Tipifarnib

– NDA submitted in 1Q 2025 for ziftomenib for the treatment of adult patients with relapsed or refractory AML with an NPM1 mutation – – Data from Phase 1b/2 registration-directed trial of ziftomenib selected for oral presentation at ASCO Annual Meeting – – $45.0 million milestone payment earned for NDA submission under collaboration agreement with Kyowa Kirin – – First patients dosed in Phase 1 trial of ziftomenib plus imatinib in GIST – – $703.2 million in pro forma cash, together with anticipated collaboration agreement payments, expected to support ziftomenib commercialization through the frontline AML combination setting – – Management to host webcast and conference call today at 4:30 p.m. ET – SAN DIEGO , May 01, 2025 (GLOBE NEWSWIRE) -- Kura Oncology, Inc. (Nasdaq: KURA), a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer, today reported first quarter 2025 financial results and provided a corporate update. “In the first quarter of 2025, we achieved a significant milestone with the submission of our first NDA for ziftomenib,” said Troy Wilson , Ph.D., J.D., President and Chief Executive Officer of Kura Oncology . “We are committed to working with FDA to support its review and are strategically advancing our pre-commercial activities to prepare for potential approval for the treatment of adult patients with relapsed or refractory NPM1-mutant AML. Beyond the monotherapy setting, we look forward to sharing data on the combination of ziftomenib with intensive and non-intensive standards of care, while gearing up for two Phase 3 studies in the frontline setting. With a strong pipeline, multiple clinical data readouts expected this year, and a solid financial foundation, we are well-positioned to drive progress across our programs.” Recent Highlights Submission of New Drug Application for ziftomenib to FDA – Kura and Kyowa Kirin Co., Ltd. (Kyowa Kirin) announced submission of the New Drug Application (NDA) for ziftomenib for the treatment of adult patients with relapsed or refractory (R/R) acute myeloid leukemia (AML) with a nucleophosmin 1 (NPM1) mutation to the U.S. Food and Drug Administration (FDA) on March 31, 2025 . From the time of submission, the FDA has a 60-day filing review period, and the Company expects to receive notification from the FDA on this preliminary evaluation in the second quarter of 2025. If Priority Review is granted, it would provide a target FDA review period of six months after NDA acceptance. Abstracts accepted for presentation at ASCO and EHA – In February 2025 , Kura and Kyowa Kirin announced positive topline results from the KOMET-001, the Phase 2 registration-directed trial of ziftomenib in patients with R/R NPM1-mutant (NPM1-m) AML. These data have been accepted for oral presentation at the American Society of Clinical Oncology (ASCO) Annual Meeting in Chicago and accepted for an encore presentation at the European Hematology Association (EHA) Congress in Milan, Italy . In addition, preliminary clinical data from the Phase 1b expansion