail and/or oral events appear more benign with BMS-986393 than with Talvey likely due to the one dose nature of BMS-986393. 
⁠⁠BMS-986393 是一款潜在同类首创的 GPRC5D 靶向 CAR-T 疗法⁠⁠。关键性 II 期试验 QUINTESSENTIAL 正在招募既往接受过至少四类多发性骨髓瘤治疗（包括免疫调节剂、蛋白酶体抑制剂、抗 CD38 抗体和抗 BCMA 疗法）的四线或后线患者。验证性 III 期试验 QUINTESSENTIAL-2 正在来那度胺难治性二线或后线患者中比较 BMS-986393 与标准方案（Dara-Pd 或 Kd）的疗效。与 Talvey 相比，BMS-986393 的靶向/脱靶毒性（如皮肤、指甲和/或口腔不良事件）表现更为温和，这很可能得益于 BMS-986393 的单次给药特性。

The anti-BCMA antibody-drug conjugate (ADC) Blenrep (belantamab mafodotin) had received accelerated approval that was then revoked following the failure of a confirmatory Phase III trial. However, Blenrep’s outlook has improved after reporting positive results in two additional Phase III trials, DREAMM-7 and DREAMM-8, both of which were in the second-line or later setting. Blenrep is currently approved in the UK and Japan and is under regulatory review in the US and EU. Due to concerns over ocular toxicity, Blenrep will likely be sequenced after other anti-BCMA therapies such as CAR-Ts and bispecific antibodies. Development of a safer, optimized dosing protocol that allows the corneal epithelium to recover between doses could help increase uptake. A Phase III trial in the newly diagnosed, transplant-ineligible setting (DREAMM-10) is comparing Blenrep combined with Rd to Darzalex combined with Rd. 
⁠⁠抗 BCMA 抗体药物偶联物（ADC）Blenrep（贝兰他单抗莫福汀）曾获得加速批准，后因确证性 III 期试验失败而被撤销许可。然而，该药物在 DREAMM-7 和 DREAMM-8 两项针对二线及以上治疗场景的 III 期试验中取得积极结果后，市场前景有所改善。目前 Blenrep 已在英国和日本获批上市，并正在美国和欧盟接受监管审查。由于存在眼部毒性风险，该药物可能会被安排在其他抗 BCMA 疗法（如 CAR-T 细胞疗法和双特异性抗体）之后使用。通过开发更安全的优化给药方案——使角膜上皮在给药间隔期得以修复——有望提升该药物的临床应用。针对新诊断且不适合移植患者的 III 期试验 DREAMM-10 正在比较 Blenrep 联合 Rd 方案与达雷妥尤单抗联合 Rd 方案的疗效。⁠⁠

Bristol Myers Squibb, which also markets Revlimid, has positioned Pomalyst (pomalidomide) as a subsequent therapy option. Pomalyst, another IMiD, was originally approved for the third-line or later setting, but in 2019 it received a label expansion in the EU and Japan to the second-line setting. In the US, approval for the second-line or later setting in combination with SC Darzalex and dex is noted in the FDA label for SC Darzalex. The first pomalidomide generics were launched in the EU in August 2024 and following a settlement with Dr. Reddy’s, are expected to launch in the US Q1 2026. Pomalyst has regulatory exclusivity until June 2026 in Japan. 
⁠⁠同样销售瑞复美的百时美施贵宝公司已将泊马度胺（Pomalyst）定位为后续治疗选择。作为另一款免疫调节药物，泊马度胺最初获批用于三线或更后线治疗，但 2019 年在欧盟和日本获准扩展至二线治疗适应症。在美国，其与达雷妥尤单抗皮下注射剂（SC Darzalex）及地塞米松联用的二线或更后线治疗方案已获食品药品监督管理局批准，相关说明标注于达雷妥尤单抗皮下制剂的药品标签中。⁠⁠首批泊马度胺仿制药于 2024 年 8 月在欧盟上市，根据与瑞迪博士实验室达成的协议，预计将于 2026 年第一季度在美国上市。该药在日本的市场独占权将持续至 2026 年 6 月。

Second-generation PI Kyprolis (carfilzomib) is approved for the treatment of RRMM as a monotherapy and in combination with either dex, Darzalex and dex, or Revlimid and dex. Kyprolis remains the favored PI in the RRMM setting as it demonstrated improved safety and efficacy over Velcade, another PI, in the Phase III ENDEAVOR trial. However, unlike Velcade, Kyprolis does not offer an SC formulation. In the front-line setting, a Kyprolis regimen (Kyprolis + Revlimid + dex; KRd) failed to show superiority to a Velcade regimen (VRd). Nevertheless, the KRd regimen will likely continue to see some off-label use in the front-line setting due to KRd and VRd having different toxicity profiles. Generic versions of carfilzomib are expected to enter the EU and Japan markets in Q4 2025 and Q3 2026, respectively. In June 2020, after a challenge from Cipla, a US court upheld several Kyprolis patents, with the latest expiring in December 2027. In June 2021, Breckenridge and its Indian partner Natco Pharma disclosed a settlement allowing launch of a generic carfilzomib on a date “in 2027 or sooner depending on certain occurrences.” 
⁠⁠第二代蛋白酶体抑制剂 Kyprolis（卡非佐米）获批作为单药或与地塞米松、Darzalex 联合地塞米松、或 Revlimid 联合地塞米松的方案用于复发难治性多发性骨髓瘤的治疗。⁠⁠在 III 期 ENDEAVOR 试验中，Kyprolis 相较于另一款蛋白酶体抑制剂 Velcade 展现出更优的安全性和疗效，因此仍是该疾病领域的首选 PI 类药物。但与 Velcade 不同，Kyprolis 未提供皮下注射剂型。在一线治疗中，Kyprolis 方案（KRd：卡非佐米+来那度胺+地塞米松）未能显示出对 Velcade 方案（VRd）的优越性。不过由于 KRd 与 VRd 具有不同的毒性特征，KRd 方案预计仍会在超适应症范围内继续用于一线治疗。卡非佐米的仿制药预计将分别于 2025 年第四季度和 2026 年第三季度进入欧盟和日本市场。2020 年 6 月，经过 Cipla 公司的专利挑战后，美国法院维持了 Kyprolis 多项专利的有效性，其中最晚到期日为 2027 年 12 月。2021 年 6 月，Breckenridge 及其印度合作伙伴 Natco Pharma 披露的和解协议允许其"在 2027 年或更早时间（取决于特定条件）"推出仿制版卡非佐米。

In combination with Revlimid + dex, Ninlaro (ixazomib), the first oral PI approved by the FDA, is part of an all-oral regimen for the treatment of second-line or later patients. However, Ninlaro has not been able to break through to front-line therapy after the Phase III TOURMALINE-MM2 trial investigating it as an induction therapy failed to meet the PFS primary endpoint. 
⁠⁠与来那度胺+地塞米松联用的 Ninlaro（伊沙佐米）是首个获得食品药品监督管理局批准的口服蛋白酶体抑制剂，构成全口服方案用于二线及以上患者的治疗。然而在 TOURMALINE-MM2 三期试验中，Ninlaro 作为诱导疗法的研究未能达到无进展生存期主要终点，因此始终未能突破进入一线治疗领域。⁠⁠

Empliciti (elotuzumab), the only SLAMF7-targeted mAb approved for MM, has seen moderate uptake since the combination of Empliciti + Revlimid + dex (ERd) was approved for the treatment of MM patients who have received one to three prior lines of therapy. A label expansion in combination with Pomalyst + dex for the treatment of third-line or later patients expanded options for the use of Empliciti in the treatment of RRMM, but did not significantly improve the drug’s commercial potential in this crowded treatment space.  
⁠⁠作为目前唯一获批用于多发性骨髓瘤的 SLAMF7 靶向单抗，Empliciti（埃罗妥珠单抗）自获批联合来那度胺+地塞米松（ERd 方案）用于接受过 1-3 线治疗的患者以来，市场接受度较为温和。⁠⁠虽然该药与泊马度胺+地塞米松联用治疗三线及以上患者的适应症扩展为复发难治性多发性骨髓瘤提供了更多治疗选择，但在这个竞争激烈的治疗领域并未显著提升该药物的商业潜力。

Xpovio (selinexor) received supplementary approvals in the US (December 2020) and EU (July 2022) as part of a triple combination with bortezomib and dex for second- to fourth-line MM. While Xpovio cannot compete with bispecifics on efficacy, its novel mechanism of action means it is used in patients who have exhausted other options or who are not suited for bispecifics or CAR-T therapy. EMN29 is a Phase III trial evaluating the all-oral triplet of Xpovio + Pomalyst + dex for second-line or later MM; the comparator is Empliciti + Pomalyst + dex, and topline data are expected in H1 2025.  
⁠⁠Xpovio（塞利尼索）在美国（2020 年 12 月）和欧盟（2022 年 7 月）获得补充批准，作为与硼替佐米和地塞米松三联方案用于二至四线多发性骨髓瘤治疗。虽然 Xpovio 在疗效上无法与双特异性抗体竞争，但其新颖的作用机制使其适用于已耗尽其他治疗选择或不适合双抗及 CAR-T 疗法的患者。⁠⁠EMN29 是一项评估 Xpovio+泊马度胺+地塞米松全口服三联方案用于二线及以上骨髓瘤治疗的 III 期试验，对照组采用埃罗妥珠单抗+泊马度胺+地塞米松方案，顶线数据预计于 2025 年上半年公布。

Iberdomide is a next-generation IMiD being developed by Bristol Myers Squibb, and binds the E3 ligase cereblon with higher affinity than Revlimid and Pomalyst. A Phase III trial (EXCALIBER-RRMM) is comparing iberdomide + Darzalex + dex versus Darzalex + bortezomib + dex in second-line and third-line MM patients. A second Phase III trial, EXCALIBER-Maintenance, will compare iberdomide to lenalidomide in the post-transplant maintenance setting. 
⁠⁠伊伯度胺是百时美施贵宝研发的新一代免疫调节剂，其与 E3 泛素连接酶 cereblon 的结合亲和力高于来那度胺和泊马度胺。⁠⁠III 期试验 EXCALIBER-RRMM 正在比较伊伯度胺+达雷妥尤单抗+地塞米松与达雷妥尤单抗+硼替佐米+地塞米松在二线及三线骨髓瘤患者中的疗效。另一项 III 期试验 EXCALIBER-Maintenance 将在移植后维持治疗中对比伊伯度胺与来那度胺的疗效。

Just as Pomalyst was developed for patients who progress on Revlimid, Bristol Myers Squibb is developing mezigdomide, an IMiD even more potent than iberdomide, for second-line or later patients who progress on iberdomide. SUCCESSOR-1 is a head-to-head Phase III trial comparing mezigdomide + bortezomib + dex to Pomalyst + bortezomib + dex. A second Phase III trial, SUCCESSOR-2, is an add-on trial comparing mezigdomide + Kyprolis + dex to Kyprolis + dex. 
⁠⁠正如泊马度胺是为对来那度胺进展的患者所研发，百时美施贵宝正在开发比伊伯度胺更有效的免疫调节药物 mezigdomide，用于对伊伯度胺进展的二线或后线患者。⁠⁠SUCCESSOR-1 是一项头对头的 III 期临床试验，比较 mezigdomide+硼替佐米+地塞米松与泊马度胺+硼替佐米+地塞米松的疗效。另一项 III 期试验 SUCCESSOR-2 则是附加试验，比较 mezigdomide+卡非佐米+地塞米松与卡非佐米+地塞米松的疗效。

Key recent events include approval of Lynozofic in the EU, Blenrep in the UK and Japan, and supplementary approvals for SC Darzalex (approval in the US and EU supported by PERSEUS, approval in the EU supported by CEPHEUS), and Sarclisa (supported by IMROZ), as well as positive Phase III data for Blenrep (DREAMM-7 and DREAMM-8), SC Darzalex (PERSEUS, CEPHEUS and AQUILA), and Sarclisa (IMROZ, GMMG HD7 and IRAKLIA). 
⁠⁠近期重要事件包括：Lynozofic 在欧盟获批，Blenrep 在英国和日本获批，SC Darzalex 获得补充批准（美国及欧盟批准基于 PERSEUS 研究，欧盟批准基于 CEPHEUS 研究），Sarclisa 获得批准（基于 IMROZ 研究），以及 Blenrep（DREAMM-7 和 DREAMM-8 研究）、SC Darzalex（PERSEUS、CEPHEUS 和 AQUILA 研究）和 Sarclisa（IMROZ、GMMG HD7 和 IRAKLIA 研究）取得积极的 III 期临床数据⁠⁠。

Key pivotal trial readouts expected during 2025 include Xpovio’s EMN29, Sarclisa’s IMROZ (PFS following a second randomization after transplant to determine the effect of adding Sarclisa to maintenance therapy), anito-cel's iMMagine-1, Elrexfio’s MagnetisMM-5, and Tecvayli’s MajesTEC-3. 
⁠⁠2025 年预计将公布的关键性临床试验结果包括：Xpovio 的 EMN29 研究、Sarclisa 的 IMROZ 研究（移植后二次随机分组的无进展生存期分析，旨在评估维持治疗中加入 Sarclisa 的效果）、anito-cel 的 iMMagine-1 研究、Elrexfio 的 MagnetisMM-5 研究以及 Tecvayli 的 MajesTEC-3 研究。⁠⁠

Key FDA approvals expected during 2025 include Blenrep for second-line or later MM, Lynozyfic for fourth-line or later MM, and a Darzalex quadruplet for transplant-ineligible MM (CEPHEUS). 
⁠⁠2025 年预计将获得美国食品药品监督管理局批准的关键药物包括：用于二线及以上多发性骨髓瘤治疗的 Blenrep、用于四线及以上治疗的 Lynozyfic，以及针对不适合移植患者的 Darzalex 四联疗法（CEPHEUS 研究方案）。⁠⁠

Three drugs with accelerated approval have been removed from the US market: Blenrep, which failed its confirmatory Phase III trial but is expected to return to the market in 2025 after positive results in two other Phase III trials; Pepaxto (melphalan-flufenamide), which reported a negative OS signal in its Phase III trial; and Farydak (panobinostat), which did not complete a required post-approval clinical study. Pepaxto and Farydak continue to be marketed in the EU. 
⁠⁠三款获得加速审批的药物已从美国市场撤市：Blenrep 虽在三期验证性试验中失败，但基于另外两项三期试验的积极结果，预计将于 2025 年重返市场；Pepaxto（美法仑-氟芬那胺）在其三期试验中报告了总生存期负面信号；Farydak（帕比司他）则未完成批准后要求的临床研究。Pepaxto 和 Farydak 目前仍在欧盟市场销售。⁠⁠

Like other CAR-T therapies, Abecma and Carvykti must be administered at a Risk Evaluation and Mitigation Strategy (REMS)-certified facility because of the risks of cytokine release syndrome (CRS) and neurological toxicities. 
与其他 CAR-T 疗法类似，由于存在细胞因子释放综合征（CRS）和神经毒性的风险，Abecma 和 Carvykti 必须在获得风险评估与缓解策略（REMS）认证的机构中实施。

