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Isatuximab plus carfilzomib and dexamethasone in patients with relapsed multiple myeloma based on prior lines of treatment and refractory status: IKEMA subgroup analysis
American Journal of Hematology ( IF 10.1 ) Pub Date : 2022-05-23 , DOI: 10.1002/ajh.26602
Meletios A Dimopoulos 1 , Philippe Moreau 2 , Bradley Augustson 3 , Nelson Castro 4 , Tomas Pika 5 , Sosana Delimpasi 6 , Javier De la Rubia 7 , Angelo Maiolino 8 , Tony Reiman 9 , Joaquin Martinez-Lopez 10 , Thomas Martin 11 , Joseph Mikhael 12 , Kwee Yong 13 , Marie-Laure Risse 14 , Gaelle Asset 15 , Sylvia Marion 16 , Roman Hajek 17, 18
Affiliation  

Patients with multiple myeloma (MM) often relapse or become refractory to successive lines of therapy (LOT), warranting more effective treatments. Novel treatments have improved outcomes; however, MM is associated with a significant patient burden. Patients who are refractory to immunomodulatory drugs and proteasome inhibitors (PIs) have poor prognosis. Many patients with MM are exposed to lenalidomide or bortezomib in early LOT; those refractory to these agents are challenging to treat and represent a high unmet medical need.1

Based on the Phase 3 ICARIA-MM study (NCT02990338),2 isatuximab (Sarclisa), a CD38 monoclonal antibody, is approved in combination with pomalidomide and dexamethasone (Isa-Pd) for adult patients with relapsed and refractory MM (RRMM) who have received ≥2 prior therapies, including lenalidomide and a PI. Based on the IKEMA study (NCT03275285),3 to date, isatuximab in combination with carfilzomib and dexamethasone (Isa-Kd) is approved in the United States for adult patients with relapsed or refractory MM with 1–3 prior LOT, in the European Union for adult patients with MM with ≥1 prior therapy, and in Japan for adult patients with relapsed or refractory MM with one prior treatment.

IKEMA demonstrated that, in patients with relapsed MM, Isa-Kd significantly improved progression-free survival (PFS) compared with Kd (hazard ratio [HR] 0.53; 99% confidence interval [CI] 0.32–0.89; p = .0007), with a clinically meaningful increase in minimal residual disease (MRD) negativity and complete response (CR) rates in the intent-to-treat population, and a manageable safety profile.3 We conducted a prespecified subgroup analysis of IKEMA to evaluate the efficacy and safety of Isa-Kd versus Kd according to number of prior LOT (1 vs. >1), and an exploratory subgroup analysis based on refractoriness to two frequently used front-line agents, lenalidomide and bortezomib.

Randomized patients (N = 302) received Isa-Kd (n = 179) or Kd (n = 123). Subgroup analyses were conducted by number of prior LOT (1 vs. >1) as entered by the investigator at randomization and by refractory status (defined as: (i) reason for discontinuation was progression, or (ii) progression ≤60 days posttreatment, or (iii) best response was stable disease or progressive disease). The study design and procedures are described in Supporting Information.

In the overall population, patients received a median (range) of 2 (1–4) prior LOT in both treatment arms; 44.4% of patients received 1 prior line, 32.8% were lenalidomide-refractory, and 30.1% were bortezomib-refractory. Table S1 shows patient baseline characteristics in each subgroup. Compared with Kd, more patients with Isa-Kd were aged ≥75 years in the 1 prior line subgroup, fewer patients were International Staging System Stage I in the >1 prior line subgroup, and more were aged <65 years in the lenalidomide-refractory subgroup.

