Introduction

Preliminary studies have demonstrated that the combination of daratumumab (Dara), pomalidomide (Pom), and dexamethasone (Dex) (DPd regimen) is both safe and effective in relapsed/refractory light-chain amyloidosis (AL) patients previously exposed to Dara, with a 100% complete response (CR) rate in measurable dFLC groups, a 67% partial response (PR) rate in low dFLC groups, and an 83% renal response rate (median time: 2 cycles). However, to date, no prospective trials have investigated the efficacy and safety of DPd regimen in newly diagnosed light-chain amyloidosis (NDAL) patients.We hypothesize that in NDAL patients, the DPd regimen may induce deeper hematologic responses compared to those observed in previously Dara-exposed RAL patients.This prospective study aimed to evaluate the efficacy of DPD in NDAL pts.

Primary Objective is to evaluate the best hematologic response rate within 12 months of DPd treatment.Secondary Objectives:Overall response rate (ORR) and very good partial response rate (VGPR), Stringent dFLC response criteria, PR rates in low dFLC patients, Minimal residual disease (MRD) negativity assessed by next-generation sequencing (NGS), Serum M-protein detection via mass spectrometry (MS), Time to first/best hematologic response, Time to next therapy, Median progression-free survival (PFS) and overall survival (OS),Organ response rates and duration of response.

Methods

Our study planned to enroll 20 NDAL pts aged 18-80 years receiving the DPD regimen. All pts met the hematologic response eligibility criteria,including a baseline difference of involved to uninvolved free light chains (dFLC)greater than 20 mg/L.Dara 1800mg SQ or 16mg/kg iv weekly (qwk) x 8, every 2 wk x 8 doses & monthly starting C7;Pom 2-4mg PO Days(D)1-21/28; dex C1: 20mg IV D1/8,20mg PO D2/9 & 40mg PO C1D15 wkly through C6, then 20mg IV monthly starting C7D1 & 20mg PO D8,15,22.A reduced dose of Pom was allowed for significant renal impairment.The primary endpoint was hematologic ORR(partial response or better).Hematological and organ responses were assessed according to consensus criteria.All participants provided written informed consent prior to enrollment.

Results

As of the cutoff date (July 6,2025), 9 pts were enrolled(median age: 68 years [range 47-73]; male: 8 [89%]). At screening, 2 (22%) and 3 (33%) pts had Mayo 2012 stage III and IV, respectively. The median (range)NT-proBNP, hsTnT and dFLC were 2249 ng/L(92-70000), 60.7 ng/L(13.7-392.0), and 155 mg/L (31-1023) respectively.8(89%) had ≥2 organs involvement of amyloidosis, including 6(67%) with cardiac (2 Stage II, 2 Stage IIIa, 2 Stage IIIb),8(89%) with renal, 8(89%) with subcutaneous involvement.

The median number of DPD cycles completed was 2(range 0.5-6).Two pts underwent auto-SCT after completing 3 and 4 cycles,respectively.

Hematological Response: Considering the best hematologic response at any time,of the 8 pts evaluable for response, 7 pts achieved hematologic response(4 PR,1VGPR,2CR),with a median time to response of 1 cycle(range 1-3).At the end of the first cycle,a hematologic response (≥PR) was achieved by 5 (71.43%) pts (CR:1[14.3%];VGPR: 1 [14.3%];PR: 3 [42.9%]).

Organ Response: Six patients were evaluable for organ responses.67% (5/8) and 56% (4/5) of patients were evaluable for renal and cardiac responses, respectively. 100% (5/5) achieved renal responses within a median of 2 cycles, and 25% (1/4) showed cardiac response. The patient achieved a cardiac PR after 2 cycles and subsequently a cardiac CR after 3 cycle.No organ progression was observed in evaluable patients. All patients remain alive.

Safety Profile:All pts experienced ≥1 non-serious hematological adverse events(AEs),mostly neutropenia(78%) and anemia(89%).Grade 3/4 AEs included neutropenia in 3 patients (without associated infections) and anemia in 1 patient..A single pt experienced a grade 1 respiratory infection,unrelated to neutropenia.There were no gr 4 infections/ non-hem AEs or discontinuations due to TEAEs.

Conclusions

This prospective study demonstrates that frontline DPd induces high rates of deep hematologic responses and organ responses in newly diagnosed AL amyloidosis, with a manageable safety profile. Rapid clinical improvements were observed within the first treatment cycle.Even 2 pts had the opportunity to undergo auto-SCT after 3 and 4 cycles respectively.Ongoing enrollment and extended follow-up will further define the durability of remission and long-term outcomes.

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2025
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