Both Abecma and Carvykti have black box warnings for CRS, neurological toxicities, hemophagocytic lymphohistiocytosis/macrophage activation syndrome (HLH/MAS) related to excessive immune activation associated with CAR-T therapy, T-cell malignancies, and prolonged cytopenia following the lymphodepleting conditioning regimen and CAR-T infusion. In addition, Carvykti has black box warnings for parkinsonism (a form of delayed neurotoxicity), Guillain-Barré syndrome, and for secondary hematologic malignancies, including myelodysplastic syndrome and acute myeloid leukemia. With regard to the heightened risk for delayed neurotoxicity with Carvykti, a physician noted that their Carvykti patients stay on monitoring for 100 days post-infusion compared to 30 days for Abecma. This translates to Carvykti patients having to stay close to the hospital for longer than Abecma patients. 
Abecma 和 Carvykti 均针对以下情况设有黑框警告：与 CAR-T 疗法相关的过度免疫激活引发的细胞因子释放综合征（CRS）、神经毒性、噬血细胞性淋巴组织细胞增多症/巨噬细胞活化综合征（HLH/MAS）；T 细胞恶性肿瘤；以及淋巴细胞清除预处理方案和 CAR-T 输注后的长期血细胞减少。此外，Carvykti 还针对帕金森综合征（迟发性神经毒性的一种表现）、吉兰-巴雷综合征以及继发性血液系统恶性肿瘤（包括骨髓增生异常综合征和急性髓系白血病）设有黑框警告。关于 Carvykti 迟发性神经毒性风险升高的问题，有内科医生指出，其 Carvykti 患者需在输注后接受 100 天监测，而 Abecma 患者仅需监测 30 天。这意味着 Carvykti 患者必须比 Abecma 患者更长时间留在医院附近。

KarMMa-3 compared Abecma to standard triplet regimens in patients who had received two to four prior MM regimens. At ASH 2023 and with a median follow-up of 31 months, the trial reported significant improvements in PFS (13.8 months vs. 4.4 months; HR 0.49), overall response rate (ORR) (71% vs. 41%), and complete response or better (≥CR) rate (44% vs. 5%). An interim analysis presented in February 2023 had reported a median duration of response of 14.8 months for Abecma versus 9.7 months for the standard regimens. However, as reported at ASH 2023, the trial failed to show a significant improvement in OS, with an HR of 1.01 and median OS of 41.4 months and 37.9 months for the Abecma and standard therapy arms, respectively. Company officials noted that 56% of patients in the standard regimen arm crossed over to Abecma, which may explain why an improvement in OS was not seen. However, this would also suggest that moving Abecma up to third line may not improve OS compared to keeping it for fourth-line or later therapy. 
KarMMa-3 研究将 Abecma 与标准三联方案在既往接受过 2 至 4 线多发性骨髓瘤治疗方案的患者中进行对比。2023 年美国血液学会年会公布的中位随访 31 个月数据显示，该试验在无进展生存期（13.8 个月 vs 4.4 个月；风险比 0.49）、总体缓解率（71% vs 41%）以及完全缓解或更佳（≥CR）率（44% vs 5%）方面均取得显著改善。2023 年 2 月公布的中期分析显示，Abecma 组中位缓解持续时间为 14.8 个月，标准方案组为 9.7 个月。但 2023 年 ASH 年会报告表明，该试验未显示总生存期的显著改善（风险比 1.01），Abecma 组与标准治疗组的中位总生存期分别为 41.4 个月和 37.9 个月。公司人员指出，标准方案组 56%的患者后续交叉使用了 Abecma，这可能是未观察到总生存期改善的原因。不过这也意味着，与保留 Abecma 用于四线或后续治疗相比，将其提前至三线使用可能不会改善总生存期。

CARTITUDE-4 evaluated Carvykti in patients who had previously received one to three lines of therapy. The study used a triplet comparator consisting of Pomalyst, bortezomib or Darzalex, and dex, and with 34 months of follow-up reported significant improvements in PFS (median not reached vs. 11.8 months; HR 0.26), OS (median not reached in either arm, HR 0.55, 30 month OS rates were 76% vs. 64%), ORR (85% vs. 67%), and ≥CR rate (77% vs. 22%). 
CARTITUDE-4 研究评估了 Carvykti 在既往接受过 1-3 线治疗患者中的疗效。该研究采用由泊马度胺、硼替佐米或达雷妥尤单抗联合地塞米松组成的三联方案作为对照，经过 34 个月随访显示，Carvykti 在无进展生存期（中位数未达到 vs 11.8 个月；风险比 0.26）、总生存期（两组中位数均未达到，风险比 0.55，30 个月 OS 率为 76% vs 64%）、总体缓解率（85% vs 67%）和完全缓解及以上比率（77% vs 22%）方面均有显著改善。

Two Phase III trials are evaluating Carvykti in first-line patients: CARTITUDE-5 is comparing VRd induction followed by Carvykti to VRd induction followed by Rd maintenance in patients not suited for transplant, while CARTITUDE-6 is evaluating Dara-VRd followed by Carvykti versus Dara-VRd followed by ASCT in transplant-eligible patients. The EPCDs of CARTITUDE-5 and CARTITUDE-6 are June 2026 and June 2033, respectively. 
两项 III 期试验正在评估 Carvykti 用于一线治疗患者的效果：CARTITUDE-5 研究在不适合移植的患者中比较 VRd 诱导后接 Carvykti 与 VRd 诱导后接 Rd 维持治疗的方案，而 CARTITUDE-6 研究则在适合移植的患者中评估 Dara-VRd 后接 Carvykti 与 Dara-VRd 后接自体干细胞移植(ASCT)的疗效。CARTITUDE-5 和 CARTITUDE-6 的预计主要完成日期分别为 2026 年 6 月和 2033 年 6 月。

GSK’s Blenrep (belantamab mafodotin) is an anti-BCMA ADC that has had a rocky history but is now approved for second-line or later patients in the UK and Japan. The approvals are for Blenrep combined with bortezomib + dex or, in the case of patients previously treated with lenalidomide, with Pomalyst + dex. A regulatory application is currently under review in the US with an FDA Advisory Committee set the discuss the submission on July 17 2025 (the PDUFA date is July 23 2025). An application to EU authorities received a positive CHMP opinion with a final decision expected in Q3 2025. Although Blenrep monotherapy received separate conditional approvals from the FDA and EMA in August 2020 for RRMM patients who have received at least four prior therapies, these approvals were withdrawn in 2022 and 2023 after a confirmatory trial, DREAMM-3, failed to meet its primary endpoint of PFS. DREAMM-3 was a head-to-head superiority trial comparing Blenrep monotherapy to Pomalyst + dex (Pd) in third-line or later MM. In a surprising turn of events, Blenrep subsequently reported positive results in two additional Phase III trials, DREAMM-7 and DREAMM-8, both of which enrolled second-line or later patients. DREAMM-7 compared Blenrep combined with bortezomib + dex (Vd) to Darzalex + Vd. Numerical results were presented in February 2024 and included a statistically significant increase in the primary endpoint of PFS (37 months vs. 13 months; HR 0.41). A subsequent interim analysis found a significant increase in OS for the Blenrep arm (median OS not reached in either arm with a median follow-up of 28 months; HR 0.57). OS rates at 18 months were improved in the Blenrep arm (84% vs 73%). DREAMM-7 reported induction of deep responses as measured by ≥CR rate (35% vs. 17%) and by the MRD negativity rate in patients with a very good partial response or better (≥VGPR) (39% vs. 17%). DREAMM-8 compared Blenrep + Pd versus bortezomib + Pd and impressed at ASCO 2024 with a statistically significant improvement in median PFS (not reached vs. 12.7 months with a median follow-up of 21.8 months) and improvements in the ≥CR rate (40% vs. 16%) and in the MRD negativity rate in patients with ≥VGPR (32% vs. 5%). DREAMM-8 also showed a trend for improvement in OS that will be re-examined after a longer follow-up. Unlike the other approved BCMA-targeting agents, which include bispecific antibodies and CAR-T therapies, Blenrep does not require any hospitalizations and its efficacy is independent of T-cell activity, which may make it attractive for patients with T-cell exhaustion. As such, Blenrep is well suited for older patients, including those who are transplant-ineligible and those whose immune systems have been degraded by previous treatments. One drawback to Blenrep is that it is associated with keratopathy, an ocular toxicity that can lead to decreases in visual acuity which are managed primarily by dose interruptions. When it was still being marketed in the US, the FDA required participation in the Blenrep REMS program, which required education for both prescribing physicians and patients regarding the ocular risks of Blenrep as well as monitoring of patients by an ophthalmologist/optometrist before every dose (every three weeks). Due to ocular toxicity, KOLs do not anticipate that Blenrep will play a major role the relapsed/refractory setting. However, physician education and development of a safer, optimized dosing protocol that allows the corneal epithelium to recover between doses (every eight weeks or every twelve weeks) could help increase uptake. 
葛兰素史克的 Blenrep（贝兰他单抗马夫多汀）是一款靶向 BCMA 的抗体偶联药物，其上市历程颇为坎坷，现已在英国和日本获批用于二线及以上治疗。获批方案为 Blenrep 联合硼替佐米+地塞米松，或针对曾接受来那度胺治疗的患者联合泊马度胺+地塞米松。美国食品药品监督管理局目前正在审评该药的上市申请，其咨询委员会定于 2025 年 7 月 17 日讨论该申请（PDUFA 日期为 2025 年 7 月 23 日）。欧盟监管机构已给出 CHMP 积极意见，最终决定预计将于 2025 年第三季度作出。尽管 Blenrep 单药疗法曾于 2020 年 8 月分别获得美国食品药品监督管理局和欧洲药品管理局有条件批准用于接受过至少四种前期治疗的复发难治性多发性骨髓瘤患者，但在验证性试验 DREAMM-3 未能达到无进展生存期主要终点后，这些批准于 2022 年和 2023 年被撤销。DREAMM-3 是一项头对头优效性试验，在三线及以上多发性骨髓瘤治疗中比较了 Blenrep 单药与泊马度胺+地塞米松（Pd）方案的疗效。 令人意外的是，Blenrep 随后在 DREAMM-7 和 DREAMM-8 两项针对二线及以上患者的 III 期试验中均取得积极结果。DREAMM-7 试验将 Blenrep 联合硼替佐米+地塞米松（Vd）方案与 Darzalex 联合 Vd 方案进行对比。2024 年 2 月公布的数值结果显示，主要终点无进展生存期（PFS）具有统计学显著改善（37 个月 vs 13 个月；HR 0.41）。后续中期分析发现 Blenrep 组总生存期（OS）显著延长（中位随访 28 个月时两组均未达到中位 OS；HR 0.57），18 个月 OS 率更高（84% vs 73%）。该试验还显示 Blenrep 组诱导出更深度的缓解：完全缓解率（≥CR）达 35% vs 17%，在达到非常好部分缓解及以上（≥VGPR）的患者中，微小残留病灶阴性率（MRD-）达 39% vs 17%。 DREAMM-8 试验则对比了 Blenrep+Pd 方案与硼替佐米+Pd 方案，在 2024 年 ASCO 年会上以显著改善的中位 PFS（中位随访 21.8 个月时未达到 vs 12.7 个月）、更高的≥CR 率（40% vs 16%）以及≥VGPR 患者更高的 MRD-率（32% vs 5%）令人瞩目。 DREAMM-8 研究还显示出总生存期改善的趋势，将在更长期随访后重新评估。与其他已获批的 BCMA 靶向药物（包括双特异性抗体和 CAR-T 疗法）不同，Blenrep 无需住院治疗且其疗效不依赖 T 细胞活性，这对存在 T 细胞耗竭的患者可能颇具吸引力。因此，Blenrep 非常适合老年患者，包括不适合移植的患者和因既往治疗导致免疫系统受损的患者。Blenrep 的一个缺点是可能引发角膜病变（一种可导致视力下降的眼部毒性），主要通过暂停给药来控制。当该药物仍在美国销售时，食品药品监督管理局要求参与 Blenrep 风险评估与减低策略（REMS）计划，该计划要求对处方医师和患者进行关于 Blenrep 眼部风险的教育，并要求在每次给药前（每三周）由眼科医生/验光师对患者进行监测。由于存在眼部毒性，关键意见领袖预计 Blenrep 在复发/难治性治疗领域不会发挥主要作用。 然而，通过内科医生的教育以及制定更安全、优化的给药方案（如每八周或每十二周给药一次，让角膜上皮在给药间隔期得以恢复），将有助于提高该疗法的采用率。

A Phase III trial in the newly diagnosed, transplant-ineligible setting (DREAMM-10) is comparing Blenrep combined with Rd to Darzalex combined with Rd. DREAMM-10 has an EPCD of December 2030. 
针对新确诊且不适合移植患者的三期临床试验（DREAMM-10）正在比较 Blenrep 联合 Rd 方案与 Darzalex 联合 Rd 方案的疗效。该试验预计于 2030 年 12 月完成主要终点数据收集。

Johnson & Johnson’s Darzalex (daratumumab) was the first mAb approved for MM. Since its initial approval in 2015 as a monotherapy for fourth-line or later patients, uptake of this CD38-targeted drug has increased steadily with multiple label expansions that have helped it grow to become a major MM blockbuster. With the risk of infections being the main safety concern, Darzalex is well tolerated and can even be used in the elderly/frail population. 
强生公司的 Darzalex（达雷妥尤单抗）是首个获批用于多发性骨髓瘤的单克隆抗体。自 2015 年首次获批作为四线及以上患者的单药治疗方案以来，这款靶向 CD38 的药物通过多次适应症扩展，使用率持续攀升，现已发展成为多发性骨髓瘤领域的重磅产品。尽管存在感染风险这一主要安全性问题，但 Darzalex 耐受性良好，甚至可用于老年/体弱患者群体。

Darzalex is infused over several hours, so the approval of a more convenient SC formulation has helped the drug grow its blockbuster status. The SC formulation (Darzalex Faspro/daratumumab hyaluronidase) was approved in the US following a BLA, thereby granting it 12 years of exclusivity. Approvals in the US (May 2020), EU (June 2020), and Japan (March 2021) were for the same settings as for Darzalex. Additionally, SC Darzalex + Pomalyst + dex was approved for second-line or later patients in the US (July 2021) and EU (June 2021) based on the APOLLO trial. In November 2021, SC Darzalex was approved by the FDA in combination with Kyprolis + dex for second- to fourth-line patients based on the PLEIADES trial. 
达雷妥尤单抗需要数小时静脉输注，因此更便捷的皮下制剂获批进一步巩固了这款重磅药物的市场地位。皮下制剂（Darzalex Faspro/达雷妥尤单抗透明质酸酶）通过生物制品许可申请在美国获批，由此获得 12 年市场独占权。该剂型在美国（2020 年 5 月）、欧盟（2020 年 6 月）和日本（2021 年 3 月）的获批适应症与静脉剂型一致。此外，基于 APOLLO 试验数据，皮下制剂达雷妥尤单抗联合泊马度胺与地塞米松方案在美国（2021 年 7 月）和欧盟（2021 年 6 月）获批用于二线及以上治疗。2021 年 11 月，根据 PLEIADES 试验结果，食品药品监督管理局批准皮下制剂达雷妥尤单抗联合卡非佐米与地塞米松用于二线至四线治疗。