cohort evaluating ziftomenib in combination with intensive (7+3) in the frontline setting has been accepted for an oral presentation at EHA. Abstract titles and presentation details can be found on the ASCO and EHA meeting sites at the lift of the respective embargos. Submission of the NDA for ziftomenib has triggered a $45 million milestone payment obligation from Kyowa Kirin – As a result of the NDA submission for ziftomenib, Kura has earned a $45 million milestone payment under the global strategic collaboration agreement between Kura and Kyowa Kirin to develop and commercialize ziftomenib in acute leukemias (Kyowa Agreement). Under the terms of the Kyowa Agreement, Kura received an upfront payment of $330 million in December 2024 and accounting for this $45 million milestone payment, Kura expects to receive up to $375 million in additional, near-term milestone payments. First patients dosed in KOMET-015 trial in GIST – Earlier this week, Kura announced the first patients have been dosed in its KOMET-015 Phase 1 clinical trial of ziftomenib in patients with advanced gastrointestinal stromal tumors (GIST) after imatinib failure. In October 2024 , Kura presented preclinical data at the 36th EORTC-NCI-AACR Symposium on Molecular Targets and Cancer Therapeutics in Barcelona , supporting the potential for ziftomenib in combination with KIT inhibitors for the treatment of GIST. The combination of ziftomenib and imatinib demonstrated robust and durable antitumor activity in imatinib-sensitive (1L) and imatinib-resistant (2L/3L) GIST patient-derived xenograft models. Preclinical data for KO-2806 presented in oral minisymposium session at AACR Annual Meeting – Last month, Kura presented preclinical data for KO-2806, the Company’s next-generation farnesyl transferase inhibitor (FTI), in combination with cabozantinib for the treatment of clear cell renal cell carcinoma at the American Association for Cancer Research (AACR) Annual Meeting in Chicago . These data add to a growing body of preclinical evidence demonstrating the potential of FTIs as companion therapeutic agents to augment the antitumor activities of and to overcome resistance to various targeted therapies. Financial Results Collaboration revenue from our Kyowa Kirin partnership for the first quarter of 2025 was $14.1 million , compared to no revenue for the first quarter of 2024. Research and development expenses for the first quarter of 2025 were $56.0 million , compared to $36.3 million for the first quarter of 2024. General and administrative expenses for the first quarter of 2025 were $22.8 million , compared to $18.2 million for the first quarter of 2024. Net loss for the first quarter of 2025 was $57.4 million , compared to a net loss of $49.5 million for the first quarter of 2024. Net loss for the first quarter of 2025 included non-cash, share-based compensation expense of $7.8 million . This compares to $8.5 million for the same period in 2024. As of March 31, 2025 , Kura had cash, cash equivalents and short-term investments of $658.2 million , compared to $727.4 million as of December 31, 2024 . As adjusted for the $45 million NDA submission milestone payment earned under our collaboration agreement with Kyowa Kirin, Kura had, on a pro forma basis, $703.2 million in cash, cash equivalents and short-term investments as of March 31, 2025 . Based on our current plans, we believe our cash, cash equivalents and short-term investments as of March 31, 2025 will be sufficient to enable us to fund our current operating expenses into 2027 and, combined with anticipated collaboration funding under the Kyowa Agreement, should support our ziftomenib AML program through commercialization in the frontline combination setting. Forecasted Milestones Present data from the KOMET-001 Phase 1b/2 registration-directed trial in R/R NPM1-m AML at ASCO and EHA in the second quarter of 2025. Present preliminary clinical data from the KOMET-007 Phase 1b expansion cohort evaluating ziftomenib with intensive chemotherapy (7+3) in the frontline setting at EHA in the second quarter of 2025. Present preliminary clinical data from the KOMET-007 Phase 1b expansion cohort evaluating ziftomenib with venetoclax and azacitidine in the frontline setting at a medical meeting in the second half of 2025. Initiate two independent Phase 3 registration-enabling trials in 1L intensive (KOMET-017-IC) and non-intensive (KOMET-017-NIC) AML in the second half of 2025. Nominate a development candidate for next-generation menin inhibitor program in diabetes in mid-2025. Initiate one or more FIT-001 expansion cohorts of KO-2806 and cabozantinib in patients with advanced renal cell carcinoma in the second half of 2025. Present data from the FIT-001 Phase 1 trial evaluating KO-2806 and cabozantinib in patients with renal cell carcinoma in the second half of 2025. Present data from the FIT-001 Phase 1 monotherapy dose escalation of KO-2806 in patients with RAS mutations in the second half of 2025. Present data from the KURRENT-HN trial evaluating tipifarnib and alpelisib in PIK3CA-dependent head and neck squamous cell carcinoma (HNSCC) in the second half of 2025. Conference Call and Webcast Kura’s management will host a webcast and conference call at 4:30 p.m. ET / 1:30 p.m. PT today, May 1, 2025 , to discuss the financial results for the first quarter of 2025 and to provide a corporate update. The live call may be accessed by dialing (800) 245-3047 for domestic callers and (203) 518-9765 for international callers and entering the conference ID: KURAQ1. A live webcast and archived replay of the event will be available here or online from the investor relations section of the Company’s website at www.kuraoncology.com. About Kura Oncology Kura Oncology is a clinical-stage biopharmaceutical company committed to realizing the promise of precision medicines for the treatment of cancer. The Company’s pipeline consists of small molecule drug candidates designed to target cancer signaling pathways. Ziftomenib, a once-daily, oral menin inhibitor, is the first and only investigational