Daratumumab induces deeper and longer responses in patients with newly diagnosed multiple myeloma
In patients with newly diagnosed, transplant-eligible multiple myeloma, the addition of daratumumab to lenalidomide, bortezomib and dexamethasone (D-RVd), followed by daratumumab plus lenalidomide as maintenance therapy, results in deeper and improved responses compared to RVd followed by lenalidomide alone. Maintenance therapy with daratumumab-lenalidomide was shown to increase the rate of stringent complete response and minimal residual disease negativity, compared to post-consolidation rates. No new safety concerns were observed with longer follow-up.
Background
Daratumumab is an IgG1k monoclonal antibody directed against CD38, and is FDA approved as both monotherapy and in combination with standard-of-care regimens in both the relapsed/refractory and newly diagnosed multiple myeloma (NDMM) settings. The phase II GRIFFIN trial evaluates the efficacy of daratumumab in combination with lenalidomide, bortezomib and dexamethasone (D-RVd) compared to RVd alone in patients with transplant-eligible NDMM. Primary analysis of the trial already demonstrated significantly improved rates of stringent complete response by the end of post-transplantation consolidation therapy. With longer median follow-up, the efficacy of D-RVd was further demonstrated with improved MRD-negativity rates, compared to RVd (51.0% versus 20.4%) and estimated 24-month progression-free survival (PFS) rates of 95.8% and 89.9%, respectively. At ASH 2020, updated efficacy and safety data from the GRIFFIN trial following 12 months of maintenance therapy were presented.
In total, 207 patients were randomized (1:1) to D-RVd or RVd. Patients received four induction cycles, followed by ASCT, two consolidation cycles and maintenance with R ±D for 24 months. During induction and consolidation, patients received lenalidomide (25 mg orally on days 1-14), bortezomib (1.3 mg/m2 via subcutaneous injection on days 1, 4, 8 and 11) and dexamethasone (20 mg orally on days 1, 2, 8, 9, 15 and 16). Daratumumab was given at a dose of 16 mg/kg via intravenous infusion on days 1, 8 and 15 of cycles 1-4 and day 1 of cycles 5-6. During maintenance (cycles 7-32), patients received lenalidomide (10 mg [15 mg in cycles 10+ if tolerated] on days 1‐21 every 28 days) with or without daratumumab (16 mg/kg IV Q8W [or Q4W per patient decision after Amendment 2]). Demographic and clinical characteristics were well balanced across the two treatment arms.
Results
Most of the patients enrolled in the study entered the maintenance phase (D-RVd: 87 %, RVd: 68%) with fewer treatment discontinuations during maintenance in the D-RVd group (12%) compared to RVd (17%). The most common reasons for discontinuation during maintenance were adverse events and progressive disease. Responses clearly deepened over time in both treatment arms. At the end of post-transplant consolidation (median follow-up: 13.5 months) the stringent complete response (sCR) rate favored D-RVd over RVd at 42.4% versus 32.0%, respectively (1-sided p= 0.0680). With additional D-R or R maintenance therapy, responses continued to deepen and remained higher for patients in the D-RVd group compared to those in the RVd group. At the 12-months-of-maintenance therapy data cut (median follow-up: 26.7 months), the 63.6% sCR rate in the D-RVd arm remained significantly higher than the 47.4% sCR rate among patients randomized to RVd (2-sided p= 0.0253). In the intention to treat (ITT) population, MRD-negativity (10-5) was obtained in 62.5% of patients treated with D-RVd as compared to 27.2% of patient in the RVd arm (p< 0.0001). The same trend was observed in patients who achieved a complete response or better (76.5% versus 42.4%, p< 0.0001). Similarly, also MRD-negativity (10‒6) rates favoured D-RVd versus RVd in the ITT population (26.9% versus 12.6%, p= 0.0140), as well as among patients who achieved CR or better at that time (34.6% versus 18.6%, p= 0.0555). Importantly, MRD-negativity rates (10-5) lasting ≥6 months and ≥12 months were 37.5% and 28.8% in D-RVd patients, which is significantly higher than the 7.8% and 2.9% seen in RVd patients (p< 0.0001 in both cases), which underscores the durability of the deep responses to the daratumumab-based regimen. Finally, also the estimated 24-month PFS rates (94.5% versus 90.8%) and OS rates (94.7% versus 93.3%) were in favour of D-RVd, although no significant difference was observed.
From a toxicity perspective, higher rates of neutropenia (61% versus 39%) and upper respiratory infections (68% versus 50%) were observed with D-RVd than with RVd. Nevertheless, this did not lead to increased rates of treatment discontinuation. Importantly, during the maintenance phase similar rates of first onset any grade and grade 3-4 infections occurred for D-RVd versus RVd.
Conclusions
In the phase II GRIFFIN trial, D-RVd followed by D-R maintenance significantly improved response rates and depth of response versus RVd followed by R maintenance. Furthermore, D-R maintenance therapy improved the depth of response and maintained remissions. The overall safety profile of D-RVd was consistent with previous reports daratumumab plus standard of care. Finally, PFS and OS rates at 24 months in the D-RVd group are promising. The ongoing phase III PERSEUS study is evaluating subcutaneous daratumumab plus RVd in transplant-eligible patients. Overall, these results support the use of D-RVd as a potential new standard of care for transplant-eligible NDMM patients.
Reference
Kaufman JL et al., Daratumumab (DARA) Plus Lenalidomide, Bortezomib, and Dexamethasone (RVd) in Patients with Transplant-Eligible Newly Diagnosed Multiple Myeloma (NDMM): Updated Analysis of Griffin after 12 Months of Maintenance Therapy. Presented at ASH 2020; abstract 549.