The table below summarizes Darzalex’s label expansions for MM. 
下表总结了达雷妥尤单抗在多发性骨髓瘤领域的适应症扩展情况。

PERSEUS compared a Darzalex quadruplet (Dara-VRd) to VRd as induction therapy prior to transplant and as consolidation therapy post-transplant. PERSEUS also evaluated Darzalex + lenalidomide versus lenalidomide alone as maintenance therapy but the lack of a second randomization after transplant means that the trial will not support approval of maintenance with Darzalex + lenalidomide. 
PERSEUS 研究将 Darzalex 四联疗法（Dara-VRd）与 VRd 方案作为移植前诱导治疗及移植后巩固治疗进行对比。该研究还评估了 Darzalex 联合来那度胺对比单用来那度胺作为维持治疗的疗效，但由于移植后缺乏二次随机分组，试验结果将无法支持 Darzalex 联合来那度胺维持治疗的获批。

At ASH 2023, PERSEUS reported that Dara-VRd significantly improved PFS, MRD negativity, and CR rates in transplant-eligible patients. With a median follow-up of 47.5 months, the estimated 48-month PFS for Dara-VRd and VRd was 84% and 68%, respectively, with an HR of 0.40. According to the FDA label, at the end of consolidation, the Dara-VRd regimen significantly improved the depth of response versus the VRd regimen as measured by the ≥CR rate (44% vs. 35%) and the MRD negativity rate measured at 10-5 (57% vs. 32%). Although PERSEUS showed a trend for improved survival in the Dara-VRd arm, it will be many years before an improvement in OS can be established. 
在 2023 年美国血液学会年会上，PERSEUS 研究公布数据显示：对于适合移植的患者，Dara-VRd 方案显著改善了无进展生存期（PFS）、微小残留病（MRD）阴性率和完全缓解（CR）率。中位随访 47.5 个月时，Dara-VRd 组和 VRd 组的 48 个月预估 PFS 率分别为 84%和 68%（风险比 HR=0.40）。根据食品药品监督管理局的标签信息，在巩固治疗结束时，通过≥CR 率（44%对比 35%）和 10^-5 灵敏度检测的 MRD 阴性率（57%对比 32%）评估，Dara-VRd 方案较 VRd 方案显著提升了缓解深度。尽管 PERSEUS 研究显示 Dara-VRd 组存在生存改善趋势，但总生存期（OS）获益的确立仍需多年随访验证。

Following these positive results from PERSEUS, the Dara-VRd quadruplet is set to become the standard of care for induction and consolidation of first-line transplant-eligible patients. The PERSEUS regimen was approved in the US and EU in July and October 2024, respectively. A key question discussed at ASH 2023 was whether maintenance with Darzalex + lenalidomide is superior to lenalidomide alone. However, PERSEUS was not designed to answer this question, as there was no rerandomization after transplant and it is unclear if adding Darzalex to the maintenance regimen contributed to the increase in PFS or if the improvement was solely due to adding Darzalex at the induction and consolidation phases. Both the US and the EU approvals were only for induction and consolidation and not for maintenance with Darzalex + lenalidomide. Another Phase III trial, AURIGA, compared Darzalex + lenalidomide versus lenalidomide maintenance in patients who were MRD-positive after induction and ASCT. Results from AURIGA were presented in September 2024 and showed that the trial met its primary endpoint of conversion to MRD-negativity, as well as its secondary endpoint of PFS. However, since AURIGA did not enroll patients treated with Darzalex during induction, it is unlikely that it will support approval of Darzalex + lenalidomide for maintenance after ASCT. With no formal approval, we expect to see limited uptake of Darzalex in the first-line transplant-eligible maintenance setting. 
随着 PERSEUS 研究取得积极成果，Dara-VRd 四联疗法即将成为适合一线移植患者诱导和巩固治疗的新标准。该方案分别于 2024 年 7 月和 10 月在美国及欧盟获批。ASH 2023 会议上讨论的核心问题是：达雷妥尤单抗联合来那度胺的维持治疗是否优于单用来那度胺。但 PERSEUS 研究设计并未解答这个问题——因移植后未进行再随机分组，无法确定 PFS 的提升是源于维持阶段添加达雷妥尤单抗，还是仅由诱导/巩固阶段的联合用药驱动。美欧两地批准范围均仅限于诱导和巩固阶段，不包括达雷妥尤单抗联合来那度胺的维持治疗。另一项 III 期试验 AURIGA 则针对诱导治疗和自体干细胞移植后 MRD 阳性患者，对比了达雷妥尤单抗联合来那度胺与单用来那度胺的维持效果。2024 年 9 月公布的数据显示，该试验同时达到了 MRD 转阴的主要终点和 PFS 的次要终点。 然而，由于 AURIGA 试验未纳入在诱导期接受 Darzalex 治疗的患者，该数据不太可能支持 Darzalex 联合来那度胺用于自体干细胞移植（ASCT）后维持治疗的获批。在缺乏正式批准的情况下，我们预计 Darzalex 在一线适合移植患者的维持治疗中应用有限。

Another Darzalex Phase III trial that read out in 2024 was CEPHEUS which evaluated Dara-VRd for newly diagnosed transplant-ineligible patients. Patients received Dara-VRd for eight cycles followed by DRd until disease progression. The comparator was eight cycles of VRd followed by Rd until disease progression. Results presented in September 2024 showed that the trial met its primary endpoint of MRD-negativity rate at 10-5 (61% vs. 39%) as well as the secondary endpoint of median PFS (not reached vs. 53 months; HR 0.57). A regulatory submission supported by CEPHEUS was approved in the EU in April 2025 and is currently under review in the US with an approval expected by mid-2025. Sarclisa-VRd was approved for this setting in the US (September 2024), EU (January 2025) and Japan (February 2025). Once the CEPHEUS regimen is approved, Dara-VRd will compete with Sarclisa-VRd to become the standard of care for fit, transplant-ineligible patients while DRd will be reserved for the frail population. Given Darzalex’s advantages of a subcutaneous formulation and physician familiarity, we expect Dara-VRd to be favored over Sarclisa-VRd. 
2024 年公布的另一项 Darzalex III 期临床试验 CEPHEUS 评估了 Dara-VRd 方案在新诊断不适合移植患者中的应用。患者接受 8 个周期 Dara-VRd 治疗后继续 DRd 方案直至疾病进展，对照组为 8 个周期 VRd 后接 Rd 方案维持治疗。2024 年 9 月公布的数据显示，该试验达到了 10^-5 水平微小残留病灶阴性率（61% vs 39%）的主要终点，以及中位无进展生存期（未达到 vs 53 个月；风险比 0.57）的次要终点。基于 CEPHEUS 数据的注册申请已于 2025 年 4 月在欧盟获批，目前正在美国审评中，预计 2025 年年中获批。Sarclisa-VRd 方案已相继在美国（2024 年 9 月）、欧盟（2025 年 1 月）和日本（2025 年 2 月）获批该适应症。CEPHEUS 方案获批后，Dara-VRd 将与 Sarclisa-VRd 竞争成为体能良好但不适合移植患者的标准治疗方案，而 DRd 方案将保留用于虚弱患者群体。考虑到 Darzalex 具有皮下制剂优势和内科医生熟悉度，我们预计 Dara-VRd 将比 Sarclisa-VRd 更受青睐。

The final Darzalex Phase III trial to read out in 2024 was AQUILA which compared Darzalex monotherapy to observation in high-risk smoldering myeloma. With a median follow-up of 65 months, the trial met its primary endpoint of PFS (63 months vs 41 months; HR 0.49). There was also a significant improvement in OS (60-month OS rates of 93% vs. 87%; HR 0.52). A regulatory submission supported by AQUILA is currently under review by the FDA, EU and Japanese authorities. In May 2025, an FDA advisory committee voted 6-2 that AQUILA provided sufficient evidence of a favorable benefit-risk profile increasing the likelihood that Darzalex will be FDA approved for high-risk smoldering multiple myeloma. Similarly, in June 2025 a European panel recommended that Darzalex be approved for this setting.   
2024 年公布的 Darzalex 最终 III 期临床试验是 AQUILA 研究，该研究比较了 Darzalex 单药治疗与观察治疗在高危冒烟型骨髓瘤患者中的效果。中位随访 65 个月后，试验达到了无进展生存期（PFS）的主要终点（63 个月 vs 41 个月；风险比 0.49）。总生存期（OS）也有显著改善（60 个月 OS 率为 93% vs. 87%；风险比 0.52）。基于 AQUILA 研究数据的监管申请目前正在接受美国食品药品监督管理局、欧盟和日本当局的审查。2025 年 5 月，FDA 咨询委员会以 6 比 2 的投票结果认定 AQUILA 研究提供了足够的证据表明其具有有利的获益-风险特征，这增加了 Darzalex 获得 FDA 批准用于高危冒烟型多发性骨髓瘤的可能性。同样在 2025 年 6 月，欧洲专家小组建议批准 Darzalex 用于该适应症。

Pfizer’s Elrexfio (elranatamab) is a second-to-market BCMA x CD3 bispecific antibody, with cross-trial comparisons suggesting that it has similar efficacy to Tecvayli but a higher rate of grade 5 infections and treatment discontinuations due to adverse events. Elrexfio benefits from a lower rate of ICANS and from fewer required hospitalizations compared to Tecvayli. Elrexfio requires 48-hour and 24-hour hospitalizations for step-up doses one and two, respectively, compared to Tecvayli which requires three 48-hour hospitalizations. Elrexfio has received conditional approval from the FDA (in August 2023) for fifth-line or later MM, from the European Commission (in December 2023) for fourth-line or later MM and full approval from Japanese authorities (in March 2024) for second-line or later MM. All three approvals specified patients previously treated with a PI, an IMiD, and an anti-CD38 antibody. In December 2024, Elrexfio received positive NICE guidance but only in the context of managed access. Elrexfio is administered subcutaneously with the option to switch from weekly to every-other-week dosing after 24 weeks of treatment for patients with a PR or better. The every-other-week dosing regimen is expected to lower the risk of infection associated with long-term treatment. Elrexfio has a black box warning for CRS and neurological toxicity, and is only available through a REMS program. MagnetisMM-3 was a pivotal Phase II trial that evaluated Elrexfio in triple-refractory MM patients. Per the FDA label, for 97 patients not previously treated with a BCMA agent and with a median follow-up of 11 months, the ORR was 58% and the CR/sCR rate was 26%. This is comparable to Tecvayli, whose FDA label reports that with a median follow-up of seven months, the ORR was 62% and the CR/sCR rate was 28%. Compared to Tecvayli, Elrexfio reported lower rates of CRS (58% vs. 72%) and grade 1/2 ICANS (3% vs. 6%). The rate of grade 3/4 infections was high at 31%, with 7% of patients having a grade 5 infection (Tecvayli reported grade 3/4 infections in 35% of patients, and grade 5 infections in 4% of patients). The rate of permanent discontinuation due to treatment-related adverse events was higher for Elrexfio than Tecvayli (17% vs. 1.2%). A confirmatory Phase III trial, MagnetisMM-5, is designed to demonstrate superiority of Elrexfio over Darzalex-based regimens in the second-line or later setting and is evaluating Elrexfio monotherapy as well as Elrexfio + Darzalex in patients refractory to lenalidomide and a PI; the comparator is Darzalex + Pomalyst + dex and the EPCD is December 2025. Another trial in the second-line or later setting, MagnetisMM-32, is designed to establish a new standard of care for patients who received Darzalex in the front-line setting. MagnetisMM-32 is comparing Elrexfio monotherapy to Elo-Pd, PVd, or Kd, is enrolling patients refractory to lenalidomide and a CD38 inhibitor, and has an EPCD of August 2026. In the newly diagnosed setting, MagnetisMM-7 is evaluating Elrexfio as maintenance therapy after ASCT; the comparator is lenalidomide, and the EPCD is August 2027. Finally, an ex-US Phase III trial, MagnetisMM-6, is evaluating Elrexfio + Darzalex + lenalidomide or Elrexfio + lenalidomide in newly diagnosed, transplant-ineligible patients; the comparator is Darzalex + lenalidomide + dex, and the EPCD is March 2028.  
辉瑞公司的 Elrexfio（elranatamab）是第二款上市的 BCMA x CD3 双特异性抗体，跨试验比较显示其疗效与 Tecvayli 相似，但 5 级感染率和因不良事件导致治疗中止的比例更高。与 Tecvayli 相比，Elrexfio 的优势在于 ICANS 发生率更低且住院需求更少。Elrexfio 的阶梯剂量一和二分别需要 48 小时和 24 小时住院观察，而 Tecvayli 则需要三次 48 小时住院。Elrexfio 已获得美国食品药品监督管理局（2023 年 8 月）有条件批准用于五线或更后线多发性骨髓瘤治疗，欧洲委员会（2023 年 12 月）批准用于四线或更后线治疗，日本监管机构（2024 年 3 月）则给予二线或更后线治疗的完全批准。三项批准均明确要求患者既往接受过蛋白酶体抑制剂、免疫调节药物和抗 CD38 抗体治疗。2024 年 12 月，Elrexfio 获得英国国家卫生与临床优化研究所（NICE）积极指导，但仅限于管理准入框架下使用。该药采用皮下注射方式给药，对于达到部分缓解或更好疗效的患者，可在治疗 24 周后从每周给药调整为隔周给药。 隔周给药方案预计将降低与长期治疗相关的感染风险。Elrexfio 因存在细胞因子释放综合征（CRS）和神经毒性的黑框警告，仅能通过风险评估与缓解策略（REMS）计划获取。MagnetisMM-3 是一项关键性 II 期试验，评估了 Elrexfio 在三线难治性多发性骨髓瘤患者中的疗效。根据食品药品监督管理局标签数据，在 97 例既往未接受过 BCMA 靶向治疗且中位随访 11 个月的患者中，总缓解率（ORR）为 58%，完全缓解/严格完全缓解（CR/sCR）率为 26%。这一结果与 Tecvayli 相当——后者在食品药品监督管理局标签中报告的中位随访 7 个月数据显示，ORR 为 62%，CR/sCR 率为 28%。与 Tecvayli 相比，Elrexfio 报告的 CRS 发生率（58% vs. 72%）和 1/2 级免疫效应细胞相关神经毒性综合征（ICANS）发生率（3% vs. 6%）更低。但 3/4 级感染发生率高达 31%，其中 7%患者出现 5 级感染（Tecvayli 报告的 3/4 级感染率为 35%，5 级感染率为 4%）。Elrexfio 因治疗相关不良事件导致的永久停药率高于 Tecvayli（17% vs. 1.2%）。验证性 III 期试验 MagnetisMM-5 旨在证明 Elrexfio 在二线或后线治疗中优于基于 Darzalex 的方案，该试验正在评估 Elrexfio 单药治疗及 Elrexfio 联合 Darzalex 对来那度胺和蛋白酶体抑制剂难治性患者的疗效；对照组采用 Darzalex 联合泊马度胺与地塞米松方案，预计主要终点完成日期为 2025 年 12 月。另一项针对二线或后线治疗的试验 MagnetisMM-32 旨在为前线接受过 Darzalex 治疗的患者建立新标准，该试验将 Elrexfio 单药与 Elo-Pd、PVd 或 Kd 方案进行对比，入组对象为对来那度胺和 CD38 抑制剂难治的患者，主要终点完成日期为 2026 年 8 月。在新诊断患者群体中，MagnetisMM-7 评估 Elrexfio 作为自体干细胞移植后的维持治疗；对照组采用来那度胺方案，主要终点完成日期为 2027 年 8 月。最后，一项国际多中心 III 期试验 MagnetisMM-6 正在评估 Elrexfio 联合 Darzalex 与来那度胺或 Elrexfio 单联合来那度胺用于不适合移植的新诊断患者；对照组采用 Darzalex 联合来那度胺与地塞米松方案，主要终点完成日期为 2028 年 3 月。

