Abstract Topic: 14. Myeloma and other monoclonal gammopathies - Clinical
Background: Daratumumab (Dara), given as monotherapy or in combination with other agents, and ixazomib (Ixa), combined with lenalidomide (len) and dexamethasone (dex), have shown antitumor activity with acceptable safety in patients (pts) with relapsed/refractory multiple myeloma (RRMM).
Aims: To present the final outcomes of the DARIA study assessing the efficacy/safety of the Dara-Ixa-dex combination as second-line therapy in pts with RRMM previously treated with a len-based regimen.
Methods: DARIA, a prospective, open-label, multicenter, phase 2 study, included adult pts with RRMM after one prior line with a len-based regimen and a Karnofsky Performance Status (KPS) score ≥70. In the induction phase (nine 28-day cycles), pts received: Dara 16mg/kg (weekly for cycles 1–2, bi-weekly for cycles 3–6, and every 4 weeks [Q4W] thereafter) given IV until November 2020 and SC at a fixed dose of 1800 mg thereafter; oral Ixa 4mg (days 1, 8, 15 of each cycle); and oral dex 40mg (weekly, each cycle). In the maintenance phase, pts received Dara Q4W and Ixa on the same schedule until disease progression/unacceptable toxicity. The primary endpoint was overall response rate (ORR). Other endpoints included overall survival (OS), progression-free survival (PFS), safety, and the effects of the Dara-Ixa-dex combination on serum bone metabolism markers (C-terminal telopeptide of type 1 collagen [CTX], tartrate-resistant acid phosphatase isoform 5b [TRACP-5b], bone-specific alkaline phosphatase [bALP], and osteocalcin [OC]). PFS and OS were analyzed with the Kaplan–Meier method. Statistical significance was set at a=5%.
Results: Fifty pts were included (median [range] age: 69 [50–89] years; male: 28 [56%]). At screening, 38 (76%) pts had a KPS score ≥90, and most were at stage ≤II by the International Staging System (ISS; 42, 84%) or by the revised ISS (47, 94%). Thirty-two (64%) pts were len-refractory and 17 (34%) had prior ASCT. At study completion, 13 (26%) pts were still on treatment and 37 (74%) pts had discontinued (disease progression, 29 [58%]; fatal serious adverse event [SAE], 3 [6%]; physician decision, 3 [6%]; adverse event [AE], 2 [4%];). The median (range) number of study treatment cycles was 9 (1–38).
ORR was 64% (32 pts; complete response, 1 [2%] pt; very good partial response, 16 [32%] pts; partial response [PR], 15 [30%] pts). The median (range) time from first Dara-Ixa-dex dose until first response (≥PR) was 1 (1–18) months. At a median (range) follow-up of 22 (1–40) months, the median (95% confidence interval) OS and PFS were 29 (17–not reached) and 8 (5–16) months.
The changes from baseline to 12 and 15 months for TRACP-5b and bALP were significant (p<0.05), as were those for OC at 3, 12 and 15 months (Table). Overall, 21 (42%) pts had ≥1 AE of grade ≥3. The most common grade 3-4 AE was thrombocytopenia (9 pts, 18%); four fatal SAEs were reported (pneumonia, infection, urinary tract infection, and lower respiratory tract infection). Fourteen (28%) pts had ≥1 SAE, the most common being acute kidney injury and pneumonia (2 pts [4.0%] each).
Summary/Conclusion: Second-line treatment with Dara-Ixa-dex in pts with RRMM who were pretreated with a len-based regimen resulted in rapid (1 month) responses to ≥PR with an ORR of 64%. Less than half of the pts experienced grade ≥3 AEs. Overall, significant increases in CTX, TRACP-5b, bALP, and OC levels from baseline to 15 months were observed, with the respective trend being evident even from 3 months, suggesting an improvement in the osteolytic bone disease and a normalization of the bone remodeling process.
Keywords: Multiple myeloma