Exposure to study treatment was longer with Isa-Kd than Kd. The median (range) number of treatment cycles with Isa-Kd versus Kd was: 20.0 (1–25) versus 16.5 (1–28), 1 prior line; 18.0 (1–27) versus 12.5 (1–26), >1 prior line; 14.0 (1–27) versus 11.5 (1–28), lenalidomide-refractory; 13.5 (1–26) versus 13.0 (1–28), bortezomib-refractory. More patients with Isa-Kd than Kd received ≥18 cycles in all subgroups: 65.8% versus 48.1%, 1 prior line; 51.0% versus 32.4%, >1 prior line; 43.9% versus 33.3%, lenalidomide-refractory; 38.5% versus 25.6%, bortezomib-refractory. These results are consistent with IKEMA overall population where a longer treatment duration was reported with Isa-Kd (median [range] number of cycles 19.0 [1–27] and 57.6% patients with ≥18 cycles) than Kd (14.5 [1–28] and 39.3% patients with ≥18 cycles).

Consistent with IKEMA overall population, PFS improvement was observed with Isa-Kd versus Kd across all subgroups analyzed, regardless of number of prior LOT (HR 0.59 [95% CI, 0.31–1.12], 1 prior line; HR 0.48 [95% CI, 0.29–0.78], >1 prior line) or refractory status (HR 0.60 [95% CI, 0.34–1.1], lenalidomide-refractory; HR 0.69 [95% CI, 0.35–1.39], lenalidomide-refractory at last regimen; HR 0.62 [95% CI, 0.33–1.16], bortezomib-refractory; HR 0.38 [95% CI, 0.16–0.92], bortezomib-refractory at last regimen; Figure 1A). The p values for interaction suggest no interaction with any of the parameters evaluated. The PFS-event-free probability at 18 months for Isa-Kd versus Kd was: 77% versus 64%, 1 prior line; 68% versus 45%, >1 prior line; 53% versus 31%, lenalidomide-refractory patients; and 63% versus 43%, bortezomib-refractory (Table S2).

Details are in the caption following the image
FIGURE 1
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Efficacy with Isa-Kd versus Kd. (A) PFS by number of prior lines of therapy and refractory status; depth of response by (B) number of prior lines of therapy, (C) lenalidomide-refractory status, or (D) bortezomib-refractory status. Bor, bortezomib; CI, confidence interval; CR, complete response; d, dexamethasone; IMiD, immunomodulatory drug; Isa, isatuximab; K, carfilzomib; Len, lenalidomide; mPFS, median progression-free survival; MRD−, minimal residual disease negativity; NC, not calculated; ORR, overall response rate; PFS, progression-free survival; PI, proteasome inhibitor; VGPR, very good partial response

Overall response rate (ORR) in IKEMA overall population was high in both treatment groups with no statistically significant difference (87%, Isa-Kd vs. 83%, Kd; one-sided p = 0.19); thus, p values of subsequent key secondary endpoints (≥very good partial response [VGPR] and MRD negativity rates) were provided for descriptive purposes only.3 Similar results were observed irrespective of number of prior LOT (Figure 1B; 87.5% vs. 85.5%, 1 prior line; 85.9% vs. 80.9%, >1 prior line), but a trend toward higher ORR with Isa-Kd versus Kd was seen in refractory subgroups (Figure 1C,D; 82.5% vs. 71.4%, lenalidomide-refractory; 88.9% vs. 74.2%, lenalidomide-refractory at last regimen; 75.0% vs. 71.8%, bortezomib-refractory; 84.4% vs. 73.9%, bortezomib-refractory at last regimen).

Consistent with overall population (≥VGPR 73% vs. 56%, p = 0.0011; MRD negativity 29.6% vs. 13.0%, p = 0.0004),3 numerically and clinically meaningful higher ≥VGPR and MRD negativity rates, respectively, with Isa-Kd versus Kd were observed across all subgroups: 1 prior line (75.0% vs. 61.8% and 33.8% vs. 18.2%), >1 prior line (70.7% vs. 51.5% and 26.3% vs. 8.8%), lenalidomide-refractory (66.7% vs. 35.7% and 24.6% vs. 9.5%), lenalidomide-refractory at last regimen (72.2% vs. 38.7% and 27.8% vs. 9.7%), bortezomib-refractory (55.8% vs. 51.3% and 17.3% vs. 10.3%), and bortezomib-refractory at last regimen (62.5% vs. 47.8% and 25.0% vs. 8.7%; Figure 1). A clinically meaningful difference in CR rates with Isa-Kd versus Kd was observed for >1 prior line subgroup (38.4% vs. 20.6%) and 1 prior line subgroup (41.3% vs. 36.4%; Figure 1). Similarly, a clinically meaningful difference in CR rates with Isa-Kd versus Kd was also observed in refractory subgroups: lenalidomide-refractory (38.6% vs. 11.9%), lenalidomide-refractory at last regimen (47.2% vs. 12.9%), bortezomib-refractory (28.8% vs. 17.9%), and bortezomib-refractory at last regimen (31.3% vs. 17.4%).