Bristol Myers Squibb’s Empliciti (elotuzumab), the only SLAMF7-targeted mAb approved for MM, has seen moderate uptake since its US (2015), EU (2016), and Japanese (2019) approvals as part of a combination with Revlimid + dex (ERd) for the treatment of MM patients who have received one to three prior lines of therapy. A label expansion for the combination of Empliciti + Pomalyst + dex for the treatment of third-line or later MM patients provided expanded options for the use of Empliciti in the treatment of RRMM but did not significantly improve the drug’s commercial potential in this crowded treatment space. Furthermore, the Phase III failure of the ERd combination in ELOQUENT-1 precluded a potential label expansion to the lucrative first-line setting. Although results from the Phase II E-PRISM study of ERd for the treatment of high-risk smoldering MM were positive, there is no indication that Bristol Myers Squibb will explore the combination further. 
百时美施贵宝的 Empliciti（elotuzumab）是唯一获批用于多发性骨髓瘤的 SLAMF7 靶向单抗。自其在美国（2015 年）、欧盟（2016 年）和日本（2019 年）获批作为 Revlimid+地塞米松（ERd）联合疗法用于接受过 1-3 线既往治疗的 MM 患者以来，市场接受度中等。Empliciti 与 Pomalyst+地塞米松联合用于三线或更晚期 MM 患者的标签扩展为 RRMM 治疗提供了更多选择，但在这个竞争激烈的治疗领域并未显著提升该药物的商业潜力。此外，ERd 组合在 ELOQUENT-1 三期研究的失败使其错失了向利润丰厚的一线治疗领域扩展标签的可能。尽管 ERd 治疗高危冒烟型 MM 的 II 期 E-PRISM 研究结果积极，但尚无迹象表明百时美施贵宝会进一步探索该组合疗法。

Secura Bio’s Farydak (panobinostat) is a histone deacetylase inhibitor with limited commercial potential due to its relatively poor risk/benefit profile. Both the FDA and EMA raised concerns about the high toxicity observed in the pivotal PANORAMA-1 trial and subsequently limited approval of the Farydak + bortezomib + dex combination (Pano-Vd) to the treatment of third-line or later MM patients. Given the associated toxicities and multitude of other therapies available for the treatment of RRMM, Farydak has experienced only limited uptake since its approval in 2015. In November 2021, Secura Bio withdrew its NDA for Farydak. Farydak was approved based on a surrogate endpoint (PFS), and the pivotal trial failed to show an improvement in OS. Secura Bio explained that it was not feasible for the company to complete the required post-approval clinical studies to support the accelerated approval. Farydak continues to be marketed in the EU. 
Secura Bio 公司的 Farydak（帕比司他）是一种组蛋白去乙酰化酶抑制剂，由于风险收益比较差，其商业潜力有限。食品药品监督管理局和 EMA 均对关键性 PANORAMA-1 试验中观察到的高毒性表示担忧，随后将 Farydak+硼替佐米+地塞米松联合疗法（Pano-Vd）的批准限制用于三线或更晚期的多发性骨髓瘤患者治疗。鉴于相关毒性及 RRMM 治疗领域存在大量其他可用疗法，Farydak 自 2015 年获批以来市场接受度一直较低。2021 年 11 月，Secura Bio 撤回了 Farydak 的新药申请。该药物基于替代终点（无进展生存期）获批，但关键试验未能显示总生存期的改善。Secura Bio 解释称，公司无法完成支持加速审批所需的上市后临床研究。目前 Farydak 仍在欧盟市场销售。

Amgen’s second-generation PI Kyprolis (carfilzomib) is approved for the treatment of RRMM as a monotherapy and as part of combinations with dex or with Revlimid and dex. In the UK, Kyprolis + dex for second-line patients is recommended by the National Institute for Health and Care Excellence (NICE). Kyprolis remains the favored PI in the RRMM setting as it demonstrated improved safety and efficacy over bortezomib, another PI, in the Phase III ENDEAVOR trial. Kyprolis is expected to see continued growth in this setting following FDA approval of the Kyprolis + Darzalex + dex combination in August 2020. This triplet has also been approved in the EU (December 2020) and Japan (November 2020). In the front-line setting, Kyprolis failed to show superiority over Velcade in the Phase III CLARION study that evaluated Kyprolis or Velcade combined with melphalan and prednisone. Furthermore, at ASCO 2020, an ECOG study (ENDURANCE) comparing Kyprolis and Velcade combined with Revlimid and dex reported that the Kyprolis regimen (KRd) failed to show superiority to the Velcade regimen (VRd). Nevertheless, the KRd regimen will likely continue to see some off-label use in the front-line setting due to KRd and VRd having different toxicity profiles. In ENDURANCE, the KRd arm reported more cardiopulmonary and renal adverse events (16.1% vs. 4.8%), while the VRd arm reported more peripheral neuropathy events (53.4% vs. 24.4%). As such, KRd may be better suited for patients with baseline neuropathy, while VRd may be better suited for patients with renal insufficiency. Kyprolis’s revenues will be threatened by generic versions of carfilzomib, which are expected to enter the EU and Japan markets in Q4 2025 and Q4 2030, respectively. In June 2020, after a challenge from Cipla, a US court upheld several Kyprolis patents, with the latest expiring in December 2027. In June 2021, Breckenridge and its Indian partner Natco Pharma disclosed a settlement allowing launch of a generic carfilzomib on a date “in 2027 or sooner depending on certain occurrences.” 
安进公司的第二代蛋白酶体抑制剂 Kyprolis（卡非佐米）已获批作为单药治疗或与地塞米松联用、以及与瑞复美和地塞米松联用的组合方案，用于治疗复发难治性多发性骨髓瘤（RRMM）。在英国，国家健康与护理卓越研究院（NICE）推荐将 Kyprolis 联合地塞米松用于二线治疗患者。在 RRMM 治疗领域，Kyprolis 仍是首选的蛋白酶体抑制剂，因为在 III 期 ENDEAVOR 试验中，其安全性和疗效均优于另一种蛋白酶体抑制剂硼替佐米。随着美国食品药品监督管理局于 2020 年 8 月批准 Kyprolis 联合达雷妥尤单抗及地塞米松的三联方案，预计 Kyprolis 在该适应症中将持续增长。该三联方案还获得了欧盟（2020 年 12 月）和日本（2020 年 11 月）的批准。然而在一线治疗中，评估 Kyprolis 或万珂联合美法仑和泼尼松的 III 期 CLARION 研究显示，Kyprolis 未能表现出优于万珂的疗效。此外，在 2020 年美国临床肿瘤学会（ASCO）年会上，ECOG 研究（ENDURANCE）比较了 Kyprolis 和万珂分别联合瑞复美及地塞米松的疗效，结果显示 Kyprolis 方案（KRd）未能超越万珂方案（VRd）。 尽管如此，KRd 方案（卡非佐米+来那度胺+地塞米松）仍可能在一线治疗中继续获得部分超适应症使用，因为 KRd 与 VRd（硼替佐米+来那度胺+地塞米松）具有不同的毒性特征。在 ENDURANCE 研究中，KRd 组报告了更多心肺和肾脏不良事件（16.1% vs. 4.8%），而 VRd 组则报告了更多周围神经病变事件（53.4% vs. 24.4%）。因此，KRd 可能更适合基线存在神经病变的患者，而 VRd 可能更适合肾功能不全的患者。卡非佐米的仿制药预计将分别于 2025 年第四季度和 2030 年第四季度进入欧盟和日本市场，这将威胁 Kyprolis 的销售收入。2020 年 6 月，在 Cipla 提出专利挑战后，美国法院维持了 Kyprolis 的多项专利有效性，其中最晚到期日为 2027 年 12 月。2021 年 6 月，Breckenridge 及其印度合作伙伴 Natco Pharma 披露了一项和解协议，允许"在 2027 年或更早（取决于特定条件）"推出卡非佐米仿制药。

Regeneron’s Lynozyfic (linvoseltamab) is a BCMA x CD3 bispecific antibody administered intravenously. At ASCO 2024, Regeneron presented updated data from LINKER-MM1, a pivotal Phase I/II trial. At the recommended Phase II dose, and with a median follow-up of 14 months, Lynozyfic reported an ORR of 71% in 117 fourth-line or later patients. CR/sCR responses were seen in 50% of patients, which is higher than what was reported for Tecvayli (28% with a median follow-up of 7.4 months per its FDA label) and Elrexfio (26% with a median follow-up of 11 months per its FDA label). CRS was reported in 46% of patients and was mostly grade 1, with only 10% of patients reporting grade 2 CRS, and one patient (1%) reporting grade 3 CRS. Grade ≥3 ICANS was reported in 3% of patients, and treatment-related discontinuations were reported in 7% of patients. Finally, infections occurred in 74% of patients, with grade 3/4 infections reported in 36% of patients, while grade 5 infections were reported in 4% of patients. Apart from the increased CR/sCR rate compared to Tecvayli and Elrexfio, another point of differentiation for Lynozyfic is its dosing schedule, which is weekly for weeks 1–14, every two weeks for weeks 16–23, and then for week 24+ the dose was reduced to every four weeks if the patients had a ≥VGPR. Finally, Lynozyfic requires shorter hospitalizations during initial step-up dosing (two 24-hour hospitalizations) compared to Elrexfio (one 48-hour hospitalization and one 24-hour hospitalization) and Tecvayli (three 48-hour hospitalizations). Lynozyfic received conditional approval in the EU in April 2025 for fourth-line or later MM and is under regulatory review in the US with a decision expected by July 2025. In September 2023, Regeneron initiated LINKER-MM3, a Phase III trial comparing Lynozyfic monotherapy to Empliciti + Pomalyst + dex. LINKER-MM3’s EPCD is April 2033, and the trial is enrolling second-line or later patients. After reporting positive results in a Phase I trial for Lynozyfic combined with Kyprolis (ORR and CR rates of 90% and 76%, respectively), Regeneron has indicated that it will initiate a randomized Phase III trial for this combination. This combination could help differentiate Lynozyfic from the other anti-BCMA bispecifics which, in the relapsed/refractory setting, are being evaluated either as monotherapy or in combination with Darzalex. Lynozyfic combined with Kyprolis may be a good combination for patients who are refractory to Darzalex. 
再生元的 Lynozyfic（linvoseltamab）是一种静脉注射的 BCMA x CD3 双特异性抗体。在 2024 年美国临床肿瘤学会年会上，再生元公布了关键性 I/II 期试验 LINKER-MM1 的最新数据。在推荐 II 期剂量下，中位随访 14 个月时，Lynozyfic 在 117 例四线或更晚期患者中报告的总缓解率为 71%。50%的患者达到完全缓解/严格完全缓解，这一数据高于 Tecvayli（根据其食品药品监督管理局标签，中位随访 7.4 个月时为 28%）和 Elrexfio（根据其食品药品监督管理局标签，中位随访 11 个月时为 26%）的报告值。46%的患者报告出现细胞因子释放综合征，多为 1 级，仅 10%患者报告 2 级 CRS，1 例患者（1%）报告 3 级 CRS。≥3 级免疫效应细胞相关神经毒性综合征发生率为 3%，7%的患者因治疗相关不良反应停药。最终，74%的患者发生感染，其中 3/4 级感染占 36%，5 级感染占 4%。 与 Tecvayli 和 Elrexfio 相比，Lynozyfic 除了提高 CR/sCR 率外，另一差异化特点在于其给药方案：第 1-14 周每周给药一次，第 16-23 周每两周给药一次，若患者达到≥VGPR 则从第 24 周起调整为每四周给药一次。此外，Lynozyfic 在初始阶梯给药阶段所需的住院时间更短（两次 24 小时住院），优于 Elrexfio（一次 48 小时加一次 24 小时住院）和 Tecvayli（三次 48 小时住院）。该药物于 2025 年 4 月在欧盟获得有条件批准用于四线及以上多发性骨髓瘤治疗，目前正在美国接受监管审查，预计 2025 年 7 月前做出决定。2023 年 9 月，Regeneron 启动了 LINKER-MM3 III 期临床试验，将 Lynozyfic 单药与 Empliciti+Pomalyst+地塞米松方案进行对比。该试验主要终点期为 2033 年 4 月，入组对象为二线及以上患者。在报告 Lynozyfic 联合 Kyprolis 的 I 期试验积极结果（ORR 和 CR 率分别达 90%和 76%）后，Regeneron 表示将启动该联合疗法的随机 III 期试验。 这种组合方案有助于将 Lynozyfic 与其他抗 BCMA 双特异性抗体区分开来——在复发/难治性治疗场景中，其他抗体目前正作为单药疗法或与 Darzalex 联用进行评估。对于 Darzalex 难治性患者而言，Lynozyfic 与 Kyprolis 联用可能是一种理想的组合方案。

Takeda’s Ninlaro (ixazomib) was the first oral PI approved by the FDA and, in combination with Revlimid and dex, is part of an all-oral regimen approved for the treatment of patients with relapsed MM with one prior line of therapy. While Ninlaro offers convenient administration and a relatively favorable safety profile, it has not been able to break through to front-line therapy after the Phase III TOURMALINE-MM2 trial investigating Ninlaro as an induction therapy failed to meet the PFS primary endpoint. Furthermore, while Ninlaro reported positive PFS results from two Phase III trials that compared the drug to placebo as single-agent maintenance therapy for newly diagnosed patients treated (TOURMALINE-MM3) or not treated (TOURMALINE-MM4) with stem cell transplantation, interim OS data presented at ASH 2021 reported slightly more deaths in the Ninlaro arm (HR 1.008 for MM3; HR 1.136 for MM4). In April 2022, the FDA modified Ninlaro’s label to note that it is not recommended for use in the maintenance setting or for newly diagnosed patients in combination with Revlimid and dex. Ninlaro has fared better in Japan, where it received supplemental approval as maintenance therapy for patients who have or have not undergone ASCT (in May 2020 and July 2021, respectively).  
武田制药的 Ninlaro（伊沙佐米）是首个获得美国食品药品监督管理局批准的口服蛋白酶体抑制剂，与来那度胺及地塞米松联用构成全口服方案，获批用于接受过一线治疗的复发多发性骨髓瘤患者。尽管 Ninlaro 具备给药便利性和相对良好的安全性特征，但作为诱导疗法的 III 期 TOURMALINE-MM2 试验未能达到无进展生存期主要终点，使其未能突破至一线治疗领域。此外，虽然 Ninlaro 在两项 III 期试验中作为单药维持疗法（分别针对接受干细胞移植的 TOURMALINE-MM3 试验和未接受移植的 TOURMALINE-MM4 试验）相比安慰剂显示出无进展生存期获益，但 2021 年美国血液学会年会公布的中期总生存数据显示 Ninlaro 组死亡人数略高（MM3 试验风险比 1.008；MM4 试验风险比 1.136）。2022 年 4 月，美国食品药品监督管理局修订了 Ninlaro 的说明书，注明不推荐将其用于维持治疗或与来那度胺及地塞米松联用治疗新确诊患者。 在日本，Ninlaro 的表现更为出色，先后于 2020 年 5 月和 2021 年 7 月获得补充批准，用于接受或未接受自体干细胞移植（ASCT）患者的维持治疗。

