Daratumumab Plus VRd Improved Depth of Response in Transplant-Eligible, Newly Diagnosed Myeloma

Peter Voorhees, MD

Peter Voorhees, MD

The GRIFFIN study showed that the addition of daratumumab (Darzalex) to bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (VRd), improved stringent complete response (sCR) in transplant-eligible patients with newly diagnosed multiple myeloma without affecting stem cell mobilization or hematopoietic reconstitution, according to results presented at the 17th International Myeloma Workshop.¹

Specifically, at a median follow-up of 13.5 months, the (sCR) rate by end of consolidation was 42.4% with the daratumumab regimen (D-VRd) and 32.0% for VRd (odds ratio [OR], 1.57; 95% CI, 0.87-2.82; 1-sidedP= .068). The results support D-VRd as a potential new standard of care for transplant-eligible newly diagnosed multiple myeloma, said lead study author Peter M. Voorhees, MD, Levine Cancer Institute, Atrium Health, who presented the data during the meeting.

The rationale for adding daratumumab to induction therapy with a proteasome inhibitor plus immunomodulatory drug for transplant-eligible patients with multiple myeloma is supported by the phase III CASSIOPEIA trial,²among others.

At the meeting, Voorhees explained that the addition of daratumumab to VRd (D-RVd) for transplant-eligible multiple myeloma holds the promise for an unprecedented PFS. However, given the increasingly long PFS seen in trials with newer, highly active agents, surrogate markers with an early read-out are needed to facilitate patient access to therapy.

Voorhees proposed sCR and minimal residual disease (MRD) as surrogate endpoints for PFS and overall survival (OS), because they are associated with better PFS and OS after autologous stem cell transplant (ASCT).

In the phase II GRIFFIN study (NCT02874742), investigators randomized patients with transplant-eligible multiple myeloma 1:1 to receive VRd with or without daratumumab. Patients received 4 induction cycles, stem cell mobilization, high-dose therapy, ASCT, 2 consolidation cycles, and maintenance lenalidomide with D-VRd (n = 104) or VRd (n = 103) for 24 months.

During induction/consolidation (cycles 1‐6), patients received bortezomib 1.3 mg/m2 subcutaneously on days 1, 4, 8, and 11; lenalidomide at 25 mg twice daily on days 1 to 14; and dexamethasone 40 mg twice daily (20 mg in induction and 20 mg in consolidation) on days 1, 2, 8, 9, 15, and 16. Daratumumab was administered at 16 mg/kg intravenously (IV) on days 1, 8, and 15 of cycles 1‐4 and on day 1 of cycles 5‐6. During maintenance (cycles 7-32), patients received lenalidomide 10 mg (15 mg in cycles 10 and thereafter if tolerated) on days 1 to 21 every 28 days with or without 16 mg/kg IV of daratumumab every 8 weeks ,or every 4 weeks per patient decision after Amendment 2 of the protocol.

The primary endpoint was the sCR rate by the end of consolidation. The study had 80% power to detect a 15% improvement with a 1-sided alpha of 0.1 (equivalent to 2-sided alpha of 0.2). Secondary endpoints included MRD by next-generation sequencing with a sensitivity of 10-5, complete response, overall response rate (ORR), and ≥very good partial response (VGPR).

Voorhees pointed out that the GRIFFIN trial was designed as a "practice-informing" trial. Key differences between GRIFFEN and CASSIOPEIA include the use of granulocyte-colony stimulating factor (G-CSF) with and without plerixafor for stem cell mobilization in the former, and G-CSF with cyclophosphamide in the latter.

In addition, in CASSIOPEIA, there was a second randomization to maintenance with and without daratumumab. Baseline characteristics were well-balanced between arms. Median age was 60 years, and about half of patients had an ECOG performance status of 1.

Additional data showed that the post-consolidation ORR was 99.0% for D-VRd versus 91.8% for VRd (2-sidedP= .0160), with ≥CR of 51.5% for D-VRd compared with 42.3% for VRd (sCR 1-sided P = .068). The daratumumab regimen was also associated with higher VGPR than VRd alone (90.9% vs 73.2%). Responses deepened over time, and response rates and depths were greater for D-VRd than VRd at all time points, including the ends of induction, ASCT, consolidation, and clinical cutoff.

D-VRd significantly increased the rate of MRD-negativity (10—5) rates at the end of consolidation regardless of response versus VRd at 44.2% and 14.6% respectively (OR, 4.70; 95% CI, 2.38-9.28;P<.0001). MRD negativity was also significantly higher among patients achieving &ge;CR with D-VRd (58.8% vs 24.4%; OR, 4.65; 95% CI, 1.76-12.28;&nbsp;P<.0014).

A significantly higher percentage of patients had both MRD negativity and &ge;CR in the D-VRd arm than the VRd arm. A post-hoc analysis looked at MRD negativity in patients who received ASCT, because more patients in the VRd arm did not go to transplant because of a suboptimal response. MRD negativity occurred in 47.9% of patients who received ASCT and D-VRd compared with 17.9% with ASCT and VRd (OR, 4.31; 95% CI, 2.10-8.85;P<.0001).In a pre-specified subgroup analysis, D-VRd was favored over VRd for MRD negativity and sCR, except among patients with high-risk cytogenetics (OR, 1.67; 95% CI, 0.32-8.74) and International Staging System stage III disease (OR, 4.89; 95% CI, 1.80-12.99). Duration of response, PFS, and OS require longer follow-up.

Regarding safety, the treatment-related adverse events were as expected. Any-grade infections occurred in 82% of patients in the D-VRd arm and 55% of patients in the VRd arm; the grade &ge;3/4 infection rate was similar between arms (17%), as was the rate of pneumonia (10% vs 9%). Infusion-related reactions occurred in 41% of patients treated with daratumumab, and were mainly grade 1/2 and occurring with the first infusion. D-VRd did not affect stem cell mobilization or hematopoietic reconstitution.

Voorhees said these results support D-VRd as a potential new standard of care for patients with transplant-eligible newly diagnosed multiple myeloma. However, the potential for MRD as a surrogate for PFS or OS will require additional follow-up. An ongoing phase III trial in evaluating subcutaneous daratumumab added to VRd in transplant-eligible patients, which is powered for PFS, requiring longer time to results.

References

1. Voorhees P, Kaufman JL, Laubach J, et al. Daratumumab + lenalidomide, bortezomib & dexamethasone improves depth of response in transplant-eligible newly diagnosed multiple myeloma: GRIFFIN. Presented at: The 17th International Myeloma Workshop; September 12-15, 2019; Boston, MA. Abstract 906.
2. Moreau P, Attal M, Hulin C et al. Bortezomib, thalidomide, and dexamethasone with or without daratumumab before and after autologous stem-cell transplantation for newly diagnosed multiple myeloma (CASSIOPEIA): a randomised, open-label, phase 3 study.Lancet.2019;394:29-38. doi: 10.1016/S0140-6736(19)31240-1.