Daratumumab Plus RVd Improved Responses for Older and Some High-Risk Patients Compared With Triplet Alone in Newly Diagnosed MM

Key subgroups of patients with newly diagnosed, transplant-eligible multiple myeloma (NDMM) who were treated with daratumumab and a well-known triplet regimen had improved responses—including progression free-survival (PFS)—compared with similar patients receiving only the triplet, according to a post hoc analysis of the phase 2 GRIFFIN study (NCT02874742).¹

The analysis, which was presented during the 64th American Society of Hematology (ASH) Annual Meeting and Exposition December 11, 2022, highlighted stringent complete response (sCR) data for patients 65 years and older and those with high cytogenic risk.

The findings are the latest involving the quadruplet of daratumumab (Darzalex) with lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (D-RVd) in patients with NDMM who are transplant eligible. In August, the final, 4-year data for GRIFFIN were presented at the 2022 International Myeloma Society Annual Meeting, confirming prior results that showed combining the monoclonal antibody with RVd offered improved sCR compared with the triplet. Final results revealed a 55% improved PFS (HR 0.45; 95% CI, 0.21-0.95; P = .0324).²

Initially in GRIFFIN, 16 patients received the quadruplet, which included daratumumab, to evaluate its safety. The trial had a maintenance phase from cycles 7 to 32, which was updated every 28 days based on pharmacokinetic data. Later in the phase 2 part of the study, 207 patients were randomly assigned to either RVd induction and consolidation, autologous stem cell transplant (ASCT), and maintenance with lenalidomide; or D-RVd, ASCT, and maintenance with daratumumab and lenalidomide.

After a median of 13.5 months, GRIFFIN met its primary end point, with a higher percentage of patients taking D-RVd achieving sCR compared with those taking RVd alone after ASCT consolidation therapy: 42.4% vs 32%, respectively.³ Updated results presented at ASH 2021 had confirmed these earlier results and that minimal residual disease (MRD) negativity (10-5) rates were higher for patients in the daratumumab arm.⁴

New Analysis at ASH 2022

Ajai Chari, MD, professor of medicine and director of clinical research in the Multiple Myeloma Program at Mount Sinai in New York, New York, presented the post hoc analysis on key subgroups. Subgroups had a similar number of patients in each arm. The subgroups included patients 65 years and older, patients with stage III disease, patients with high cytogenic risk, patients with revised high cytogenic risk, patients with 1 high-risk cytogenic abnormality (HRCA), patients with 3 or more copies of chromosome 1q21 (gain/amp1q), patients with gain/amp1q plus 1 HRCA, and patients with more than 2 HRCAs. Outcomes for patients with baseline extramedullary plasmacytomas were explored, but there were only 3 of those patients in the study, so outcomes could not be evaluated.¹

Among response evaluable patients, results showed:

• The rate of sCR following maintenance therapy was numerically higher for D-RVd vs RVd among patients 65 years or older (63% vs 40.7%. respectively), with overall response (OR) of 2.47 (95% CI, 0.83-7.39).

• Rates of sCR for D-RVd and RVd arms were numerically higher for those with high cytogenic risk (50.0% vs 38.5%, respectively) (OR 1.60; 95% CI, 0.36-7.07), those with gain/amp1q plus 1 HRCA (55.6% vs 33.3%) (OR 2.50; 95% CI, 0.29-21.40), and those with at least 2 HRCAs (50.0% vs 37.5) (OR, 1.67; 95% CI, 0.25-11.07).
• Rates of sCR were similar for D-RVd and RVd arms among patients with stage III disease (64.3% vs 61.5%, respectively) (OR 1.13; 95% CI, 0.24-5.37), those with revised high cytogenic risk (56.1% vs 55.6%) (OR, 1.02; 95% CI, 0.42-2.52), those with gain/amp1q (57.6% vs 57.1%) (OR 1.02; 95% CI, 0.37-2.82), and those with 1 HRCA (58.1% vs 60.7%) OR, 0.90; 95% CI, 0.32-2.54).

Although sCR was the primary end point of GRIFFIN, MRD negativity rates following the end of maintenance favored D-RVd over RVd across all subgroups, and PFS was favored across all subgroups except those with more than 2 HRCAs.