therapy to receive Breakthrough Therapy Designation from the FDA for the treatment of R/R NPM1-m AML. In November 2024 , Kura Oncology entered into a global strategic collaboration agreement with Kyowa Kirin to develop and commercialize ziftomenib for AML and other hematologic malignancies. Enrollment in a Phase 2 registration-directed trial of ziftomenib in R/R NPM1-m AML has been completed, and in the second quarter of 2025, the companies announced submission of an NDA for ziftomenib for the treatment of adult patients with R/R NPM1-m AML. Kura and Kyowa Kirin are conducting a series of clinical trials to evaluate ziftomenib in combination with current standards of care in newly diagnosed and R/R NPM1-m and KMT2A-rearranged AML. KO-2806, a next-generation FTI, is being evaluated in a Phase 1 dose-escalation trial (FIT-001) as a monotherapy and in combination with targeted therapies for patients with various solid tumors. Tipifarnib, a potent and selective FTI, is currently in a Phase 1/2 trial (KURRENT-HN) in combination with alpelisib for patients with PIK3CA-dependent HNSCC. For additional information, please visit Kura’s website at www.kuraoncology.com and follow us on X and LinkedIn. Forward-Looking Statements This news release contains certain forward-looking statements that involve risks and uncertainties that could cause actual results to be materially different from historical results or from any future results expressed or implied by such forward-looking statements. Such forward-looking statements include statements regarding, among other things, the efficacy, safety and therapeutic potential of Kura’s product candidates, ziftomenib, KO-2806 and tipifarnib; the expected timing of clinical trials; the expected timing and presentation of results and data from clinical trials; the anticipated timing of FDA’s notification on its preliminary evaluation of the NDA for ziftomenib; the potential duration of FDA’s review of the NDA; the potential FDA approval of product candidates; the success and impact of interactions with the FDA; the strength of Kura’s balance sheet and the sufficiency of cash, cash equivalents and short-term investments to fund its current operating plan to 2027 and, combined with anticipated collaboration funding under the Kyowa Agreement, to support Kura’s ziftomenib AML program through commercialization in the 1L combination setting. Factors that may cause actual results to differ materially include the risk that compounds that appeared promising in early research or clinical trials do not demonstrate safety and/or efficacy in later preclinical studies or clinical trials, the risk that Kura may not obtain approval to market its product candidates, uncertainties associated with performing clinical trials, regulatory filings, and other interactions with regulatory bodies, risks associated with reliance on third parties to successfully conduct clinical trials, the risks associated with reliance on outside financing to meet capital requirements, the risk that the