Oncopeptides’ Pepaxto (melphalan-flufenamide) is a dipeptide consisting of the chemotherapy drug melphalan conjugated to phenylalanine. Pepaxto + dex is approved in the EU (since August 2022) for triple-refractory MM patients who have received at least three prior therapies. In the EU4 countries, Pepaxto is commercially available in Spain, Germany and Italy but received a decision from the French National Authority for Health advising against reimbursement in France. After the company failed to provide an evidence submission, the UK’s NICE announced in April 2024 that it was unable to make a recommendation. In Q4 2024, Oncopeptides announced that it had agreed with Japanese authorities on a regulatory path forward for Pepaxto approval and that they were in advanced negotiations for a potential commercial partner for Japan. While Pepaxto received accelerated approval in the US in February 2021, in December 2022 the FDA requested withdrawal of the marketing authorization following mixed results from the confirmatory Phase III OCEAN study. An appeal from Oncopeptides was rejected by the FDA, and in February 2024 the Pepaxto NDA was ordered to be withdrawn. HORIZON, a pivotal Phase II trial, reported an ORR of 24%, a duration of response of 4.2 months, and OS of 9.1 months, which compare well to Xpovio (25% ORR; 3.8-month duration of response; 8.0-month OS). OCEAN compared Pepaxto + dex to Pomalyst + dex in third-line or later patients refractory to Revlimid. While the trial met its primary endpoint of PFS, OCEAN found a concerning safety signal in the form of reduced OS for a subgroup of patients previously treated with an ASCT, and so the FDA wanted Pepaxto used only in patients without a previous ASCT. However, such patients constituted only 30% of patients enrolled in HORIZON (45 patients in the trial, 30 patients in the label population), which is too few to establish efficacy. While OCEAN showed a substantial improvement in PFS for the subgroup of patients without a previous ASCT, this was seen by the FDA as hypothesis-generating, and a confirmatory Phase III trial, preceded by a dose-finding trial, was required. The EU approval specifies that for patients with a prior transplant, the time to progression should be at least three years after the transplant. 
Oncopeptides 公司的 Pepaxto（美法仑-氟芬酰胺）是一种由化疗药物美法仑与苯丙氨酸结合形成的二肽。Pepaxto 联合地塞米松方案于 2022 年 8 月在欧盟获批，适用于接受过至少三种前期治疗的三线难治性多发性骨髓瘤患者。在欧盟四国中，Pepaxto 已在西班牙、德国和意大利上市销售，但法国国家卫生管理局作出了不予报销的负面意见。由于企业未能提交补充证据，英国国家健康与临床卓越研究院于 2024 年 4 月宣布无法给出推荐意见。2024 年第四季度，Oncopeptides 宣布已与日本监管机构就 Pepaxto 的批准路径达成一致，并正就日本市场潜在商业合作伙伴进行深入谈判。尽管 Pepaxto 于 2021 年 2 月获得美国加速批准，但 2022 年 12 月美国食品药品监督管理局基于 III 期 OCEAN 验证性研究的混合结果要求撤销上市许可。Oncopeptides 的上诉请求被驳回后，2024 年 2 月该药物新药申请被正式要求撤回。 关键性 II 期试验 HORIZON 报告显示，客观缓解率（ORR）达 24%，中位缓解持续时间为 4.2 个月，总生存期（OS）为 9.1 个月，这些数据优于 Xpovio（ORR 25%；中位缓解持续时间 3.8 个月；OS 8.0 个月）。OCEAN 试验将 Pepaxto 联合地塞米松与泊马度胺联合地塞米松进行对比，用于对来那度胺耐药的≥三线治疗患者。虽然该试验达到了无进展生存期（PFS）的主要终点，但 OCEAN 发现曾接受自体干细胞移植（ASCT）的患者亚组存在总生存期缩短的安全隐患，因此食品药品监督管理局要求 Pepaxto 仅用于未接受过 ASCT 的患者。然而这类患者在 HORIZON 试验中仅占入组人数的 30%（试验组 45 例患者，标签人群 30 例），样本量过小难以证实疗效。尽管 OCEAN 试验显示未接受 ASCT 的患者亚组 PFS 显著改善，但监管部门认为这仅能作为假设生成依据，仍需先开展剂量探索试验，再进行确证性 III 期试验。欧盟批准文件中特别注明，对于曾接受移植的患者，其疾病进展时间应距移植至少三年。

The thalidomide analog Pomalyst (pomalidomide) adds a treatment option to Bristol Myers Squibb’s MM portfolio and forms the backbone of several different triplet regimens for RRMM. Pomalyst gained US and EU approval in 2013 for third-line or later patients previously treated with Revlimid and bortezomib. Approval in Japan was granted in 2015. Bristol Myers Squibb also markets the successful thalidomide analog Revlimid, and has positioned Pomalyst as a subsequent therapy option. The Phase III OPTIMISMM trial tested the combination of Pomalyst + Velcade + low-dose dex at an earlier line (second line or later) in patients previously treated with Revlimid, and supported label expansions in 2019 in the EU and Japan. In the US, approval for the second-line or later setting in combination with SC Darzalex + dex is noted in the FDA label for SC Darzalex. The first pomalidomide generics were launched in the EU in August 2024 and following a settlement with Dr. Reddy’s, are expected to launch in the US Q1 2026. Pomalyst has regulatory exclusivity until June 2026 in Japan. In January 2025, the US Department of Health and Human Services (HHS) announced that Pomalyst was one of 15 additional drugs selected for Medicare Part D price negotiations. The negotiated price is expected to take effect in 2027.  
沙利度胺类似物泊马度胺（Pomalyst）为百时美施贵宝的多发性骨髓瘤治疗组合增添了新选择，并成为多种复发难治性多发性骨髓瘤三联疗法的核心用药。该药物于 2013 年获得美国食品药品监督管理局和欧盟批准，用于经来那度胺和硼替佐米治疗失败后的三线及以上患者，日本于 2015 年批准其上市。百时美施贵宝旗下另一款成功的沙利度胺类似物来那度胺已占据市场主导地位，泊马度胺则被定位为后续治疗选择。III 期 OPTIMISMM 试验验证了泊马度胺联合硼替佐米及小剂量地塞米松在更早治疗线数（二线及以上）对来那度胺经治患者的疗效，推动该方案于 2019 年在欧盟和日本获批适应症扩展。美国方面，皮下注射达雷妥尤单抗联合泊马度胺及地塞米松的二线治疗方案已载入达雷妥尤单抗皮下制剂说明书。首批泊马度胺仿制药于 2024 年 8 月在欧盟上市，根据与 Reddy 博士实验室达成的和解协议，预计将于 2026 年第一季度登陆美国市场。泊马度胺在日本的市场独占权将持续至 2026 年 6 月。 2025 年 1 月，美国卫生与公众服务部（HHS）宣布将泊马度胺（Pomalyst）列入新增的 15 种医保 D 部分价格谈判药品名单。谈判价格预计将于 2027 年生效。

Thalidomide and its analogs are immunomodulators activating T cells and natural killer cells and inhibiting pro-inflammatory cytokines. These agents bind to the E3 ubiquitin ligase complex and modulate its substrate specificity. In lymphocytes, this modulation leads to degradation of Ikaros and Aiolos, two transcription factors that play an important role in MM. Bristol Myers Squibb's Revlimid (lenalidomide), a thalidomide analog, is a key therapy across patient segments, both as a monotherapy and as a backbone for combination regimens, and has broad approvals across all markets. In the US, Revlimid lost market exclusivity in March 2022; however, Bristol Myers Squibb has several settlements with generics companies that will allow Revlimid to retain a portion of its market share until volume limitations expire in January 2026. In the US, the list price for lenalidomide generics are currently at 80% of branded Revlimid for ten manufacturers while a manufacturer that started selling in 2025 has a list price that is at 53% of branded Revlimid. The volume limitations are thought to be set at a mid-single-digit percentage of total lenalidomide capsules sold (determined monthly) for each manufacturer. The volume limitations are expected to increase gradually every 12 months. In the case of Natco, the first company to launch generic lenalidomide, the volume limit reaches 33% by March 2025 while in the case of Alvogen, the volume limit is capped at a single digit percentage. Bristol Myers Squibb has settled patent litigation with several manufacturers and there are currently 11 manufacturers supplying generic lenalidomide in the US. Once the volume limitations expire, we expect there to be greater competition among the generic manufacturers. Lenalidomide generics were launched in the EU in early 2022 and entered the Japanese market in 2023. 
沙利度胺及其类似物是免疫调节剂，可激活 T 细胞和自然杀伤细胞并抑制促炎细胞因子。这些药物与 E3 泛素连接酶复合体结合并调节其底物特异性。在淋巴细胞中，这种调节会导致 Ikaros 和 Aiolos 两种转录因子的降解，这两种因子在多发性骨髓瘤中起重要作用。百时美施贵宝的来那度胺（Revlimid）作为沙利度胺类似物，既是各患者群体的关键单药疗法，也是联合方案的基石用药，已在全球所有市场获得广泛批准。在美国，Revlimid 于 2022 年 3 月失去市场独占权；但百时美施贵宝与多家仿制药企业达成协议，在 2026 年 1 月销量限制到期前，Revlimid 仍可保留部分市场份额。目前美国市场上，十家仿制药企业的来那度胺定价为品牌药 Revlimid 的 80%，而 2025 年开始销售的一家制造商定价仅为品牌药的 53%。 据认为，各生产商的销量限制将设定为每月销售来那度胺胶囊总量的个位数百分比（按月计算）。预计销量限制将每 12 个月逐步提高。对于首家推出仿制来那度胺的 Natco 公司，到 2025 年 3 月其销量上限将达到 33%，而 Alvogen 公司的销量上限则维持在个位数百分比。百时美施贵宝已与多家生产商达成专利诉讼和解，目前美国有 11 家生产商供应仿制来那度胺。一旦销量限制到期，我们预计仿制药生产商之间的竞争将加剧。仿制来那度胺于 2022 年初在欧盟上市，并于 2023 年进入日本市场。