TREATMENT-EMERGENT ADVERSE EVENTS (TEAES). Among patients 65 years or older, grade 3/4 TEAE events were seen in 88.9% of patients in the D-RVd arm vs 77.8% of those in the RVd arm. Most common were neutropenia (37.0% vs 29.6%, respectively) and lymphopenia (25.9% vs 11.1%). TEAEs led to discontinuation in 37.0% of the D-RVd arm vs 25.9% of the RVd arm. One patient in the D-RVd arm died of pneumonia, unrelated to treatment.

RESULTS FOR BLACK PATIENTS. Of the 207 randomly assigned patients in GRIFFIN, 32 were Black. MM disproportionately affects Black communities in the United States; these patients account for 14% of the US population but 20% of new MM cases.⁵ Underenrollment of Black patients in clinical trials is a recognized problem that the FDA and major cancer centers are working to address.⁶

A separate abstract presented December 12, 2022, at ASH found that after 48 months Black patients enrolled in GRIFFIN in the D-RVd arm saw significant clinical benefits but had lower PFS rates than White patients.⁷ “This may have been attributed to the higher rates of study treatment discontinuation following TEAEs in Black patients,” investigators wrote, calling for more research in this area.

At the end of maintenance, sCR rates among Black patients were 93% in the D-RVd arm vs 39% in the RVd arm (P = .0021); among White patients at this point, the sCR rates were 65% in the D-RVd arm vs 50% in the RVd arm (P = .0589). At a median follow-up of 49.6 months, D-RVd reduced the risk of disease progression or death by 61% in Black patients and 53% in White patients, compared with RVd, investigators found. “For Black patients, estimated 48-month PFS rates were 79% for D-RVd and 65% for RVd; among White patients, estimated 48-month PFS rates were 89% for D-RVd and 74% for RVd,” the investigators wrote.

Janssen funded the GRIFFIN study and is collaborating with the European Myeloma Network on a phase 3 study, PERSEUS (NCT03710603). PERSEUS is not yet recruiting patients.⁸

References

1. Chari A, Kaufman JL, Laubach JP, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone (D-RVd) in transplant-eligible newly diagnosed multiple myeloma (NDMM) patients (Pts): final analysis of GRIFFIN among clinically relevant subgroups. Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022; New Orleans, LA. Abstract 3238. https://ash.confex.com/ash/2022/webprogram/Paper162339.html

2. Final analysis of phase 2 GRIFFIN study presented of Darzalex (daratumumab)-based investigational quadruplet regimen in patients with newly diagnosed, transplant-eligible multiple myeloma. News release. Johnson & Johnson. August 27, 2022. Accessed December 17, 2022. http://bit.ly/3BEsvvV

3. Voorhees PM, Kaufman JL, Laubach J, et al. Daratumumab, lenalidomide, bortezomib, and dexamethasone for transplant-eligible newly diagnosed multiple myeloma: the GRIFFIN trial. Blood. 2020;20;136(8):936-945. doi:10.1182/ blood.2020005288.

4. Laubach JP, Kaufman JL, Sborov DW, et al. Daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients (Pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): updated analysis of GRIFFIN after 24 months of maintenance. Blood. 2021;138(suppl 1):79. doi:10.1182/blood-2021-149024

5. Disparities in African Americans. International Myeloma Foundation. Accessed December 10, 2022. https://bit.ly/3G14cuM

6. Gormley N. Fashoyin-Aje L, Locke T, et al. Recommendations on eliminating racial disparities in multiple myeloma therapies: a step toward achieving equity in healthcare. Blood Cancer Discov. 2021;2(2):119-124. doi:10.1158/2643-3230. BCD-20-0123

7. Nooka AK, Kaufman JL, Rodriguez C, et al. An end-of-study subgroup analysis of Black patients from the phase 2 GRIFFIN study of daratumumab (DARA) plus lenalidomide, bortezomib, and dexamethasone (RVd) in patients with transplant-eligible newly diagnosed multiple myeloma (NDMM). Presented at: 64th American Society of Hematology Annual Meeting and Exposition; December 10-13, 2022, New Orleans, LA. Abstract 4560. https://ash.confex.com/ash/2022/webprogram/ Paper162473.html

8. Daratumumab, Velcade (bortezomib), lenalidomide and dexamethasone compared to Velcade, lenalidomide and dexamethasone in subjects with previously untreated multiple myeloma (Perseus). ClinicalTrials.gov. Updated September 27, 2022. Accessed December 17, 2022. https://www.clinicaltrials.gov/ ct2/show/NCT03710603