collaboration with Kyowa Kirin is unsuccessful, and other risks associated with the process of discovering, developing and commercializing drugs that are safe and effective for use as human therapeutics, and in the endeavor of building a business around such drugs. You are urged to consider statements that include the words “may,” “will,” “would,” “could,” “should,” “believes,” “estimates,” “projects,” “promise,” “potential,” “expects,” “plans,” “anticipates,” “intends,” “continues,” “designed,” “goal,” or the negative of those words or other comparable words to be uncertain and forward-looking. For a further list and description of the risks and uncertainties the Company faces, please refer to the Company's periodic and other filings with the Securities and Exchange Commission , which are available at www.sec.gov. Such forward-looking statements are current only as of the date they are made, and Kura assumes no obligation to update any forward-looking statements, whether as a result of new information, future events or otherwise. Contacts Investors: Patti Bank Managing Director(415) 513-1284patti.bank@icrhealthcare.com Media: Alexandra Weingarten Associate Director, Corporate Communications (858) 500-8822alexandra@kuraoncology.com Source: Kura Oncology, Inc.

点击蓝字 关注我们引用本文：中国临床肿瘤学会淋巴瘤专家委员会，中国临床肿瘤学会白血病专家委员会，中国临床肿瘤学会骨髓瘤专家委员会，等．多发性骨髓瘤骨病临床诊疗指南（2024年版）[J/CD]．肿瘤综合治疗电子杂志，2025，11（2）：85-94．1 概述多发性骨髓瘤（multiple myeloma，MM）是浆细胞异常增生并分泌单克隆免疫球蛋白及其片段（M蛋白），进而引发相关组织及器官损伤的一种血液系统恶性肿瘤[1]。多发性骨髓瘤骨病（multiple myeloma bone disease，MBD）是其进展的重要临床表现，MBD是指由MM细胞所致的骨破坏病变，临床表现为骨质疏松、高钙血症、溶骨性破坏及病理性骨折等。2014年国际骨髓瘤工作组（International Myeloma Working Group，IMWG）更新了MM的诊断标准，其中MBD的定义为骨放射学检查[X线、计算机断层扫描（computed tomography，CT）、全身低剂量CT（whole body low dose CT，WBLD CT）、磁共振成像（magnetic resonance imaging，MRI）或正电子发射断层扫描/CT（positron emission tomography/CT，PET/CT）]上可见≥ 1个穿凿样溶骨性骨破坏病灶（≥ 5 mm）[2]。这些患者发生骨相关事件（skeletal-related event，SRE）的风险高，包括病理性骨折、脊髓压迫等，需要手术或放射治疗（以下简称放疗）干预，增加了患者的疾病负担，降低了患者的生活和生存质量[3]。中华医学会血液学分会与中国抗癌协会血液肿瘤专业委员会于2011年制定了《多发性骨髓瘤骨病诊治指南（2011版）》[4]，国际骨髓瘤基金会中国多发性骨髓瘤工作组外科治疗专家委员会2016年制订了《多发性骨髓瘤骨病外科治疗中国专家共识》[5]，中国临床肿瘤学会指南工作委员会2021年制定了《多发性骨髓瘤骨病临床诊疗专家共识2021》[6]，中国抗癌协会血液肿瘤专业委员会与中华医学会血液学分会2022年制定了《中国多发性骨髓瘤骨病诊疗指南（2022年版）》[7]，有力推动了我国MBD的规范诊疗。近年来，随着MBD领域的诊疗发展，以及强调多学科协作模式和MBD的全程管理，优化了MBD的治疗。中国临床肿瘤学会淋巴瘤专家委员会、中国临床肿瘤学会白血病专家委员会、中国临床肿瘤学会骨髓瘤专家委员会、北京慢性病防治与健康教育研究会组织专家对既往共识进行了更新，升级为《多发性骨髓瘤骨病临床诊疗指南（2024年版）》，以更好地指导MBD诊疗的临床实践。2 多发性骨髓瘤骨病的诊断MBD的影像学检查方法包括X线检查、CT、MRI、PET/CT等，其中X线检查因敏感度低，骨量丢失达到30%～50%才能被检出，其已逐步被其他手段取代。目前认为WBLD CT是评估MBD的首选影像学检查，MRI是评价骨髓浸润程度和脊髓压迫的首选手段，PET/CT主要用于髓外病变的范围和骨髓微小残留病变（minimal residual disease，MRD）的评估以及对疾病预后的判断[8]。2.1 X线检查X线检查敏感度低，据统计，约20% X线检查阴性的患者，通过其他检查可发现MM活动的证据[9]。由此X线检查已经逐步被其他检查取代。专家组建议仅在其他影像学手段不可及的情况下，推荐使用X线检查作为MBD的诊断。2.2 CTCT可发现早期骨质破坏，对于溶骨性病变尤其敏感，对于脊柱、肋骨和骨盆的病灶检出率高于X线检查，费用相对较低，可及性较好，故专家组建议将WBLD CT作为MBD诊断和治疗后评估的主要手段。2.3 MRIMRI是检测MM骨髓浸润的“金标准”，对于可疑病灶是否存在肿瘤浸润有重要的鉴别价值。对于存在脊柱压缩性骨折的患者，MRI检查可以了解脊髓压迫情况。上海交通大学医学院附属瑞金医院的临床研究数据显示，弥散加权成像（diffusion weighted imaging，DWI）能有效反映骨髓血管形成和细胞增生程度，表观扩散系数的变化与缓解深度明确相关，可作为预测深度缓解的有效手段[10]。