The incidence of patients with all-grade treatment-emergent adverse events (TEAEs) in all subgroups was similar to IKEMA safety population3 (97.2%, Isa-Kd vs. 95.9%, Kd; Table S3), with infusion-related reactions being the most frequent (Tables S4 and S5). Other most common TEAEs reported more frequently (≥10% patients) with Isa-Kd versus Kd included pneumonia and bronchitis in 1 prior line; upper respiratory infection, fatigue, and vomiting in >1 prior line (Table S4); diarrhea, cough, hypertension, fatigue, dyspnea, upper respiratory tract infection, constipation, bronchitis, arthralgia, and nausea in lenalidomide-refractory; and cough, fatigue, and bronchitis in bortezomib-refractory subgroups (Table S5).

The incidence of patients with Grade ≥3 TEAEs was higher with Isa-Kd versus Kd across all subgroups (77.2% vs. 64.8%, 1 prior line; 76.5% vs. 69.1%, >1 prior line; 73.7% vs. 61.9%, lenalidomide-refractory; 76.9% vs. 66.7%, bortezomib-refractory), and consistent with overall safety population3 (76.8% vs. 67.2%; Table S3).3 The most frequent Grade ≥3 TEAEs were hypertension and pneumonia, with similar incidences between treatment arms in all subgroups (Tables S4 and S5).

The incidence of patients with serious TEAEs with Isa-Kd versus Kd was similar to that in the overall population3 (59.3% vs. 57.4%) in all subgroups, except in 1 prior line (62.0% vs. 48.1%) and lenalidomide-refractory (59.6% vs. 50.0%) subgroups (Table S3). Grade 5 TEAEs occurred in 3.8% versus 0% in 1 prior line, 3.1% versus 5.9% in >1 prior line, 3.5% versus 4.8% in lenalidomide-refractory, and 1.9% versus 7.7% in bortezomib-refractory patients.

The incidence of patients with TEAEs leading to discontinuations was lower or similar with Isa-Kd versus Kd in all subgroups (8.9% vs. 11.1%, 1 prior line; 8.2% vs. 16.2%, >1 prior line; 7.0% vs. 11.9%, lenalidomide-refractory; 3.8% vs. 17.9%, bortezomib-refractory; Table S3).

The current analysis strongly supports similar treatment benefit of Isa-Kd versus Kd on PFS and depth of response regardless of number of prior lines or lenalidomide- or bortezomib-refractory status versus the control arm Kd, which has shown in ENDEAVOR subgroup analysis to be an efficient treatment in lenalidomide- or bortezomib-exposed patients, irrespective of number or type of prior LOT, with improved outcomes versus bortezomib-dexamethasone.4 CANDOR reported favorable benefit-to-risk profile of another CD38 antibody, daratumumab, plus Kd versus Kd in patients with RRMM, regardless of number of prior lines (1 vs. ≥2) or refractoriness to bortezomib/ixazomib or lenalidomide.5 One key difference between these studies is the lack of M-protein interference assay for isatuximab; CR was assessed without correction for M-protein interference and is likely underestimated in IKEMA. The clinical significance of numerical differences observed between IKEMA and CANDOR has not been elucidated. Notably, a similar ICARIA-MM subgroup analysis showed that Isa-Pd improved PFS and ORR regardless of number of prior LOT and in patients who were lenalidomide-refractory, lenalidomide-refractory at last line, and double-refractory to lenalidomide and PIs.2, 6

Limitations of the current study are exclusion of daratumumab-treated patients and a relatively small number of patients owing to subgroup analysis (limiting the statistical analysis power). However, the efficacy and safety benefits of Isa-Kd in patients with relapsed MM were seen irrespective of number of prior LOT, or lenalidomide- or bortezomib-refractory status and were consistent with IKEMA overall population. Isa-Kd is a new treatment option for patients with relapsed MM, particularly in the difficult-to-treat lenalidomide- and bortezomib-refractory patients.



