Introduction

Unprecedented depth of response is obtained with regimens incorporating monoclonal antibodies in the management of newly diagnosed multiple myeloma (NDMM). The incremental benefit of AHCT in this setting is being reconsidered but can be appraised by systematic assessment of disease burden pre- and post-AHCT utilizing NGS MRD.

Methods

We performed a multi-center clinical trial with Dara-KRd induction, AHCT (Melphalan conditioning), and post-AHCT, MRD response-adapted Dara-KRd consolidation. Primary endpoint was MRD <10⁻⁵ using the NGS platform clonoSEQ. Secondary endpoints included the achievement of MRD <10⁻⁶. MRD assessment happened in parallel with IWMG response assessment after completion of 4 cycles of Dara-KRd, 60-80 days after AHCT, and during each of up to two additional 4-cycle blocks of Dara-KRd consolidation. Patients with MRD <10⁻⁵ in two consecutive phases of therapy discontinue treatment without maintenance and were actively monitored for the resurgence of MRD or clinical relapse.

Results

To date, 82 patients have been enrolled, and 77 (94%) have disease trackable by NGS. Of those, 54 have completed post-induction and 29 post-AHCT assessment. The median age of the cohort is 61 years (range 36-79), with 46% females, 31% with high-risk FISH abnormality [t(4;14) or t(14;16) or del17p] and 20.3% ISS III disease. All patients obtained objective responses with the rate of best responses ≥VGPR of 93% after induction and 100% after AHCT and rate of sCR of 46% and 79%, respectively. MRD responses are displayed in Figure 1a. Patients with MRD <10⁻⁵ were 31% post-induction and 76% post-AHCT. Patients with MRD<10⁻⁶ were 24% post-induction and 48% post-AHCT. All 7 patients with MRD <10⁻⁶ post-induction had confirmed MRD <10⁻⁶ after AHCT. Of the remaining 22 patients, 20 (90%) had a reduction in MRD burden with AHCT (figure 1b). The median reduction in disease burden was 0.94 Log₁₀ (range -1.3 to 3.3), and 10/22 patients (45%) had a reduction in more than one Log₁₀. Of the two patients without a reduction in MRD with AHCT, one had minimal change from 1.3 to 1.8 × 10⁻⁵ and one patient had increased from 2.3 × 10⁻² post-induction (while in sCR) to 4.6 × 10⁻¹ post-AHCT corresponding to morphologically positive marrow and clinical disease progression.

Conclusion

While a subset of patients with NDMM receiving Dara-KRD achieved MRD negativity after four cycles of induction, subsequent AHCT significantly increased the number of patients obtaining this status. Despite a quadruple induction regimen utilizing what are considered the most effective anti-myeloma drugs, AHCT resulted in a substantial reduction of disease burden in a majority of patients and should remain part of current therapy for fit, NDMM patients. Future trial designs with the intent to defer AHCT for patients may need to demonstrate high rates of MRD negativity to show benefit ultimately.

中文翻译：

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在Daratumumab，Carfilzomib，Lenalidomide和地塞米松（Dara-KRd）四联体诱导的情况下，通过下一代测序（NGS）对自体造血干细胞移植（AHCT）对可测量残留疾病（MRD）的影响。

介绍

在新诊断的多发性骨髓瘤（NDMM）的治疗中，采用掺入单克隆抗体的方案可获得前所未有的反应深度。人们正在考虑在这种情况下AHCT的增加收益，但可以通过使用NGS MRD对AHCT前后的疾病负担进行系统评估来评估。

方法

我们进行了一项多中心临床试验，其中包括Dara-KRd诱导，AHCT（Melphalan调节）和AHCT后，MRD反应适应的Dara-KRd合并。使用NGS平台clonoSEQ的主要终点是MRD <10 ^-5。次要终点包括达到MRD <10 ^-6。在完成4个周期的Dara-KRd之后，AHCT之后60-80天，以及在多达两个额外的4个周期的Dara-KRd合并期间，MRD评估与IWMG响应评估同时进行。在两个连续治疗阶段中MRD <10 ^-5的患者在不维持治疗的情况下中断治疗，并积极监测其MRD复发或临床复发。

结果

迄今为止，已有82例患者入组，其中77例（94％）患者可通过NGS追踪到疾病。其中有54人完成了入职后评估，有29人完成了AHCT后评估。该队列的中位年龄为61岁（范围为36-79），其中女性46％，高危FISH异常[t（4; 14）或t（14; 16）或del17p] 31％和ISS的20.3％三，疾病。所有患者均获得客观缓解，诱导后≥VGPR的最佳缓解率达93％，AHCT后≥100％，sCR率分别达46％和79％。MRD响应显示在图1a中。MRD <10 ^-5的患者诱导后为31％，AHCT后为76％。MRD <10 ^-6的患者诱导后为24％，AHCT后为48％。诱导后所有7例MRD <10 ^-6的患者均已确认MRD <10 ^-6在AHCT之后。在其余的22位患者中，有20位（90％）的AHCT减轻了MRD负担（图1b）。疾病负担的中位数减少量为0.94 Log ₁₀（范围-1.3至3.3），而10/22患者（45％）的减少量多于一个Log ₁₀。两个患者没有在MRD的降低与AHCT的，一个具有从1.3变化最小，以1.8×10 ^-5和一个病人已经从2.3×10增加^-2诱导后（而在SCR）到4.6×10 ^-1交-AHCT对应于形态学阳性的骨髓和临床疾病的进展。

结论

虽然接受Dara-KRD的NDMM患者子集在四个诱导周期后达到MRD阴性，但随后的AHCT显着增加了获得这种状态的患者数量。尽管采用了被认为是最有效的抗骨髓瘤药物的四重诱导方案，AHCT仍使大多数患者的疾病负担显着降低，对于适合的NDMM患者，AHCT应该仍然是当前治疗的一部分。旨在推迟患者进行AHCT的未来试验设计可能需要证明高MRD阴性率才能最终显示出益处。