2.4 PET/CTPET/CT可有效检测MM细胞的代谢活性，对于溶骨性病灶和骨质破坏非常敏感，且易检测出髓外病灶，在整体MBD的诊断方面有重要作用。但在无骨质破坏的情形下，如仅有代谢活性增强，不足以诊断MBD。同时，作为影像学MRD评估的检测手段，残留的局部病灶对于MM患者的预后有判断价值，有临床研究推荐在骨髓瘤患者诱导治疗后或维持治疗前进行PET/CT检查。但受到高昂费用和可及性差的影响，专家组建议应当根据具体情况决定是否采用PET/CT用于MBD诊断的各类影像学检查的优点和缺点比较见表1。2.5 实验室诊断在MBD的实验室诊断方面，高特异度和敏感度的实验室指标还有待进一步的研究。MBD患者存在骨吸收亢进和骨转换率增高，国内研究者发现，β-异构化的C-端肽Ⅰ型胶原片段（β-CTx）（反映骨吸收能力）、骨钙素（反映骨转换率）可有效反映MBD患者的骨损伤程度，在广泛型骨损伤的MBD患者中，β-CTx、骨钙素含量及β-CTx与总Ⅰ型胶原氨基端延长肽TP1NP（反映骨合成能力）的比值显著增加。尤其是β-CTx对广泛型骨损伤MBD患者的诊断具有重要价值[11-12]。而国外学者研究发现，在达到缓解的患者中，治疗6个月时β-CTx水平与基线时无明显差异，而在治疗无效的患者中，治疗6个月时β-CTx水平对比基线时显著升高，提示监测β-CTx变化有助于判断患者对治疗的反应[13]。指南推荐意见：（1）MBD的诊断是活动性MM全面诊断的重要组成部分。凡是考虑诊断为活动性MM患者均应进行影像学检查。同时对于无靶器官损害的患者，MRI检查出现＞1处且＞5 mm的局灶性骨质破坏也是需要启动治疗的指征。（2）普通X线检查：推荐在其他检查不可及时，作为MBD的筛查；对颅骨、四肢长骨病灶敏感度好，可作为其他检查手段的补充。（3）WBLD CT检查：推荐作为诊断和评估MBD的常规检查手段，肋骨CT三维成像有助于发现肋骨病变。（4）MRI检查：推荐作为评估骨髓浸润的“金标准”，可以鉴别可疑溶骨性病灶和骨质疏松部位是否存在骨髓浸润。对于CT未检出明显骨质破坏的患者，可考虑行脊柱和骨盆MRI检查以排查符合骨髓瘤定义事件的局部病灶。MRI同时适用于颈椎、胸椎、腰椎、骨盆病变及脊髓压迫等检查。（5）PET/CT检查：推荐对于存在可疑髓外浆细胞瘤的患者进行检查。对于达到骨髓MRD阴性的患者，推荐作为影像学MRD检测。（6）不再推荐骨密度和发射型计算机断层成像（emission computed tomography，ECT）作为诊断MBD的常规检查手段。3 多发性骨髓瘤骨病预防与治疗标准化、规范化的抗MM治疗是治疗MBD的基础和最重要的部分。通过抗肿瘤治疗可以延缓MM的病理进程，避免进一步加剧骨质破坏，达到治疗骨病的作用。此外，针对MBD的预防和治疗还包括减少骨质破坏、减轻骨痛症状以及降低骨病并发症的发生率。骨靶向药物是治疗骨病、延缓SRE发生的常用药物。3.1 一般治疗除外脊椎骨骨折的急性期，一般情况下不建议患者绝对卧床，否则更易发生脱钙。鼓励患者进行适当的活动，如步行、游泳等，但应避免剧烈运动或对抗性运动。存在脊柱病变的患者应卧加有软垫的硬板床，预防脊椎骨骨折导致的脊髓压迫。3.2 骨靶向药物专家组推荐临床应用骨靶向药物的适应证包括：①所有活动性MM患者，无论在影像学检查中是否存在MM相关骨病证据，均应接受骨靶向治疗，包括双膦酸盐或地舒单抗[14]。②MM伴高钙血症：中、重度高钙血症（校正后血钙≥2.9 mmol/L）需要立即使用骨靶向药物，同时给予静脉水化，加用呋塞米等利尿药，并使用糖皮质激素。③孤立性浆细胞瘤、意义未明单克隆免疫球蛋白血症、冒烟型MM：仅在伴有骨质疏松的情况下推荐使用骨靶向药物[14-15]，应用方法应参照骨质疏松指南[16]。临床用于MBD预防和治疗的骨靶向药物的适应证以及禁忌证见表2。其中第一代不含氮的双膦酸盐以氯屈膦酸为代表；第二代含氮双膦酸盐以帕米膦酸钠为代表；第三代双膦酸盐延长了侧链，药物活性进一步增强，如加入饱和羟链的伊班膦酸钠、环状结构的唑来膦酸和环庚胺衍生的因卡膦酸二钠[17]，相比前两代，除减轻症状、延缓SRE获益外，还可显著降低高钙血症风险、提升骨密度、改善骨代谢，例如：因卡膦酸相比其他第三代双膦酸盐，发热、肾毒性及下颌骨坏死等不良反应发生率更低[18]。目前，尚缺乏确凿的循证医学证据支持伊班膦酸钠在预防和治疗MBD方面的有效性。3.2.1 双膦酸盐药物的选择双膦酸盐是一类焦膦酸盐分子的稳定类似物，被破骨细胞内吞后，可诱导破骨细胞凋亡，抑制溶骨[19]。多项临床试验表明，应用双膦酸盐可有效降低MM的SRE、病理性骨折的发生和缓解骨痛。双膦酸盐类药物化学结构不同，因此其临床活性和功效亦有不同。目前在MM中研究较多的双膦酸盐主要有氯屈膦酸、帕米膦酸、唑来膦酸等。选择双膦酸盐时应综合考虑不同药物的优缺点，尤其应注意双膦酸盐可能引起的肾毒性和颌骨坏死（osteonecrosis of the jaw，ONJ）。一项大型双盲、随机临床试验表明，每月静脉注射帕米膦酸钠较安慰剂可以减轻患者疼痛和骨相关并发症，并改善MM DS Ⅲ期患者和≥1处溶骨性病变患者的生活质量[20]。另一项Ⅲ期研究中，研究人员对比了唑来膦酸和帕米膦酸在乳腺癌及MM患者中的长期疗效和安全性。结果显示，唑来膦酸组和帕米膦酸组在预防≥1次SRE发生率上无显著差异（P＝0.593），且至首次发生SRE的时间也相似（P＝0.538），从而证实了唑来膦酸和帕米膦酸在骨病治疗方面的疗效和安全性[21]。Ⅲ期MRCIX研究比较了在抗MM治疗基础上加入唑来膦酸对比氯屈膦酸的疗效。研究结果显示，相比氯屈膦酸，唑来膦酸能明显降低SRE发生风险（P＝0.0004），显著延长MM患者中位无进展生存（progression-free survival，PFS）时间（19.5个月比17.5个月，P＝0.07）和中位总生存（overall survival，OS）时间（52个月比46个月，P＝0.04）[22]。进一步的安全性数据显示，唑来膦酸与氯屈膦酸不良事件发生率相当。但研究显示，唑来膦酸的ONJ发生率高于氯屈膦酸（3.7%比0.5%）[23]。以上研究表明，唑来膦酸治疗MBD疗效优于氯屈膦酸，与帕米膦酸相当。鉴于唑来膦酸简易的给药程序和与降低死亡率相关联的显著效果，可能在临床选择上优于帕米膦酸。一项单中心回顾性队列研究表明，与持续双膦酸盐治疗相比，连续接受＞3个月双膦酸盐治疗后转为地舒单抗治疗的患者SRE风险显著降低（HR＝0.47，P＝0.019）[24]。这些证据表明，从双膦酸盐转换至地舒单抗治疗可能带来临床上的益处，双膦酸盐转换治疗也是骨转移患者治疗的一种选择。另一项研究显示，双膦酸盐转换治疗可以为进展性骨转移患者带来生存获益，接受双膦酸盐转换治疗的患者OS时间显著延长（P＜0.01）[25]。3.2.2 地舒单抗地舒单抗作为首个全人源化的IgG2单抗，通过特异性结合核因子κB受体活化因子配体（receptor activator of nuclear factor-κ B Ligand，RANKL），阻断其与RANK的相互作用，抑制破骨细胞的活化，减少了骨质吸收并促进了骨骼的重建。地舒单抗的适应证和禁忌证见表2。