Sanofi’s Sarclisa (isatuximab) became the second CD38-directed mAb to enter the market when the combination of Sarclisa + Pomalyst + dex received approval in the US in March 2020 for the treatment of RRMM patients who have received at least two prior therapies. European approval followed shortly after in June 2020. In March 2021 and April 2021, Sarclisa + Kyprolis + dex was approved by the FDA and EMA, respectively, as a second-line or later treatment for RRMM patients, based on the IKEMA trial. Sarclisa will compete with blockbuster Darzalex in these markets, though its second-to-market status and lack of a currently approved SC formulation will be difficult to overcome. While Sanofi declined to submit for NICE approval in the UK for this combination, it has reported PFS data from IKEMA. The Sarclisa-Kd combination reported a median PFS of 36 months compared to 19 months for Kd (HR 0.58). For comparison, in the CANDOR trial, Dara-Kd reported an HR of 0.63. The Phase III IMROZ study compared Sarclisa-VRd to VRd for the treatment of newly diagnosed MM patients not eligible for transplant. Following four 42-day cycles of Sarclisa-VRd, Sarclisa-Rd was given as maintenance therapy until disease progression. At ASCO 2024, Sanofi announced that IMROZ had met its primary endpoint of PFS (median PFS not reached vs. 54 months; HR 0.596). Based on current trends, Sanofi projects that the median PFS for the Sarclisa arm may reach approximately 90 months, which would surpass the median PFS of 62 months reported for Dara-Rd in the MAIA trial. The IMROZ regimen is approved in the US (September 2024), EU (January 2025), and Japan (February 2025). While the US and EU approvals specified approval for newly diagnosed transplant-ineligible patients, the Japanese approval was for a broader population of newly diagnosed multiple myeloma. FDA approval of a Darzalex quadruplet in the transplant-ineligible setting (based on CEPHEUS) is expected in mid-2025 marking one of the few settings were Sarclisa was approved ahead of Darzalex. Sarclisa is also being evaluated for newly diagnosed MM patients eligible for transplant. A German study (GMMG HD7) is examining the Sarclisa-VRd quadruplet (EPCD of May 2025), and at ASH 2021, Sanofi presented results from Part I of GMMG HD7, which met its primary endpoint of an improved MRD negativity rate for the Sarclisa quadruplet compared to the VRd triplet after induction therapy. Patients in the trial then underwent SCT and were randomized a second time to receive Revlimid maintenance therapy with or without Sarclisa for up to three years. At ASH 2024, Sanofi announced that the Sarclisa quadruplet arm had shown improved PFS from the first randomization regardless of the maintenance regimen (HR 0.70) with three-year PFS rate of 83% and 75% for the Sarclisa-VRd and VRd arms, respectively. A regulatory submission to EU authorities to support approval of Sarclisa-VRd as induction therapy for transplant eligible patients was submitted in January 2025. A submission to the FDA is expected in H1 2025 meaning that the Sarclisa quadruplet is positioned to be approved in the transplant-eligible setting one to two years after Dara-VRd, which was approved in the US and EU in July and October 2024, respectively. Sanofi has not provided a timeline for regulatory submissions for the maintenance setting. However, the trial has an estimated PCD of May 2025 so we are expecting PFS data after second randomization (a co-primary endpoint) this year. Approval for the maintenance setting would give Sarclisa an advantage over Darzalex which lacks suitable data for approval in this setting. IRAKLIA is a Phase III non-inferiority trial comparing a fixed dose subcutaneous formulation of Sarclisa + Pomalyst + dex to a weight-based dose of IV Sarclisa + Pomalyst + dex in RRMM. In January 2025, Sanofi announced that IRAKLIA met its co-primary endpoints of ORR and observed Sarclisa plasma concentration prior to receiving the first dose of cycle 6. Regulatory submissions to US and EU authorities supported by IRAKLIA are expected in H1 2025. Interestingly, the subcutaneous formulation of Sarclisa uses a hands-free wearable injector. A push button starts the injection and the button pops up when injection is complete retracting the needle and locking out the device. A presentation at ASCO 2025 detailed that the median infusion time was 13 minutes with 98% of infusion completed in under 20 minutes. Advantages of the wearable injector are that a nurse does not need to stay to push the injection through and with a low rate of infusion reactions (1.5% for the subcutaneous formulation compared to 25% for the IV formulation), there is the potential for at home administration. Finally, the Phase III ITHACA trial is comparing Sarclisa-Rd to Rd in patients with high-risk smoldering MM; the trial has an EPCD of October 2030. 
赛诺菲的 Sarclisa（isatuximab）成为第二个上市的 CD38 靶向单抗，其与泊马度胺+地塞米松的联合疗法于 2020 年 3 月在美国获批，用于治疗既往接受过至少两种疗法的 RRMM 患者。欧洲紧随其后于 2020 年 6 月批准该方案。基于 IKEMA 试验数据，2021 年 3 月和 4 月，Sarclisa 联合卡非佐米+地塞米松方案分别获得 FDA 和 EMA 批准作为 RRMM 患者的二线及以上治疗选择。Sarclisa 将在这些市场与重磅药物 Darzalex 展开竞争，但其作为后来者且目前缺乏获批的皮下制剂配方将面临较大挑战。虽然赛诺菲未向英国 NICE 提交该联合疗法的审批申请，但已公布了 IKEMA 试验的无进展生存期数据：Sarclisa-Kd 组中位 PFS 达 36 个月，显著优于 Kd 组的 19 个月（风险比 0.58）。作为对照，CANDOR 试验中 Dara-Kd 方案的风险比为 0.63。针对不适合移植的新诊断多发性骨髓瘤患者，III 期 IMROZ 研究正在评估 Sarclisa-VRd 方案对比 VRd 方案的疗效。 在完成四个 42 天的 Sarclisa-VRd 周期治疗后，采用 Sarclisa-Rd 作为维持疗法直至疾病进展。2024 年美国临床肿瘤学会年会上，赛诺菲宣布 IMROZ 研究已达到无进展生存期（PFS）主要终点（中位 PFS 未达到 vs. 54 个月；风险比 0.596）。根据当前趋势预测，Sarclisa 组的中位 PFS 可能达到约 90 个月，这将超越 MAIA 试验中 Dara-Rd 组报告的 62 个月中位 PFS。IMROZ 方案已在美国（2024 年 9 月）、欧盟（2025 年 1 月）和日本（2025 年 2 月）获批。虽然美欧批准明确限定用于不适合移植的新诊断患者，日本批准则覆盖更广泛的新诊断多发性骨髓瘤人群。食品药品监督管理局预计将于 2025 年年中批准 Darzalex 四联疗法用于不适合移植患者（基于 CEPHEUS 研究），这将成为少数 Sarclisa 先于 Darzalex 获批的适应症之一。Sarclisa 目前也正在针对适合移植的新诊断多发性骨髓瘤患者进行评估。 德国 GMMG HD7 研究正在评估 Sarclisa-VRd 四联疗法（2025 年 5 月 EPCD），赛诺菲在 2021 年美国血液学会年会上公布了该研究第一部分结果：与 VRd 三联疗法相比，Sarclisa 四联疗法在诱导治疗后达到了改善微小残留病阴性率的主要终点。随后试验患者接受干细胞移植，并二次随机分组接受来那度胺维持治疗（联合或不联合 Sarclisa），持续最长三年。2024 年 ASH 年会上，赛诺菲宣布无论采用何种维持方案，Sarclisa 四联疗法组从首次随机化起均显示无进展生存期改善（风险比 0.70），Sarclisa-VRd 组和 VRd 组的三年无进展生存率分别为 83%和 75%。2025 年 1 月已向欧盟监管机构提交申请，支持将 Sarclisa-VRd 批准为适合移植患者的诱导治疗方案。预计 2025 年上半年将向美国食品药品监督管理局提交申请，这意味着 Sarclisa 四联疗法有望在达雷妥尤单抗-VRd（2024 年 7 月和 10 月分别在美国和欧盟获批）之后 1-2 年内获批用于适合移植的患者群体。 赛诺菲尚未提供维持治疗适应症的监管申请时间表。不过该试验预计将在 2025 年 5 月达到主要完成日期（PCD），因此我们预计今年能获得第二次随机分组后的无进展生存期（PFS）数据（共同主要终点）。维持治疗适应症的获批将使 Sarclisa 相比 Darzalex 更具优势，后者缺乏该适应症获批所需的充分数据。 IRAKLIA 是一项 III 期非劣效性试验，比较了固定剂量皮下注射剂型 Sarclisa 联合泊马度胺/地塞米松与基于体重的静脉注射 Sarclisa 联合方案在复发难治性多发性骨髓瘤（RRMM）中的疗效。2025 年 1 月，赛诺菲宣布 IRAKLIA 达到了客观缓解率（ORR）和第六周期首次给药前观察到的 Sarclisa 血浆浓度这两个共同主要终点。基于该试验结果向美国和欧盟监管机构提交的申请预计将在 2025 年上半年进行。 值得注意的是，Sarclisa 皮下制剂采用了免手持穿戴式注射器。通过按压按钮启动注射，注射完成后按钮会自动弹起，同时收回针头并锁定装置。2025 年美国临床肿瘤学会（ASCO）上公布的数据显示，其中位输注时间为 13 分钟，98%的输注可在 20 分钟内完成。 穿戴式注射器的优势在于无需护士持续操作推注，且输液反应率较低（皮下制剂为 1.5%，而静脉制剂高达 25%），这使得居家给药成为可能。最后，III 期 ITHACA 试验正在将 Sarclisa-Rd 方案与 Rd 方案用于高风险冒烟型多发性骨髓瘤患者的对比研究，该试验预计主要终点完成日期为 2030 年 10 月。

Despite the restrictions imposed on the prescription of Thalomid (thalidomide) due to its toxicity profile, it remains popular in more cost-conservative markets. The drug’s sales have been gradually decreasing since 2008, coinciding with the approval of Velcade and continued growth of Bristol Myers Squibb’s more recent thalidomide analogs Revlimid and Pomalyst. Moreover, Thalomid’s position in the MM market was further challenged by the launch of generics in the EU in 2022. 
尽管沙利度胺（Thalomid）因其毒性特征受到处方限制，但在成本敏感型市场仍保持一定需求。该药物销售额自 2008 年起持续下滑，恰逢万珂（Velcade）获批上市，以及百时美施贵宝新一代沙利度胺类似物来那度胺（Revlimid）和泊马度胺（Pomalyst）的持续增长。此外，2022 年欧盟市场仿制药的上市进一步冲击了沙利度胺在多发性骨髓瘤治疗领域的市场地位。

Johnson & Johnson’s Talvey (talquetamab) is a bispecific antibody administered subcutaneously targeting CD3 and a novel target, GPRC5D. Talvey has received PRIME designation from the EMA and breakthrough therapy designation from the FDA. In August 2023, Talvey received conditional approval in the US and EU for MM patients previously treated with a PI, an IMiD, and an anti-CD38 antibody. The US approval was for fifth-line or later patients, while the EU approval was for fourth-line or later patients. Talvey is currently under regulatory review in Japan for RRMM. Due to Talvey’s oral toxicity (see below) it will likely be used following anti-BCMA therapy although it is also seeing some use as bridging therapy prior to CAR-T administration. Both a weekly dose of 0.4mg/kg and an every-other-week dose of 0.8mg/kg were approved. The step-up dosing schedule requires three doses (on days one, four, and seven) prior to starting weekly dosing, and four doses (on days one, four, seven, and 10) prior to starting every-other-week dosing. Talvey has a black box warning for CRS and neurological toxicity and is only available through a REMS program. Due to this toxicity risk, patients should be hospitalized for 48 hours after administration of each dose in the step-up dosing schedule. The FDA label includes pivotal data from MonumenTAL-1, a Phase I/II trial enrolling fourth-line or later patients. The weekly dosing regimen reported a 73% ORR and a 35% ≥CR rate (n=100), while the every-other-week dosing regimen reported a 74% ORR and a 33% ≥CR rate (n=87). With a median follow-up of 13.8 months and 5.9 months, respectively, the median duration of response was 9.5 months and not reached, respectively. Updated data presented at ASCO 2025 reported that with a median follow-up of 38 months and 31 months, respectively, the median duration of response was 9.5 months (n=143) and 17.5 months (n=154), respectively, suggesting that the every-other week regimen has better durability. The every-other week regimen also showed improved PFS (7.5 months vs 11.2 months, respectively). According to the FDA label, CRS occurred in 76% of patients and was mostly grade 1/2. Neurological adverse events occurred in 55% of patients with grade 3/4 events occurring in 6% of patients. Talvey is associated with GPRC5D-related oral toxicity including dysgeusia (altered sense of taste). Oral toxicity was reported in 80% of patients with grade 3 events occurring in 2.1% of patients. The oral toxicity can be difficult to manage and did not resolve in 65% of patients. A confirmatory Phase III trial, MonumenTAL-3, is evaluating Talvey + Darzalex +/- Pomalyst. The comparator is Darzalex + Pomalyst + dex, and the trial is enrolling second-line or later patients. MonumenTAL-3 has an EPCD of February 2026. Another Phase III trial, MonumentTAL-6, is enrolling relapsed/refractory patients who were treated with an anti-CD38 antibody in the first line, and is evaluating Talvey combined with another bispecific antibody, Tecvayli. The comparator is Elo-Pd or Pd, and the trial has an EPCD of April 2026. A Phase II trial evaluating this combination, RedirecTT-1, has reported strong activity in patients with extramedullary disease. Finally, MajesTEC-7 is evaluating Talvey + Darzalex + lenalidomide. MajesTEC-7 is enrolling newly diagnosed patients ineligible for transplant, and has an EPCD of April 2031. The comparator is Dara-Rd. 
强生公司的 Talvey（talquetamab）是一种靶向 CD3 和新型靶点 GPRC5D 的双特异性抗体，采用皮下给药方式。该药物已获得欧洲药品管理局（EMA）的 PRIME 资格认定以及美国食品药品监督管理局的突破性疗法认定。2023 年 8 月，Talvey 在美国和欧盟获得有条件批准，用于既往接受过蛋白酶体抑制剂（PI）、免疫调节药物（IMiD）和抗 CD38 抗体治疗的多发性骨髓瘤患者。美国批准其用于五线或后线治疗，而欧盟批准用于四线或后线治疗。目前 Talvey 正在日本接受针对复发难治性多发性骨髓瘤（RRMM）的监管审查。由于 Talvey 存在口腔毒性（见下文），尽管也观察到其作为 CAR-T 治疗前桥接疗法的部分应用，但更可能用于抗 BCMA 疗法之后。每周 0.4 毫克/千克和隔周 0.8 毫克/千克两种剂量方案均获批准。阶梯式给药方案要求在开始每周给药前进行三次剂量递增（第 1、4、7 天），在开始隔周给药前进行四次剂量递增（第 1、4、7、10 天）。Talvey 附有关于细胞因子释放综合征（CRS）和神经毒性的黑框警告，且仅通过风险评估与减灾策略（REMS）计划提供。 鉴于这种毒性风险，患者应在递增给药方案中每剂给药后住院观察 48 小时。食品药品监督管理局标签包含了来自 MonumenTAL-1 研究的关键数据，这项 I/II 期试验入组了四线及以上治疗患者。每周给药方案报告的总缓解率为 73%、完全缓解率≥35%（n=100），而隔周给药方案的总缓解率为 74%、完全缓解率≥33%（n=87）。中位随访时间分别为 13.8 个月和 5.9 个月时，两组的中位缓解持续时间分别为 9.5 个月和未达到。2025 年美国临床肿瘤学会年会公布的最新数据显示，中位随访 38 个月和 31 个月时，两组的中位缓解持续时间分别为 9.5 个月（n=143）和 17.5 个月（n=154），表明隔周给药方案具有更持久的疗效。隔周给药方案还显示出更优的无进展生存期（分别为 7.5 个月 vs 11.2 个月）。根据食品药品监督管理局标签，76%的患者出现细胞因子释放综合征，且多为 1/2 级。55%的患者出现神经系统不良事件，其中 3/4 级事件发生率为 6%。 Talvey 与 GPRC5D 相关口腔毒性相关，包括味觉障碍（味觉改变）。80%的患者报告了口腔毒性，其中 2.1%的患者发生 3 级事件。口腔毒性可能难以控制，且 65%的患者症状未缓解。确证性 III 期试验 MonumenTAL-3 正在评估 Talvey 联合 Darzalex 加减 Pomalyst 的疗效，对照组为 Darzalex+Pomalyst+地塞米松方案，该试验招募二线及以上患者，预计主要终点完成日期（EPCD）为 2026 年 2 月。另一项 III 期试验 MonumentTAL-6 针对一线接受过抗 CD38 抗体治疗的复发/难治性患者，评估 Talvey 与另一种双特异性抗体 Tecvayli 的联合疗法，对照组采用 Elo-Pd 或 Pd 方案，EPCD 为 2026 年 4 月。评估该联合疗法的 II 期试验 RedirecTT-1 已报告在髓外病变患者中显示出强劲活性。最后，MajesTEC-7 研究正在评估 Talvey+Darzalex+来那度胺方案，针对不适合移植的新诊断患者，对照组采用 Dara-Rd 方案，EPCD 为 2031 年 4 月。

Johnson & Johnson’s Tecvayli (teclistamab) is a BCMA x CD3 bispecific antibody administered subcutaneously. It is the first bispecific antibody approved for MM, with approvals in the US (fifth-line or later MM), EU (fourth-line or later MM) and Japan (RRMM not amenable to standard treatment) supported by MajesTEC-1, a Phase I/II trial. Tecvayli has PRIME designation from the EMA and breakthrough therapy designation from the FDA. Both the US and EU labels specify patients previously treated with an IMiD, a PI, and an anti-CD38 antibody. The FDA label has a black box warning for CRS and neurotoxicity, and in the US, prescribers, pharmacies, and healthcare settings must be certified through a REMS program. Due to this toxicity risk, patients should be hospitalized for 48 hours after all three step-up doses, which are given on days one, four, and seven. In terms of efficacy, the FDA label reports a 62% ORR and a 28% ≥CR rate, which are similar to rates reported for Abecma (72% ORR and 28% sCR), but lower than what was reported for Carvykti (98% ORR and 78% sCR). While Tecvayli does not deliver the same efficacy as Carvykti, it does offer the convenience of an off-the-shelf product delivered subcutaneously and which has the potential for combinations at earlier lines of therapy. At ASCO 2024, Tecvayli reported a 46% ≥CR rate after extended follow-up, indicating that responses deepen with time. Median duration of response and median PFS were 24 months and 11.4 months, respectively. In terms of safety, the FDA label reports high rates of grade 3/4 neutropenia (56%) and infections (35%) with Tecvayli, while CRS was seen in 72% of patients and was almost exclusively grade 1/2; 97% of events were confined to step-up doses and cycle 1. The rate of grade 5 infection was 4% and the overall incidence of neurotoxicity events was 57%, with grade 3 or 4 neurotoxicity occurring in 2.4% of patients. ICANS occurred in 6% of patients. Overall, Tecvayli is more tolerable than CAR-T therapy, with both Abecma and Carvykti reporting higher rates of CRS and neurotoxicity, especially grade ≥3 events. However, the high rate of infections remains a concern with Tecvayli, and its EMA approval in August 2023, as well as an FDA supplementary approval in February 2024, include a reduced dosing schedule of every two weeks for patients who have achieved a ≥CR for six months or longer, which is expected to lower the high rate of grade ≥3 infections.  
强生公司的 Tecvayli（teclistamab）是一种 BCMA x CD3 双特异性抗体，采用皮下给药方式。作为首个获批用于多发性骨髓瘤的双抗药物，其在美国（五线或后线治疗）、欧盟（四线或后线治疗）和日本（不适合标准治疗的复发难治性多发性骨髓瘤）的上市许可均基于 I/II 期 MajesTEC-1 临床试验数据。该药物获得了欧洲药品管理局的 PRIME 优先药物资格以及美国食品药品监督管理局的突破性疗法认定。美欧两地说明书均明确要求患者既往接受过免疫调节剂、蛋白酶体抑制剂和抗 CD38 抗体治疗。FDA 说明书包含关于细胞因子释放综合征和神经毒性的黑框警告，在美国处方机构、药房及医疗机构需通过 REMS 项目认证。鉴于毒性风险，患者在完成第 1、4、7 天三次阶梯剂量注射后需住院观察 48 小时。疗效方面，FDA 说明书显示总体缓解率为 62%、完全缓解率 28%，与 Abecma（72%ORR，28%sCR）相近，但低于 Carvykti（98%ORR，78%sCR）报告数据。 虽然 Tecvayli 的疗效不及 Carvykti，但它具备现成制剂、皮下给药的优势，并有望用于更早治疗阶段的联合疗法。在 2024 年美国临床肿瘤学会年会上，Tecvayli 的长期随访数据显示其完全缓解率（≥CR）达 46%，表明疗效随时间推移而增强。中位缓解持续时间和中位无进展生存期分别为 24 个月和 11.4 个月。安全性方面，食品药品监督管理局标签显示 Tecvayli 导致 3/4 级中性粒细胞减少症（56%）和感染（35%）发生率较高，72%患者出现细胞因子释放综合征且基本为 1/2 级；97%不良事件仅发生于阶梯递增给药阶段和首个周期。5 级感染发生率为 4%，神经毒性事件总发生率为 57%，其中 3/4 级神经毒性见于 2.4%患者。6%患者出现免疫效应细胞相关神经毒性综合征。总体而言，Tecvayli 比 CAR-T 疗法耐受性更佳——Abecma 和 Carvykti 报告的细胞因子释放综合征与神经毒性发生率更高，尤其是≥3 级事件。 然而，Tecvayli 的高感染率仍令人担忧。该药物于 2023 年 8 月获得欧洲药品管理局批准，并于 2024 年 2 月获得美国食品药品监督管理局的补充批准，针对达到≥完全缓解（CR）状态达六个月或更长时间的患者，将给药方案调整为每两周一次，此举有望降低≥3 级感染的高发生率。