中文翻译:

伊沙妥昔单抗联合卡非佐米和地塞米松治疗复发性多发性骨髓瘤患者(基于既往治疗线和难治性状态):IKEMA 亚组分析

多发性骨髓瘤 (MM) 患者经常复发或对连续治疗 (LOT) 难以治疗,需要更有效的治疗。新疗法改善了结果;然而,MM 与显着的患者负担相关。对免疫调节药物和蛋白酶体抑制剂 (PI) 耐药的患者预后较差。许多 MM 患者在早期 LOT 时暴露于来那度胺或硼替佐米;对这些药物无效的患者治疗起来具有挑战性,代表着高度未满足的医疗需求。1个

基于 ICARIA-MM 3 期研究 (NCT02990338),2 isatuximab (Sarclisa),一种 CD38 单克隆抗体,被批准与泊马度胺和地塞米松 (Isa-Pd) 联合用于患有复发和难治性 MM (RRMM) 的成年患者接受过 ≥ 2 种既往治疗,包括来那度胺和 PI。根据迄今为止3 项IKEMA 研究 (NCT03275285),isatuximab 联合卡非佐米和地塞米松 (Isa-Kd) 在美国获准用于既往有 1-3 次 LOT 的复发或难治性 MM 成年患者,在欧盟既往接受过 ≥ 1 种治疗的成年 MM 患者,以及在日本接受过一种既往治疗的复发性或难治性 MM 成年患者。

IKEMA 证明,在复发性 MM 患者中,与 Kd 相比,Isa-Kd 显着改善了无进展生存期 (PFS)(风险比 [HR] 0.53;99% 置信区间 [CI] 0.32–0.89;p = .0007  ,在意向治疗人群中,微小残留病 (MRD) 阴性和完全缓解 (CR) 率具有临床意义的增加,并且安全性可控。3我们对 IKEMA 进行了预先指定的亚组分析,以根据先前 LOT 的数量(1 对 > 1)评估 Isa-Kd 与 Kd 的疗效和安全性,以及基于对两种常用一线药物的难治性的探索性亚组分析剂,来那度胺和硼替佐米。

随机分组的患者 ( N  = 302) 接受了 Isa-Kd ( n  = 179) 或 Kd ( n  = 123)。亚组分析根据研究者在随机化时输入的先前 LOT 数量(1 对 >1)和难治性状态(定义为:(i) 停药原因是进展,或 (ii) 进展≤治疗后 60 天, (iii) 最佳反应是疾病稳定或疾病进展)。支持信息中描述了研究设计和程序。

在总体人群中,患者在两个治疗组中接受的中位(范围)为 2 (1–4) 之前的 LOT;44.4% 的患者接受过 1 次一线治疗,32.8% 的患者对来那度胺无效,30.1% 的患者对硼替佐米无效。表 S1 显示了每个亚组的患者基线特征。与 Kd 相比,Isa-Kd 患者年龄≥75 岁的 1 线亚组较多,国际分期系统 I 期患者较少,>1 线亚组中年龄<65 岁的患者更多亚群。

Isa-Kd 的研究治疗暴露时间长于 Kd。Isa-Kd 与 Kd 的治疗周期中位数(范围)为:20.0 (1–25) 与 16.5 (1–28),1 个前线;18.0 (1–27) 对比 12.5 (1–26),>1 前行;14.0 (1–27) 对比 11.5 (1–28),来那度胺难治;13.5 (1–26) 对比 13.0 (1–28),硼替佐米难治。在所有亚组中,接受 ≥18 个周期的 Isa-Kd 患者多于 Kd:65.8% 对 48.1%,1 个先前线;51.0% 对比 32.4%,>1 个先前行;43.9% 对 33.3%,来那度胺难治;38.5% 对 25.6%,硼替佐米难治。这些结] 和 39.3% 的患者有 ≥18 个周期)。