一项Ⅲ期研究评估新诊断MM患者接受地舒单抗对比唑来膦酸治疗的疗效和安全性，在推迟首次发生SRE时间上地舒单抗不劣于唑来膦酸（HR＝0.98，P非劣效＝0.01），地舒单抗组较唑来膦酸组可显著延长患者中位PFS时间（46.1个月比35.4个月，P＝0.036）。药物安全性显示，地舒单抗组患者肾毒性发生率明显低于唑来膦酸组（10%比17%）[26]。对该研究的亚洲人群（n＝196）分析显示，地舒单抗组和唑来膦酸组的SRE发生率分别为38.8%和50.5%（HR＝0.77，95%CI为0.48～1.26），治疗过程中地舒单抗组的肾毒性发生率明显低于唑来膦酸组（8.8%比21.7%），而两组间ONJ和低钙血症的发生率相近[26-27]。地舒单抗在预防SRE方面的效果与唑来膦酸相当，为MM患者提供了一种具有新颖作用机制的治疗选择。相比唑来膦酸，地舒单抗不仅能显著延长患者的PFS时间，还具有给药便利性和较低的肾毒性发生率。此外，在中重度肾功能不全的患者群体中，地舒单抗的使用剂量无需调整。基于以上数据，地舒单抗被获批用于MM患者SRE的预防，《多发性骨髓瘤骨病临床诊疗专家共识2021》[6]、美国国家综合癌症网络《多发性骨髓瘤指南（2024第4版）》[28]、美国临床肿瘤学会临床实践《骨修饰剂在多发性骨髓瘤中的作用》[15]及国际骨髓瘤工作组骨工作组的建议《多发性骨髓瘤相关骨病的治疗》[14]均将地舒单抗更新为MBD的治疗推荐，对于肾功能不全的患者优先推荐使用地舒单抗。3.3 骨靶向药物在肾功能不全患者的应用骨靶向药物的剂量和在肾功能不全患者中的用法用量调整见表3。3.4 骨靶向药物的治疗疗程以及停药后管理（1）骨靶向治疗的持续时间：从MM初始治疗即开始持续使用骨靶向治疗（双膦酸盐或地舒单抗）直至满2年。2年后是否继续用药应根据临床判断而定。（2）治疗间隔：骨靶向治疗的用药频率（每月1次或每3个月1次）取决于患者的个体标准、对治疗的反应以及所使用的药物。接受唑来膦酸治疗的患者，建议1次/月治疗，至少持续12个月；若12个月后获得非常好的部分缓解（very good partial response，VGPR）或以上的疗效，可以降低给药频率为每2～3个月1次，或根据骨病严重程度适当延长给药间隔；若12个月时仍未达到VGPR，则需持续每月应用唑来膦酸直至疗效达到VGPR或以上，然后可以考虑降低给药频率或停用。停用双膦酸盐前需全面评估骨折的发生风险，包括性别、年龄、人种、体重指数、与继发性骨质疏松相关的全身疾病状态（MM以外）、每日及累积糖皮质激素剂量。接受地舒单抗治疗的MBD患者，建议每月1次，持续至给药后2年。（3）停药后的管理：接受地舒单抗治疗的患者如果随后中断治疗，应维持性每6个月应用1次地舒单抗，或应用1次双膦酸盐，以降低骨质疏松反弹的风险[29]。停止骨靶向治疗后建议密切随访，一旦随访期间疾病出现生化复发，则需重新开始骨靶向治疗以降低新的SRE风险。指南推荐意见：（1）建议使用骨靶向药物（双膦酸盐或地舒单抗）治疗MBD。地舒单抗对于SRE的预防效果与唑来膦酸相似。与唑来膦酸相比，地舒单抗的肾毒性更小，因此对于肾功能不全的患者优先推荐使用地舒单抗。（2）初诊治的MM应静脉注射双膦酸盐和/或皮下注射地舒单抗，无论骨病状态如何。（3）双膦酸盐和地舒单抗起始治疗间隔：1次/4周。（4）双膦酸盐1次/月，治疗至少持续12个月；若12个月后达VGPR或以上疗效，可考虑3个月的治疗间隔，总疗程满2年。（5）地舒单抗1次/月治疗应至少持续2年。（6）使用双膦酸盐应每月监测肌酐清除率、血钙及维生素D水平。（7）地舒单抗不需要监测肾功能，但需每月监测血钙及维生素D水平。（8）肾功能不全患者优先推荐地舒单抗。4 多发性骨髓瘤骨病多学科管理4.1 MBD多学科管理MBD治疗的目标包括：①缓解疼痛，降低血钙水平，改善生活质量；②治疗和预防SRE；③控制肿瘤进展，延长生存期。因此，需要血液科、放射科、放疗科、骨科、疼痛科等多学科综合治疗（multi-disciplinary treatment，MDT），全程参与共同管理。建议有条件的三级甲等医院成立MBD患者的MDT组。4.2 血液科血液科在MBD的全程管理中，需肩负治疗原发疾病以及治疗骨病的内科药物治疗责任。大部分情况下还需要决定发起MDT的时机及参加科室。4.3 放疗科在MBD治疗的全程管理中，协助处理MBD相关事宜，帮助决定是否予以放疗以及放疗后可能带来的不良反应及其处理方法。4.3.1 适应证放疗可用于孤立性浆细胞瘤、早期脊髓压迫症、药物无法缓解的严重骨痛，并用于预防病理性骨折。4.3.2 治疗剂量及注意事项局部放疗可有效控制疼痛，并有可能促进骨折愈合[30-32]，推荐剂量为8～10 Gy/次。专家组特别提醒：对放射区域和放射技术的精心规划尤为重要，以减少对脊髓、大脑、骨髓以及邻近风险器官的毒性。应限制放射野范围以减少辐照对造血干细胞采集的影响或其对未来潜在治疗的影响。例如：对于严重症状性脊髓压迫，通常更倾向于采用中等分割剂量方案，即20～25 Gy分为8～10次疗程，而非更高剂量（如30 Gy），以减少不必要的毒性，并降低对邻近/重合器官（如脊髓）未来治疗可能带来的风险[33]。放疗不应延后至全身治疗后再开始，可与全身治疗同步进行，放疗期间需密切监测以评估和控制潜在的毒性反应[34]。4.4 骨科骨髓瘤外科治疗的目的不是根治疾病，而应以缓解症状、提高生存质量为重点，通过手术早期干预治疗潜在的或已经发生的病理性骨折、解除脊髓与神经根压迫，缓解疼痛，重建骨连续性及脊柱、骨盆等重要结构的稳定性，为患者后续的治疗创造条件。4.5 疼痛科若患者出现严重疼痛时需选择镇痛药物。镇痛药的用药剂量应作为临床治疗正式记录的一部分。这些记录可以作为疼痛治疗评估的1个半定量指标。镇痛需求的减少往往意味着治疗有效。处方类镇痛药的应用应遵照世界卫生组织的“镇痛阶梯”原则[35-42]，但应尽量避免使用或谨慎使用非甾体抗炎药，原因为其有肾功能损害及胃肠道刺激等不良反应。5 多发性骨髓瘤骨病患者随访与管理在MM的治疗过程中，MBD的管理至关重要。MBD不仅影响患者的生活质量，还可能导致严重的并发症。因此，制定一个全面的管理策略，包括基线评估、治疗过程管理、监测和随访等，对于提高治疗效果和改善患者预后具有重要意义。5.1 基线评估基线评估是MM治疗中至关重要的一步，其为后续治疗提供了重要的参考信息。这一阶段的评估应包括以下内容。（1）影像学评估：全身PET/CT、WBLD CT和非增强MRI等方法，能提供MBD的详细影像学特征。这些影像学检查不仅有助于诊断，还能监测疾病的进展和治疗效果（见MBD诊断相关章节）。（2）肾功能评估：基线肾功能的评估对于后续治疗中药物剂量的调整至关重要。双膦酸盐药物的肾毒性是治疗中需要特别关注的毒副作用。（3）牙科情况评估：牙科健康状态的评估有助于预防和管理ONJ。良好的口腔卫生和定期的牙科检查是预防ONJ的基本措施。（4）维生素D水平评估：维生素D水平的检测有助于评估和预防骨靶向治疗引起的低钙血症。维生素D对于钙的吸收和骨重塑过程至关重要。5.2 治疗过程中的管理策略5.2.1 MBD的随访建议每年进行1次，或根据临床指征调整监测频率。影像学方法的选择应与诊断时保持一致（如全身PET/CT、WBLD CT和MRI等方法），以便于对比。