The Phase III MajesTEC-3 trial compares Tecvayli + Darzalex versus a Darzalex triplet with dex and either Pomalyst or bortezomib. MajesTEC-3 is enrolling second- to fourth-line patients and has an EPCD of August 2025. Another Phase III trial in the same setting, MajesTEC-9, is comparing Tecvayli monotherapy to a Pomalyst + bortezomib + dex triplet or a Kyprolis + dex doublet, and has an EPCD of February 2026. While MajesTEC-3 is enrolling patients previously treated with lenalidomide and a PI, MajesTEC-9 is enrolling patients previously treated with lenalidomide and an anti-CD38 antibody. Another Phase III trial, MonumentTAL-6, is enrolling relapsed/refractory patients who were treated with an anti-CD38 antibody in the first line, and is evaluating Tecvayli + Talvey. The comparator is Elo-Pd or Pd, and the trial has an EPCD of April 2026. MajesTEC-7 is enrolling newly diagnosed transplant-ineligible patients and has an EPCD of April 2031. MajesTEC-7 is an add-on trial comparing Tecvayli + Darzalex + lenalidomide to Darzalex + lenalidomide + dex. Finally, MajesTEC-4 is a European Myeloma Network-sponsored study comparing Tecvayli + lenalidomide versus lenalidomide alone as maintenance therapy following ASCT. The EPCD for MajesTEC-4 is April 2028. 
三期 MajesTEC-3 试验将 Tecvayli 联合 Darzalex 方案与 Darzalex 三联疗法（含地塞米松及泊马度胺或硼替佐米）进行对比。该试验正在招募二线至四线患者，预计主要完成日期为 2025 年 8 月。另一项同领域三期试验 MajesTEC-9，正在比较 Tecvayli 单药治疗与泊马度胺+硼替佐米+地塞米松三联方案或卡非佐米+地塞米松双联方案，主要完成日期设定为 2026 年 2 月。MajesTEC-3 入组的是既往接受过来那度胺和蛋白酶体抑制剂治疗的患者，而 MajesTEC-9 则招募曾使用过来那度胺和抗 CD38 抗体的患者。 三期试验 MonumentTAL-6 正在招募一线接受过抗 CD38 抗体治疗的复发/难治性患者，评估 Tecvayli 联合 Talvey 的疗效。对照组采用 Elo-Pd 或 Pd 方案，试验主要完成日期为 2026 年 4 月。MajesTEC-7 试验针对新诊断不适合移植的患者，预计主要完成日期为 2031 年 4 月。该附加试验比较 Tecvayli+Darzalex+来那度胺方案与 Darzalex+来那度胺+地塞米松方案的疗效差异。 最后，MajesTEC-4 是一项由欧洲骨髓瘤网络赞助的研究，比较了 Tecvayli 联合来那度胺与单用来那度胺作为自体干细胞移植（ASCT）后维持治疗的疗效。MajesTEC-4 的预计初步完成日期（EPCD）为 2028 年 4 月。

Takeda’s Velcade (bortezomib), a PI, is a standard-of-care backbone of MM treatment and is now genericized in the US, EU, and Japan. Bortezomib is currently approved in the US and EU for use across all lines of MM therapy, and for newly diagnosed ASCT-ineligible MM and RRMM in Japan. The introduction of SC bortezomib in early 2012 reinforced the drug’s position in the MM market. In May 2022, Fresenius Kabi and Aurobindo announced US launches of generic bortezomib for subcutaneous use. In the EU, the first generic bortezomib (formulated as a ready-to-use solution) was launched by Stada in 2019, while Fresenius Kabi has launched a powder formulation. Both formulations can be injected intravenously or subcutaneously. Bortezomib generics were launched in Japan in Q1 2022. 
武田制药的万珂（硼替佐米）作为一种蛋白酶体抑制剂，已成为多发性骨髓瘤治疗的标准基础用药，目前在美国、欧盟和日本已有多款仿制药上市。硼替佐米目前在美国和欧盟获批用于多发性骨髓瘤全线治疗，在日本则获批用于新诊断不适合自体干细胞移植的多发性骨髓瘤及复发难治性多发性骨髓瘤。2012 年初皮下注射剂型硼替佐米的推出巩固了该药物在多发性骨髓瘤市场的地位。2022 年 5 月，费森尤斯卡比和奥罗宾多宣布在美国推出皮下注射用硼替佐米仿制药。在欧盟，首批即用型溶液剂仿制药由 Stada 于 2019 年上市，而费森尤斯卡比则推出了冻干粉针剂型。两种剂型均可通过静脉或皮下注射给药。日本市场于 2022 年第一季度迎来硼替佐米仿制药上市。

Karyopharm’s Xpovio (selinexor), an oral inhibitor of the nuclear export protein XPO1, represents a novel mechanism for MM and although the original twice weekly dosing regimen was not well tolerated (nausea and fatigue was observed in 70% and 60% of patients, respectively), the switch to once weekly dosing resulted in improved tolerability (nausea and fatigue observed in 40% and 45% of patients, respectively) without sacrificing efficacy. As such, Xpovio has found use for patients refractory to multiple drugs as well as for bridging therapy to CAR-T. Based on the Phase IIb STORM trial (25% ORR; 3.8-month duration of response), Xpovio + dex received accelerated approval in the US (in 2019) and EU (in 2021) for the treatment of patients with fifth-line or later MM whose disease is refractory to two PIs, two IMiDs, and an anti-CD38 mAb. While the target patient population for the doublet is limited, Xpovio is now also approved in the US (since December 2020) and EU (since July 2022) as part of a triple combination with bortezomib and dex for second- to fourth-line MM. Both the Xpovio doublet and triplet received positive NICE recommendations in 2024. The US and EU approvals, which increase Xpovio’s commercial potential, were supported by BOSTON, a Phase III trial that reported PFS of 13.9 months for the Xpovio triplet versus 9.5 months for the doublet comparator. Interestingly, the Xpovio arm used a modified bortezomib dose (100mg once a week versus the approved dose of 80mg twice a week), which resulted in a significantly lower rate of neuropathic adverse events. Xpovio was also used at a dose of 100mg once weekly (median dosage was 80mg once weekly after dose reductions to mitigate adverse events) compared to 80mg twice weekly in STORM. Following this label expansion, Karyopharm reported the strongest sales growth in third-line MM. EMN29 is a Phase III trial evaluating the all-oral triplet of Xpovio + Pomalyst + dex for second-line or later MM. The trial is evaluating even lower doses of Xpovio, 40mg or 60mg once weekly, and the comparator is Empliciti + Pomalyst + dex. The trial has an EPCD of March 2026. 
Karyopharm 公司的 Xpovio（selinexor）是一种核输出蛋白 XPO1 的口服抑制剂，为多发性骨髓瘤（MM）提供了创新治疗机制。虽然最初每周两次的给药方案耐受性不佳（分别有 70%和 60%患者出现恶心和疲劳症状），但调整为每周一次给药后耐受性显著改善（恶心和疲劳发生率分别降至 40%和 45%），且未影响疗效。因此，Xpovio 现被用于对多种药物难治的患者以及作为 CAR-T 治疗的桥接方案。基于 IIb 期 STORM 试验（客观缓解率 25%；中位缓解持续时间 3.8 个月），Xpovio 联合地塞米松于 2019 年在美国、2021 年在欧盟获得加速批准，用于治疗对两种蛋白酶体抑制剂、两种免疫调节剂和一种抗 CD38 单抗耐药的五线及以上 MM 患者。虽然该双药方案的目标人群有限，但 Xpovio 还于 2020 年 12 月在美国、2022 年 7 月在欧盟获批作为硼替佐米和地塞米松三联方案的一部分，用于二至四线 MM 治疗。2024 年，Xpovio 双药和三联方案均获得英国 NICE 的积极推荐。 美国和欧盟的批准提升了 Xpovio 的商业潜力，这一决定基于 BOSTON 三期临床试验数据——Xpovio 三联疗法组的中位无进展生存期为 13.9 个月，而双联对照组为 9.5 个月。值得注意的是，Xpovio 组采用了调整后的硼替佐米剂量（每周一次 100mg，而非获批的每周两次 80mg 方案），这使得神经病变不良事件发生率显著降低。与 STORM 研究中每周两次 80mg 的用法不同，该方案中 Xpovio 采用每周一次 100mg 的剂量（为减轻不良事件，剂量调整后的中位给药量为每周一次 80mg）。随着适应症扩展，Karyopharm 报告该药物在三线多发性骨髓瘤治疗中实现了最强劲的销售增长。EMN29 三期试验正在评估全口服三联方案 Xpovio+泊马度胺+地塞米松用于二线及以上多发性骨髓瘤的疗效，试验探索更低剂量的 Xpovio（每周一次 40mg 或 60mg），对照组采用埃罗妥珠单抗+泊马度胺+地塞米松方案，预计主要终点完成时间为 2026 年 3 月。

AbbVie’s etentamig is positioned to be the fourth bispecific antibody targeting BCMA and CD3 to enter the market. etentamig is engineered for high-affinity binding to BCMA (due to a bivalent BCMA binder), low-affinity binding to a unique CD3 epitope on T cells (for improved safety), and a long half-life (two to three weeks) due to an IgG4 backbone. Although it is delivered intravenously with dex premedication, etentamig offers a simplified dosing regimen with monthly dosing after either no step up dose or a single step up dose. This compares to other bispecifics which require multiple step up doses and weekly or every two week dosing. At ASCO 2024, AbbVie reported results for a Phase I trial in fourth-line or later patients where 60mg etentamig given every four weeks (with no step dosing) reported an ORR and CR/sCR rate of 65% and 50%, respectively (n=21). CRS was reported in 43% of patients (grade 1 and 2 only), ICANS was reported in 5% of patients (all grade 2), and grade 3/4 infections occurred in 10% of patients. Results from a second Phase I trial were presented at ASH 2024. That trial evaluated a 2 mg step dose on day 1 followed by 60 mg on day 4 then proceeded to monthly dosing. The 2-mg step-up dose-expansion cohort (n=23) reported an ORR of 65% and a ≥VGPR rate of 39%. The low rate of CRS and grade 3/4 infections as well as the monthly dosing regimen could help differentiate ententamig from other anti-BCMA bispecific antibodies. A pivotal Phase III trial, CERVINO, is comparing etentamig to standard-of-care therapies (Kd, Elo-PD, or SVd) in third-line or later patients. Although the trial will evaluate monthly dosing, it is not yet clear whether or not it will include a single step-up dose or no step-up dose. The trial has an EPCD of December 2027, positioning ententamig for potential regulatory submission by 2028. A Phase III combination trial in second-line or later disease is expected to initiate in 2026 while a subcutaneous formulation is being evaluated in a Phase Ib trial. 
艾伯维的 etentamib 有望成为第四款靶向 BCMA 和 CD3 的双特异性抗体药物。该药物采用 IgG4 骨架结构设计，具有以下特性：通过双价 BCMA 结合域实现高亲和力结合；对 T 细胞独特 CD3 表位采用低亲和力结合（提升安全性）；半衰期长达两到三周。虽然需要地塞米松预处理后静脉给药，但 etentamib 的给药方案更为简化——无需阶梯剂量或仅需单次阶梯剂量后，即可转为每月给药一次。相比之下，其他双抗药物往往需要多次阶梯剂量调整，并需每周或每两周给药一次。在 2024 年美国临床肿瘤学会年会上，艾伯维公布了针对四线及以上患者的 I 期试验数据：每四周给药 60mg（无阶梯剂量）时，客观缓解率和完全缓解/严格完全缓解率分别达到 65%和 50%（n=21）。43%患者出现细胞因子释放综合征（均为 1-2 级），5%患者出现免疫效应细胞相关神经毒性综合征（均为 2 级），10%患者发生 3/4 级感染。2024 年美国血液学会年会上还公布了另一项 I 期试验结果。 该试验评估了第 1 天使用 2 毫克阶梯剂量，第 4 天使用 60 毫克，随后转为每月给药方案。2 毫克阶梯剂量扩展队列（n=23）报告的总缓解率（ORR）为 65%，≥非常好的部分缓解率（VGPR）达 39%。较低的细胞因子释放综合征（CRS）发生率和 3/4 级感染率，以及每月给药方案，可能有助于将 ententamig 与其他抗 BCMA 双特异性抗体区分开来。关键性 III 期试验 CERVINO 正在三线或后线患者中比较 ententamig 与标准治疗方案（Kd、Elo-PD 或 SVd）的疗效。虽然该试验将评估每月给药方案，但目前尚不清楚是否包含单次阶梯剂量或不使用阶梯剂量。该试验预计在 2027 年 12 月达到主要终点（EPCD），有望使 ententamig 在 2028 年前提交监管申请。针对二线或后线疾病的 III 期联合治疗试验预计将于 2026 年启动，而皮下制剂目前正在 Ib 期试验中进行评估。

