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Update: Find the latest report on the GRIFFIN trial, here.
The combination of bortezomib, lenalidomide, and dexamethasone (VRd), a standard induction regimen for patients with newly diagnosed multiple myeloma (NDMM), improved progression free survival (PFS) and overall survival (OS) in NDMM patients undergoing autologous stem cell transplant (ASCT). The phase II GRIFFIN study (MMY2004, NCT02874742) evaluated whether the addition of daratumumab to VRd (D-VRd), a monoclonal CD38 antibody, followed by ASCT, could further enhance the depth of response in this setting. Previously reported results of the safety run-in phase of the study demonstrated that the regimen is safe and well-tolerated, with the depth of response improving over time. Peter Voorhees and colleagues recently published in Blood the updated efficacy and safety results of the trial.1
The multicenter, randomized, open-label, active-controlled study enrolled patients between December 20, 2016, and April 10, 2018. Key eligibility criteria included:
Patients stratified by International Staging System (ISS) disease stage and creatinine clearance were randomized 1:1 to receive D-VRd or VRd. Patients in both treatment groups received four 21-day induction cycles and two 21-day consolidation cycles of oral lenalidomide (25 mg daily on Days 1–14), subcutaneous bortezomib (1.3 mg/m2 on Days 1, 4, 8 and 11), and oral dexamethasone (20 mg on Days 1, 2, 8, 9, 15, and 16).
Patients in the D-VRd group received intravenous daratumumab (16 mg/kg) on Days 1, 8, and 15 of cycles 1–4 and Day 1 of post-ASCT consolidation cycles (cycles 5– 6). From cycle 7 until disease progression or ≤ 2 years, all patients received oral lenalidomide (10 mg daily on Days 1-21, increasing to 15 mg after 3 cycles, if tolerated) as maintenance therapy (28-day cycles). Additionally, patients in the D-VRd group received intravenous daratumumab (16 mg/kg) on Day 1 every 8 weeks or every 4 weeks. Following the completion of study maintenance therapy, patients can continue on lenalidomide.
Patients underwent stem cell mobilization after 4 cycles of induction therapy, followed by high-dose therapy (HDT; melphalan 200 mg/m2) and ASCT. Consolidation therapy began 60-100 days after transplantation and maintenance therapy within 14 days of post-consolidation disease evaluation.
Study endpoints included:
Table 1. Baseline patient and disease characteristics
D-VRd, daratumumab + VRd; ECOG, Eastern Cooperative Oncology Group; ISS, International Staging System; VRd, bortezomib, lenalidomide, and dexamethasone *ECOG performance status was assessed in 101 patients from the D-VRd group and 102 patients from the VRd group †cytogenetic risk profile was assessed in 98 patients from the D-VRd group and 97 patients from the VRd group |
||
|
D-VRd (n = 104) |
VRd (n = 103) |
---|---|---|
Age, years Median (range) < 65, % |
59 (29–70) 73.1 |
61 (40–70) 72.8 |
ECOG performance status, %* 0 1 2 |
38.6 50.5 10.9 |
39.2 51.0 9.8 |
ISS disease stage, % I II III Missing |
47.1 38.5 13.5 1.0 |
48.5 35.9 13.6 1.9 |
Cytogenetic risk profile, % † Standard risk High risk |
83.7 16.3 |
85.6 14.4 |
Table 2. Primary analysis summary of responses by the end of consolidation
CI, confidence intervals; CR, complete response; D-VRd, daratumumab + VRd; sCR, stringent CR; SD, stable disease; PD, progressive disease; PR, progressive response; VRD, bortezomib + lenalidomide + dexamethasone; VGPR, very good progressive response |
||||
Best response |
D-VRd (n = 99) |
VRd (n = 97) |
Odds Ratio (95% CI) |
p value |
---|---|---|---|---|
Overall response rate, % sCR CR VGPR ≥VGPR PR SD PD |
99 42.4 9.1 39.4 90.9 8.1 1.0 0 |
91.8 32.0 10.3 30.9 73.2 18.6 7.2 1.0 |
8.7 (1.08–71.01) 1.57 (0.87–2.82)
|
0.016 0.068
0.0014 |
Table 3. MRD status at last follow-up after a median follow up of 22.1 months
CI, confidence interval; CR, complete response; D-VRd, daratumumab + VRd; ITT, intent-to-treat; MRD, minimal residual disease; VRd, bortezomib + lenalidomide + dexamethasone *< 10-5 of malignant plasma cell |
||||
MRD-negative status, n (%)* |
D-VRd |
VRd |
Odds ratio (95%, CI) |
P value |
---|---|---|---|---|
ITT population MRD negative MRD negative with ≥ CR |
53/104 (51.0) 49/104 (47.1) |
21/103 (20.4) 19/103 (18.4) |
4.07 (2.18–7.59) 3.89 (2.07–7.33) |
< 0.0001 < 0.0001 |
In patients achieving ≥ CR |
49/79 (62.0) |
19/59 (32.2) |
3.57 (1.72–7.44) |
0.0006 |
MRD-evaluable population |
53/77 (68.8) |
21/65 (32.3) |
4.47 (2.19–9.11) |
< 0.0001 |
Table 4. Grade 3/4 AEs reported in ≥ 3% of patients
AE, adverse event; D-VRd, daratumumab + VRd; NA, not applicable; VRd, bortezomib + lenalidomide + dexamethasone *There were no grade 4 infusion-related reactions |
||
AE, % |
D-VRd (n = 99) |
VRd (n = 102) |
---|---|---|
Hematologic Neutropenia Lymphopenia Thrombocytopenia Leukopenia Anaemia |
41.4 23.2 16.2 16.2 9.1 |
21.6 21.6 8.8 6.9 5.9 |
Non-hematologic Pneumonia Fatigue Peripheral neuropathy Diarrhea Back pain |
8.1 6.1 7.1 7.1 1.0 |
10.8 5.9 7.8 3.9 3.9 |
Infusion-related reaction* |
6.1 |
NA |
The study has demonstrated that the addition of daratumumab to VRd resulted in increased rates of sCR and MRD negativity, potential surrogate markers of PFS, in patients with transplant-eligible NDMM. The combination had no impact on stem cell mobilization and engraftment. The deepening of responses over time, and acceptable safety profile of the regimen suggest D-VRD could become a new standard of care for transplant-eligible NDMM. This possibility is currently being investigated in a phase III clinical trial PERSEUS (NCT03710603).
Voorhees PM, Kaufman JL, Laubach JP, et al. Daratumumab, Lenalidomide, Bortezomib, & Dexamethasone for Transplant-eligible Newly Diagnosed Multiple Myeloma: GRIFFIN. Blood. 2020;pii:blood.2020005288. DOI: 10.1182/blood.2020005288
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