5.2.2毒副作用的监测（1）应用双膦酸盐期间肾功能的监测：在MM的疾病进程中经常伴随着肾功能不全。双膦酸盐类药物有可能导致急性肾功能不全，其肾毒性的发生率为9%～15%。肾毒性具有剂量和时间依赖性[21,43]。双膦酸盐未经代谢通过尿液排出体外，因此可与肾小管中的钙形成不溶性沉淀物，目前认为急性肾小管坏死是肾毒性的一个常见发病机制。因而推荐每次使用双膦酸盐前以及在用药过程中动态监测尿常规及肾功能（应用唑来膦酸期间每月进行1次肌酐清除率和血清电解质检测，帕米膦酸还需每月进行1次尿白蛋白检测），用药前后保持水化状态，根据肌酐清除率调整药物剂量，且在使用过程中尽可能避免或减少使用非甾体类药物、造影剂等可能损害肾功能的药物[14]。如联合用药不可避免，应至少在双膦酸盐给药后24 h使用，以降低肾脏不良反应发生风险。因卡膦酸给药后在肾脏沉积量更少，且易被快速清除，与唑来膦酸相比，可在一定程度上降低肾毒性风险。相比唑来膦酸，地舒单抗分子量大于肾小球滤过阈值，几乎不经肾脏消除，展现出较低的肾毒性，使用时无需特别监测肾功能，也无需调整剂量，因此，在肾功能不全患者中优先推荐地舒单抗[14,28]。（2）ONJ的防治：双膦酸盐及地舒单抗均可引起ONJ，最常累及的部位为上、下颌骨。影响ONJ风险增加的因素包括牙槽外科手术、口腔局部感染、诊断时发生骨质破坏或骨质疏松。建议通过保持良好的口腔卫生、定期口腔检查（每年1次或出现症状时）和避免侵入性操作来预防ONJ的发生。日本一项对连续3年收集到的临床常用双膦酸盐颌骨坏死/骨髓炎的报道中，其中因卡膦酸仅有18例（中位时间1 095 d）、唑来膦酸290例（中位时间592 d）、帕米膦酸41例（中位时间867 d）[44]，因卡膦酸较其他双膦酸盐颌骨坏死的发生率更低、中位时间更长。颌骨坏死一旦发生则不可逆，随着肿瘤患者生存期的不断延长，可选择颌骨坏死风险更小的药物。在侵入性牙科操作前后应暂停双膦酸盐及地舒单抗6个月（操作前3个月及操作后3个月），考虑到MM患者由于疾病本身以及长期抗骨髓瘤治疗导致的免疫抑制状态，建议操作前1 d至操作后3 d应用抗生素预防性抗感染治疗[45]。发生ONJ的患者应停止使用双膦酸盐/地舒单抗。大多数ONJ中位4个月（2～6个月）能够获得愈合，后续可以重新开始双膦酸盐/地舒单抗治疗[29]。患者教育对于坚持牙科卫生以及早期识别和报告不良事件至关重要。（3）低钙血症的防治：维生素D为钙吸收及正常骨重塑所必需，维生素D缺乏在MM患者中常见[46]，双膦酸盐及地舒单抗的常见不良反应包括低钙血症。由此补充钙和维生素D对于预防严重的低钙血症非常重要，接受双膦酸盐及地舒单抗治疗的患者在高钙血症纠正后建议补充钙片及维生素D。专家组建议在骨靶向药物治疗期间，每月监测血清钙、维生素D、磷及镁的水平，以评估是否需要额外补充[14]。具体剂量参照健康老年人推荐的钙摄入量：51～70岁的男性1000 mg/d，＞50岁女性及＞70岁男性1200 mg/d，最大剂量2000 mg/d。维生素D：51～70岁600 IU/d，＞70岁800 IU/d，最大剂量4000 IU/d。6 总结与展望MM的规范化治疗是MBD治疗的基石和关键所在。随着MBD的诊断完善和相关指南的推广，可以帮助血液科根据实际情况规范使用双膦酸盐和地舒单抗。目前新型三代双膦酸盐因卡膦酸二钠[47-48]及IGg4亚型全人源化抗RANKL抑制剂纳鲁索拜单抗[49]治疗MBD的研究正在进行。纳鲁索拜单抗是我国原研的全球首个全人源IgG4 RANKL抑制剂，是国家1类生物制品，其Fab段采用S228P突变改造，避免lgG4抗体的Fab臂交换，抗体更加稳定[50]。一项评价纳鲁索拜单抗治疗不可切除或手术困难的骨巨细胞瘤患者疗效和安全性的单臂、开放、多中心、Ⅰb/Ⅱ期临床研究中，纳鲁索拜单抗12周的肿瘤反应率高达93.3%，整体安全可耐受[51]。另外，纳鲁索拜单抗对比地舒单抗治疗MBD的多中心、随机对照、非劣效性研究阶段性结果公布，纳鲁索拜单抗组和地舒单抗组尿肌酐校正的尿Ⅰ型胶原交联N端肽（urinary N-terminal telopeptide of type 1 collagen corrected for urine creatinine，uNTx/uCr）较基线时均呈明显的下降趋势，并在治疗期间持续维持骨破坏抑制作用。首次给药后至第13周，纳鲁索拜单抗组uNTx/uCr较基线时降幅＞65%的患者比例达87.5%，地舒单抗组患者为79.7%。纳鲁索拜单抗组与地舒单抗组患者所有等级不良事件发生率分别为47.1%和65.4%。两组患者中均有4例患者发生≥3级低钙血症，治疗期间均予钙剂和/或维生素D补充治疗。未观察到首次SRE发生，也未报告颌骨坏死病例[52]。同时MBD患者的全程管理和包括血液科、骨外科、放疗科、疼痛科等MDT团队的密切合作也同样至关重要。随着近年来对于MM骨髓微环境的深入研究，发现骨髓基质细胞可以分泌白细胞介素-6、肿瘤坏死因子-α、RANKL等因子促进破骨细胞活性[12]；同时上调Dickkopf相关蛋白1（DKK1）表达，通过抑制Wnt/β-catenin通路从而影响成骨细胞分化[53]。这些研究也为寻找MBD新治疗靶点提供了思路。《多发性骨髓瘤骨病临床诊疗指南(2024年版)》编写专家委员会专家组组长：马   军  哈尔滨血液病肿瘤研究所贡铁军  哈尔滨血液病肿瘤研究所主审专家：沈志祥  上海交通大学医学院附属瑞金医院秦叔逵  南京中医药大学临床学院撰写小组组员（以姓氏拼音为序）：蔡   真  浙江大学医学院附属第一医院陈文明 首都医科大学附属北京朝阳医院杜   鹃  海军军医大学附属长征医院范圣瑾  哈尔滨医科大学附属第一医院贡铁军  哈尔滨血液病肿瘤研究所侯   健  上海交通大学医学院附属仁济医院贾垂明  哈尔滨医科大学附属肿瘤医院江泽飞  解放军总医院第五医学中心金   洁  浙江大学医学院附属第一医院隗   佳  华中科技大学同济医学院附属同济医院李   剑  中国医学科学院北京协和医院李   娟  中山大学附属第一医院林   颖  温州医科大学第二附属医院刘   澎  复旦大学附属中山医院刘   耀  重庆大学附属肿瘤医院路   瑾  北京大学人民医院马   军  哈尔滨血液病肿瘤研究所牛   挺  四川大学华西医院牛晓辉  北京积水潭医院秦叔逵  南京中医药大学临床学院邱录贵  中国医学科学院北京协和医学院血液病医院沈志祥  上海交通大学医学院附属瑞金医院孙春艳  华中科技大学同济医学院附属协和医院吴德沛  苏州大学医学院附属第一医院吴远彬  广东省中医院肖浩文  浙江大学医学院附属邵逸夫医院徐   燕  中国医学科学院北京协和医学院血液病医院阎   骅  上海交通大学医学院附属瑞金医院余   莉  南昌大学第二附属医院战   榕  福建医科大学附属协和医院张   曦  陆军军医大学新桥医院张东华  华中科技大学同济医学院附属同济医院周道斌  中国医学科学院北京协和医院参考文献向上滑动查看[1] COLEMAN R E. 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