与 IKEMA 总体人群一致,在所有分析的亚组中观察到 Isa-Kd 与 Kd 的 PFS 改善,无论先前 LOT 的数量如何(HR 0.59 [95% CI,0.31-1.12],1 个先前线;HR 0.48 [95% CI , 0.29–0.78], >1 前线)或难治性状态(HR 0.60 [95% CI, 0.34–1.1],来那度胺难治;HR 0.69 [95% CI, 0.35–1.39],来那度胺在最后一个方案中难治; HR 0.62 [95% CI, 0.33–1.16],硼替佐米难治;HR 0.38 [95% CI, 0.16–0.92],硼替佐米在最后一个方案中难治;图 1A)。p _相互作用的值表明与任何评估的参数没有相互作用。Isa-Kd 与 Kd 在 18 个月时的无 PFS 事件概率为:77% 与 64%,1 个先前线;68% 对比 45%,>1 个先前行;来那度胺难治性患者分别为 53% 和 31%;硼替佐米难治性的分别为 63% 和 43%(表 S2)。

详细信息在图片后面的标题中
图1
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Isa-Kd 与 Kd 的疗效比较。(A) 按先前治疗线数和难治性状态划分的 PFS;通过 (B) 先前治疗线数、(C) 来那度胺难治性状态或 (D) 硼替佐米难治性状态的反应深度。硼,硼替佐米;CI,置信区间;CR,完全响应;d、地塞米松;IMiD,免疫调节药物;Isa,艾妥昔单抗;K, 卡非佐米;Len,来那度胺;mPFS,中位无进展生存期;MRD−,微小残留病阴性;NC,未计算;ORR,总反应率;PFS,无进展生存期;PI,蛋白酶体抑制剂;VGPR,非常好的部分响应

IKEMA 总体人群的总体反应率 (ORR) 在两个治疗组中都很高,没有统计学上的显着差异(87%,Isa-Kd 对比 83%,Kd;单侧 p = 0.19  ;因此,后续关键次要终点(≥非常好的部分反应 [VGPR] 和 MRD 阴性率)的p值仅用于描述目的。3个无论先前 LOT 的数量如何,都观察到类似的结果(图 1B;87.5% 与 85.5%,1 个先前线;85.9% 与 80.9%,>1 个先前线),但 Isa-Kd 与 Kd 有更高的 ORR 趋势见于难治性亚组(图 1C、D;82.5% 对 71.4%,来那度胺难治;88.9% 对 74.2%,最后一个方案来那度胺难治;75.0% 对 71.8%,硼替佐米难治;84.4% 对 74.2%,硼替佐米难治; . 73.9%,硼替佐米在最后一个方案中难治)。

与总体人群一致(≥VGPR 73% 与 56%,p  = 0.0011;MRD 阴性 29.6% 与 13.0%,p  = 0.0004),3在所有亚组中观察到 Isa-Kd 与 Kd 的≥VGPR 和 MRD 阴性率分别在数值和临床上有意义:1 个先前线(75.0% 对 61.8% 和 33.8% 对 18.2%),>1 个先前线( 70.7% 对 51.5% 和 26.3% 对 8.8%),来那度胺难治(66.7% 对 35.7% 和 24.6% 对 9.5%),最后一个方案对来那度胺难治(72.2% 对 38.7% 和 27.8%) vs. 9.7%)、硼替佐米难治性(55.8% vs. 51.3% 和 17.3% vs. 10.3%),以及硼替佐米在最后一个方案中难治性(62.5% vs. 47.8% 和 25.0% vs. 8.7%;图 1) . 对于 >1 个先前线亚组(38.4% 对 20.6%)和 1 个先前线亚组(41.3% 对 36.4%;图 1),观察到 Isa-Kd 与 Kd 的 CR 率具有临床意义的差异。同样,在难治性亚组中也观察到 Isa-Kd 与 Kd 的 CR 率具有临床意义的差异:

所有亚组中所有级别治疗中出现的不良事件 (TEAE) 患者的发生率与 IKEMA 安全人群3相似(97.2%,Isa-Kd 对比 95.9%,Kd;表 S3),其中输液相关反应为最常见的(表 S4 和 S5)。Isa-Kd 与 Kd 相比,其他最常见的 TEAE 报告更频繁(≥10% 的患者)包括 1 个既往治疗方案中的肺炎和支气管炎;上呼吸道感染、疲劳和呕吐超过 1 条既往线路(表 S4);腹泻、咳嗽、高血压、疲劳、呼吸困难、上呼吸道感染、便秘、支气管炎、关节痛和来那度胺难治性恶心;硼替佐米难治性亚组中的咳嗽、疲劳和支气管炎(表 S5)。

在所有亚组中,Isa-Kd 与 Kd 相比,≥ 3 级 TEAE 患者的发生率更高(77.2% 与 64.8%,1 个先前线;76.5% 与 69.1%,>1 个先前线;73.7% 与 61.9% ,来那度胺难治性;76.9% 与 66.7%,硼替佐米难治性),并且与总体安全人群3一致(76.8% 与 67.2%;表 S3)。3最常见的 ≥ 3 级 TEAE 是高血压和肺炎,所有亚组中治疗组之间的发生率相似(表 S4 和 S5)。

具有 Isa-Kd 和 Kd 的严重 TEAE 患者的发生率在所有亚组中与总体人群3 (59.3% 对 57.4%)相似,除了 1 个先前的治疗线(62.0% 对 48.1%)和来那度胺-难治性(59.6% 与 50.0%)亚组(表 S3)。5 级 TEAE 的发生率在 1 个先前的线中为 3.8% 对 0%,在> 1 个先前的线中为 3.1% 对 5.9%,在来那度胺难治性患者中为 3.5% 对 4.8%,在硼替佐米难治性患者中为 1.9% 对 7.7%。

在所有亚组中,使用 Isa-Kd 与 Kd 导致停药的 TEAE 患者的发生率较低或相似(8.9% 对 11.1%,1 个先前线;8.2% 对 16.2%,>1 个先前线;7.0% 对11.9%,来那度胺难治;3.8% 与 17.9%,硼替佐米难治;表 S3)。

目前的分析强烈支持 Isa-Kd 与 Kd 在 PFS 和反应深度方面的相似治疗益处,无论先前线数或来那度胺或硼替佐米难治性状态与对照组 Kd 相比,这在 ENDEAVOR 亚组分析中显示为对来那度胺或硼替佐米暴露患者的有效治疗,无论先前 LOT 的数量或类型如何,与硼替佐米-地塞米松相比具有改善的结果。4 CANDOR 报告了另一种 CD38 抗体 daratumumab 加 Kd 与 Kd 在 RRMM 患者中的有利效益风险比,无论先前线的数量(1 对≥2)或硼替佐米/伊沙佐米或来那度胺的难治性如何。5个这些研究之间的一个关键区别是缺乏对 isatuximab 的 M 蛋白干扰试验;CR 在没有校正 M 蛋白干扰的情况下进行评估,并且在 IKEMA 中可能被低估了。IKEMA 和 CANDOR 之间观察到的数值差异的临床意义尚未阐明。值得注意的是,类似的 ICARIA-MM 亚组分析表明,Isa-Pd 改善了 PFS 和 ORR,无论之前的 LOT 数量如何,以及对来那度胺难治性、最后一线来那度胺难治性以及对来那度胺和 PIs 双重难治性的患者。2, 6

当前研究的局限性在于排除了达雷妥尤单抗治疗的患者和由于亚组分析(限制了统计分析能力)而导致的相对较少的患者。然而,无论既往 LOT 数量或来那度胺或硼替佐米难治性状态如何,Isa-Kd 在复发性 MM 患者中的疗效和安全性益处均可见,并且与 IKEMA 总体人群一致。Isa-Kd 是复发性 MM 患者的一种新治疗选择,尤其是难以治疗的来那度胺和硼替佐米难治性患者。

更新日期:2022-05-23
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