Arcellx and Gilead’s anito-cel is positioned to be the third BCMA CAR-T to enter the market, but lags significantly behind its competitors in development. While Abecma and Carvykti were first approved in 2021 and 2022, respectively, anito-cel only initiated its pivotal Phase II trial, iMMagine-1, in December 2022, and a commercial launch is not expected until 2026. Instead of a single-chain variable fragment (scFv) derived from antibodies, anito-cel uses a synthetic protein as the BCMA binder in the CAR. This binder is engineered to reduce the risk of immunogenicity from host antibodies and T cells. Compared to an scFv, it is also smaller, non-glycosylated, and has no disulfide bonds. These attributes are thought to increase its stability on the CAR-T cell and increase the CAR-T cell yield. Updated data presented at ASCO 2025 from the pivotal iMMagine-1 trial (n=117) included an ORR of 97% with a ≥CR rate of 68%. In the safety evaluable population (n=98), 86% of patients had grade ≤1 CRS and while ICANS was reported in 9% of patients, there was only one case of grade 3 ICANS and no cases of delayed neurotoxicity. These are very promising results, and if anito-cel can deliver efficacy similar to Carvykti with a safety profile similar to Abecma, it would help overcome its third-to-market positioning. The iMMagine-1 trial is enrolling fourth-line or later patients and a BLA submission is expected in H2 2025. A confirmatory Phase III trial, iMMagine-3, is enrolling second-line or later patients, was initiated H2 2024, and has an EPCD of July 2028. The comparator is physician’s choice of the following standards of care: PVd, Dara-Pd, Dara-Kd, or Kd. The Phase III trial will enroll patients exposed to an anti-CD38 antibody and an IMiD, but unlike CARTITUDE-4, will not require that patients have prior exposure to a PI and be refractory to lenalidomide, which may allow anito-cel to be used in a broader population of relapsed/refractory patients than Carvykti. 
Arcellx 与吉利德合作的 anito-cel 有望成为第三款上市的 BCMA CAR-T 疗法，但研发进度显著落后于竞争对手。Abecma 和 Carvykti 分别于 2021 年和 2022 年率先获批，而 anito-cel 直到 2022 年 12 月才启动关键 II 期试验 iMMagine-1，预计 2026 年才能实现商业化。与传统采用抗体衍生单链可变片段(scFv)不同，anito-cel 使用合成蛋白作为 CAR 中的 BCMA 结合域。这种工程化结合域旨在降低宿主抗体和 T 细胞引发免疫原性的风险，其体积更小、无糖基化修饰且不含二硫键。这些特性被认为能增强 CAR-T 细胞稳定性并提高产量。2025 年 ASCO 大会公布的 iMMagine-1 关键试验更新数据（n=117）显示，总缓解率达 97%，完全缓解率≥68%。在安全性可评估人群（n=98）中，86%患者仅出现≤1 级细胞因子释放综合征，9%患者报告有神经毒性，其中仅 1 例为 3 级神经毒性且未出现延迟性神经毒性病例。 这些结果非常令人鼓舞，如果 anito-cel 能实现与 Carvykti 相当的疗效，同时保持与 Abecma 相似的安全性，将有助于克服其作为市场第三款产品的定位。iMMagine-1 试验正在招募四线或更后线治疗患者，预计 2025 年下半年提交生物制品许可申请。确证性 III 期试验 iMMagine-3 于 2024 年下半年启动，正在招募二线或更后线治疗患者，主要终点完成日期为 2028 年 7 月。对照组采用内科医生选择的以下标准治疗方案：PVd、Dara-Pd、Dara-Kd 或 Kd。该 III 期试验将招募接受过抗 CD38 抗体和免疫调节剂治疗的患者，但与 CARTITUDE-4 试验不同，不要求患者既往接受过蛋白酶体抑制剂治疗且对来那度胺耐药，这可能使 anito-cel 比特瑞莎（Carvykti）适用于更广泛的复发/难治性患者群体。

Bristol Myers Squibb’s BMS-986393 (arlocabtogene autoleucel) is a potentially first-in-class GPRC5D CAR-T product. Updated Phase I results presented at ASH 2024 reported an ORR of 87% and a ≥CR rate of 53% in fourth-line or later patients (n=79). The median duration of response was 18.0 months while the median PFS was 18.3 months. ORR was not notably impacted by exposure to previous BCMA-targeted therapy (previous CAR-T therapy was permitted). In the 49% of patients with such exposure (n=38), the ORR was 79% compared to 95% in patients without such exposure (n=41). Furthermore, in patients who were refractory to previous BCMA-targeted therapy (n=16), the ORR was still high at 81%. This suggests that BMS-986393 could be sequenced after BCMA-targeted therapy. With regards to safety, only 12% of patients received IVIG and yet the incidence of grade 3/4 infections, which are an issue with the BCMA targeted therapies, remained low (19% in all patients, 12% in patients treated with the RP2D). There were also no atypical or opportunistic infections. While there were no cases of parkinsonism, Gullain-Barré syndrome or cranial nerve palsy, there were other forms of non-ICANS neurotoxicity at the 150-450 x 106 dose level such as dizziness, ataxia, neurotoxicity, dysarthia and/or nystagmus which had a median time to onset of 30.5 days. These events showed some signs of reversibility and occurred in 12% of patients with 7% of patients having a grade 3 event (none were grade 4/5). ICANS occurred in 10% of patients with 2.5% of patients having a grade 3 event. GPR5CD is expressed on hard keratinized tissues and leads to on-target/off-tumor toxicity such as skin, nail and/or oral events. However, these events appear more benign with BMS-986393 than with Talvey likely due to the one dose nature of BMS-986393. With BMS-986393, these events were all grade 1/2 with no grade 3/4 events. Skin, nail and oral events occurred in 30%, 19% and 32% of patients and were resolved in 88%, 75% and 70% of cases, respectively with a median time to resolution of 26, 98 and 66 days, respectively. With Talvey, skin, nail and oral events occurred in 56-71%, 53-54% and 48-50% of patients, respectively. Furthermore, management of these toxicities involves withholding or discontinuing Talvey depending on the severity. With BMS-986393, weight loss was reported in 6% of patients compared to 60% of patients treated with Talvey. Overall, the CR rate for BMS-986393 was lower than what was reported for Carvykti and anito-cel, but its activity in BCMA-exposed patients suggests that it may well be suited for patients who have progressed after an anti-BCMA agent. QUINTESSENTIAL, a pivotal Phase II trial, is enrolling fourth-line or later patients previously exposed to at least four classes of MM treatments, namely an IMiD, a PI, an anti-CD38 antibody, and an anti-BCMA therapy. The trial has an EPCD of June 2027. A confirmatory Phase III trial, QUINTESSENTIAL-2 was initiated in February 2025 and has an EPCD of December 2027. The trial is comparing BMS-986393 to standard regimens (Dara-Pd or Kd) in lenalidomide refractory, second-line or later patients. 
百时美施贵宝的 BMS-986393（arlocabtogene autoleucel）是一款潜在同类首创的 GPRC5D CAR-T 产品。ASH 2024 年会上公布的最新 I 期数据显示，在四线或后线治疗患者（n=79）中总缓解率达 87%，完全缓解率≥53%。中位缓解持续时间为 18.0 个月，中位无进展生存期为 18.3 个月。既往接受过 BCMA 靶向治疗（允许曾接受 CAR-T 治疗）对总缓解率未产生显著影响——在 49%具有此类治疗史的患者（n=38）中，总缓解率为 79%，而无治疗史患者（n=41）达 95%。此外，在既往对 BCMA 靶向治疗难治的患者（n=16）中，总缓解率仍高达 81%。这表明 BMS-986393 可作为 BCMA 靶向治疗后的序贯疗法。安全性方面，仅 12%患者接受静脉免疫球蛋白治疗，且 3/4 级感染发生率（这是 BCMA 靶向疗法的常见问题）维持在较低水平（全人群 19%，RP2D 剂量组 12%），未出现非典型或机会性感染。 虽然未出现帕金森综合征、格林-巴利综合征或脑神经麻痹病例，但在 150-450×10⁶剂量水平下观察到了其他形式的非 ICANS 神经毒性反应，包括头晕、共济失调、神经毒性、构音障碍和/或眼球震颤，其中位发病时间为 30.5 天。这些事件显示出一定可逆性体征，发生在 12%的患者中，其中 7%患者出现 3 级事件（无 4/5 级事件）。ICANS 发生率为 10%，其中 2.5%患者出现 3 级事件。GPR5CD 在角质化硬组织中表达，会导致皮肤、指甲和/或口腔等靶向/脱瘤毒性。不过相较于 Talvey，BMS-986393 的这些事件表现更为良性，可能因其单次给药特性。使用 BMS-986393 时，所有事件均为 1/2 级，无 3/4 级事件。皮肤、指甲和口腔事件发生率分别为 30%、19%和 32%，缓解率分别达 88%、75%和 70%，中位缓解时间依次为 26 天、98 天和 66 天。而 Talvey 组的皮肤、指甲和口腔事件发生率分别为 56-71%、53-54%和 48-50%。 此外，根据严重程度的不同，处理这些毒副作用可能需要暂停或终止 Talvey 的使用。使用 BMS-986393 的患者中，有 6%报告了体重减轻，而使用 Talvey 的患者中这一比例为 60%。总体而言，BMS-986393 的完全缓解率低于 Carvykti 和 anito-cel 的报告数据，但其在曾接受过 BCMA 靶向治疗的患者中显示出的活性表明，该药物可能非常适合抗 BCMA 药物治疗后病情进展的患者。关键性 II 期试验 QUINTESSENTIAL 正在招募既往接受过至少四类多发性骨髓瘤治疗（即免疫调节剂、蛋白酶体抑制剂、抗 CD38 抗体和抗 BCMA 疗法）的四线或后线患者。该试验预计于 2027 年 6 月完成主要终点评估。验证性 III 期试验 QUINTESSENTIAL-2 于 2025 年 2 月启动，预计于 2027 年 12 月完成主要终点评估。该试验在来那度胺难治性二线或后线患者中比较 BMS-986393 与标准治疗方案（Dara-Pd 或 Kd）的疗效。

Iberdomide is a next-generation IMiD being developed by Bristol Myers Squibb as a follow-on to Revlimid which is associated with secondary malignacies. Iberdomide binds the E3 ligase cereblon with higher affinity than Revlimid and Pomalyst, with preclinical data showing that it is active in MM cells resistant to other IMiDs due to low cereblon expression. In a Phase I/II trial, a dose expansion cohort evaluating iberdomide + dex at the recommended Phase II dose reported an ORR of 26% in 107 triple-refractory fourth-line or later patients. The trial also evaluated iberdomide triplets containing either Darzalex + dex for third-line or later patients (n=29) or bortezomib + dex for second-line or later patients (n=24), and reported ORRs of 41% and 58%, respectively. A Phase III trial (EXCALIBER-RRMM) is comparing iberdomide + Darzalex + dex versus Darzalex + bortezomib + dex in second-line and third-line MM patients with a data read-out expected in 2025. A second Phase III trial, EXCALIBER-Maintenance, is comparing iberdomide to lenalidomide in the post-transplant maintenance setting. EXCALIBER-RRMM and EXCALIBER-Maintenance have EPCDs of March 2026 and March 2029, respectively.  
伊伯度胺是百时美施贵宝正在研发的新一代免疫调节药物（IMiD），作为来那度胺的后续产品，后者与继发性恶性肿瘤相关。伊伯度胺与 E3 泛素连接酶 cereblon 的结合亲和力高于来那度胺和泊马度胺，临床前数据显示，该药物对因 cereblon 低表达而对其他 IMiDs 耐药的骨髓瘤细胞具有活性。在一项 I/II 期试验中，采用 II 期推荐剂量（伊伯度胺+地塞米松）的剂量扩展队列在 107 例三重难治性四线或后线患者中报告了 26%的总缓解率（ORR）。该试验还评估了两种伊伯度胺三联方案：针对三线或后线患者的达雷妥尤单抗+地塞米松方案（n=29）和针对二线或后线患者的硼替佐米+地塞米松方案（n=24），报告的 ORR 分别为 41%和 58%。一项 III 期试验（EXCALIBER-RRMM）正在二线和三线骨髓瘤患者中比较伊伯度胺+达雷妥尤单抗+地塞米松方案与达雷妥尤单抗+硼替佐米松+地塞米松方案，预计 2025 年公布数据。另一项 III 期试验 EXCALIBER-Maintenance 正在移植后维持治疗中比较伊伯度胺与来那度胺。EXCALIBER-RRMM 和 EXCALIBER-Maintenance 的主要终点完成日期分别为 2026 年 3 月和 2029 年 3 月。

Just as Pomalyst was developed for patients who progress on Revlimid, Bristol Myers Squibb is developing mezigdomide, an IMiD even more potent than iberdomide, for patients who progress on iberdomide. In the relapsed/refractory setting, iberdomide is being developed in combination with Darzalex and dex, while mezigdomide is being developed in combination with a PI and dex. In a Phase I/II trial, dose escalation cohorts evaluating mezigdomide + bortezomib + dex (n=28) or mezigdomide + Kyprolis + dex (n=27) reported ORRs of 75% and 85%, respectively, ≥VGPRs of 39% and 44%, respectively, and median PFS of 12.3 months and 13.5 months, respectively. SUCCESSOR-1 is a head-to-head Phase III trial comparing mezigdomide + bortezomib + dex to Pomalyst + bortezomib + dex. The trial is enrolling second- to fourth-line patients and has an EPCD of November 2025. A second Phase III trial, SUCCESSOR-2, is an add-on trial comparing mezigdomide + Kyprolis + dex to Kyprolis + dex. The trial has an EPCD of February 2026 and is enrolling second-line or later patients previously treated with lenalidomide and an anti-CD38 antibody. 
正如泊马度胺（Pomalyst）是为来那度胺（Revlimid）治疗后进展的患者所研发，百时美施贵宝正在开发比伊伯度胺（iberdomide）更强效的免疫调节剂 mezigdomide，用于伊伯度胺治疗后进展的患者。在复发/难治性治疗背景下，伊伯度胺正与达雷妥尤单抗（Darzalex）和地塞米松（dex）联合开发，而 mezigdomide 则与蛋白酶体抑制剂（PI）及地塞米松联合研发。在一项 I/II 期临床试验中，剂量递增队列评估显示：mezigdomide+硼替佐米（bortezomib）+地塞米松组（n=28）与 mezigdomide+卡非佐米（Kyprolis）+地塞米松组（n=27）的总缓解率（ORR）分别为 75%和 85%，≥非常好的部分缓解率（VGPR）分别为 39%和 44%，中位无进展生存期（PFS）分别为 12.3 个月和 13.5 个月。SUCCESSOR-1 是一项头对头 III 期试验，直接比较 mezigdomide+硼替佐米+地塞米松与泊马度胺+硼替佐米+地塞米松方案。该试验正在招募二线至四线治疗患者，预计主要终点完成日期（EPCD）为 2025 年 11 月。另一项 III 期试验 SUCCESSOR-2 为附加试验，比较 mezigdomide+卡非佐米+地塞米松与卡非佐米+地塞米松方案，其 EPCD 为 2026 年 2 月，入组对象为既往接受过来那度胺和抗 CD38 抗体治疗的二线及以上患者。