GRIFFIN Patient-Reported Outcomes Data Support Frontline Daratumumab-Quadruplet Therapy in Transplant Eligible, Newly Diagnosed, Multiple Myeloma

Rebecca Silbermann, MD, MMS

Daratumumab (Darzalex) in addition to bortezomib (Velcade), lenalidomide (Revlimid), and dexamethasone (RVd) induction/consolidation therapy, as well as with lenalidomide maintenance, showcased a promising health-related quality of life (HRQOL) benefit for patients with transplant eligible, newly diagnosed multiple myeloma, according to findings from the phase 2 GRIFFIN study (NCT02874742) which was presented at the 2022 ASH Annual Meeting.

At a median follow-up time of 49.6 months, the median time to worsening disease symptoms (HR, 0.75; 95% CI, 0.43-1.30) and utility scores were not reached in the daratumumab plus RVd (D-RVd) arm (HR, 0.49; 95% CI, 0.30-0.81). The median time to worsening of treatment side effects in the D-RVd arm was more than twice as long as those who received RVd alone (HR, 0.82; 95% CI, 0.57-1.18).

Patients who received D-RVd also reported worsening global health score symptoms 30 months later than patients who received RVd (HR, 0.71; 95% CI, 0.46-1.10).

Moreover, there was no difference between treatment arms for median time to worsening of EQ-5D-5L visual analog scores (HR, 0.86; 95% CI, 0.56-1.33).

“Daratumumab, in combination with RVd, during induction and consolidation followed by daratumumab and lenalidomide maintenance resulted in improvements in HRQOL, with a notable reduction in pain symptoms,” Rebecca Silbermann, MD, MMS, associate professor of medicine at the Division of Hematology/Medical Oncology at Oregon Health & Science University, said in a presentation of the findings.

The standard of care regimen for fit patients with newly diagnosed multiple myeloma is induction therapy followed by high-dose therapy (HDT) and autologous stem cell transplant (ASCT) with lenalidomide maintenance. Daratumumab is a human monoclonal antibody which targeted CD38. It is approved both alone, and in combination with standard of care regimens, for multiple myeloma.

GRIFFIN was a randomized, open-label, phase 2 trial, conducted across 35 sites in the United States. The study enrolled transplant eligible patients with multiple myeloma who were between the ages of 18 to 70 years and who had ECOG performance scores between 0 and 2, to assess daratumumab in this setting. Eligible patients also needed a creatinine clearance of at least 30 mL/min. Baseline PRO scores were balanced across the study.

Patients were randomly assigned 1:1 to receive either D-RVd or RVd. Treatment included 4 twenty-one-day induction cycles of either D-RVd or RV-d, followed by transplant, during which stem cells were mobilized with a granulocyte colony-stimulating factor, with or without plerixafor, followed by 2 cycles of consolidation therapy with either D-RVd or RV-d. Patients went on to receive maintenance therapy in 28-day cycles with either a combination of daratumumab plus lenalidomide or lenalidomide alone. Following 2 years of maintenance therapy, patients could continue to receive lenalidomide therapy per local standard of care guidelines.

The final analysis was conducted after all patients completed at least 1 year of long-term follow-up after completing study maintenance therapy. The primary end points were stringent complete response rate, and detection of a 15% improvement. Other end points included minimal residual disease negativity, overall response rates, very good partial response, complete response, progression-free survival (PFS) and overall survival.

Ultimately, 207 patients were randomized to the GRIFFIN trial, including 104 patients in the D-RVd cohort and 103 in the RVd cohort. At baseline, the compliance rates were greater 81%. Post-ASCT consolidation, the compliance rates were 63% in the D-RVd group and 49% in the RVd group.Throughout 24-months of follow-up, the compliance rates decreased to 49% and 45%, respectively.

PROS were collected at baseline (day 1 of cycle 1), on the first days of cycles 2, 3, and 5, on the 21st day of cycle 4, following ASCT-consolidation, and 6, 12, 18, and 24 months of maintenance. Patients were asked to complete the European Organization for the Research and Treatment of Cancer Quality of Life Questionnaire (EORTC QLQ-C30), the EORTC Multiple Myeloma module quality of life questionnaire (EORTC QLQ MY20), and the EQ-5D 3L, which queried across functional scales, global health score symptoms, visual analog scales, utility scores, worsening of symptoms, and future health perspectives.

Compliance was calculated by dividing the number of assessments received at each time point by the number of anticipated assessments for that corresponding time. PRO scores were descriptively summarized by treatment group at each time point and the treatment effects were evaluated through a mixed-efforts model which utilized baseline scores as a dependent variable and included the following independent variables: baseline, visits, treatment, and visits by treatment interaction. Results were stratified by ISS staging, baseline creatinine clearance, and individual subject as random effect.

A distribution-based method was used to define worsening in PRO scores, this was estimated via the Kaplan-Meier method. Cox proportional hazard were used for hazard ratio computations and to find the associated 95% CI.

In the final analysis of the trial, D-RVd led to a clinically meaningful PFS benefit compared with RVd along (HR, 0.45; 95% CI, 0.21-0.95; P = .0324). Response rates, as well as minimal residual disease negativity rates, were found to deepen throughout treatment without yielding new safety concerns, according to Silberman.

The EORTC QLQ-MY20 scores showed reduction in disease symptoms with both treatments across multiple time points. The reductions favored D-RVd over RVd, with an LS mean change of –15.5(95% CI, –20.7 to –10.3) vs –8.2 (95% CI, –14.8 to –1.6) at 24 months.

Both treatment groups showcased comparable improvements in future perspective scores.

There were meaningful global health score changes in both the D-RVd and RVd treatment groups, according to the EORTC QLQ-C30 Scores over time. The LS mean change with both groups at 24 months of maintenance, respectively, were 13.6 (95% CI, 8.4-18.9) vs 9.4 (95% CI, 2.5-16.2). Similarly, both groups saw improvements in physical functioning scores, the mean change at 24 months of maintenance, respectively, were 22.0 (16.5-27.6) vs 12.6 (5.6-19.7).

Both treatment methods yielded improvements in both the EQ-5D-5L VAS and the EQ-5D-5L Utility Scores at the 24-month mark. Patients receiving D-RVd experienced an LS mean change in visual analog scale of 11.5 (95% CI, 6.6-16.4) while patients receiving RVd experienced a mean change of 8.9 (95% CI, 2.4-15.4).

In addition, at 24-months post-maintenance, there was a meaningful reduction in pain symptoms for patients who received both D-RVd and RVd, however, large reductions greater than a 20-point change, were observed in greater abundance in the D-RVd group post-ASCT consolidation (LS mean change, –30.4; 95% CI, –37.9 to –22.9) and throughout the maintenance phase (LS mean change, –19.7; 95 CI, –29.4 to –10.1). Fatigue scores also favored D-RVd; these patients experienced a greater reduction in fatigue symptoms at month 24 (LS mean change, –19.1; 95% CI, –25.6 to –12.5) than those in the RVd cohort (LS mean change, –13.1; 95% CI, –21.5 to –4.7).

Reference

Silberman R, Laubach J, Kaufman JL, et al. Health-related quality of life in transplant-eligible patients with newly diagnoses multiple myeloma treated with daratumumab, lenalidomide, bortezomib, and dexamethasone: patient-reported outcomes from GRIFFIN. Blood. 2022;140(suppl 1):1146-1149. doi:10.1182/blood-2022-162313