Myeloma Expert Provides Insight on Practice-Changing Data

Jesus Berdeja, MD

Novel therapeutic strategies presented over the last year shed light not only efficacious outcomes for patients with multiple myeloma, but also on improved supportive care methods, according to Jesus Berdeja, MD.

FDA Approval of Denosumab

Berdeja, the director of Multiple Myeloma Research at Sarah Cannon Research Institute, provided an update on practice-changing data, some of which were presented at the 2017 ASH Annual Meeting, for patients with multiple myeloma at the 2018 OncLive^® State of the Science Summit^TM on Hematologic Malignancies.In January 2018, the FDA approved denosumab (Xgeva) for the prevention of skeletal-related events (SRE) in patients with multiple myeloma based on data from the phase III 482 study.¹ In this trial, denosumab demonstrated noninferiority to zoledronic acid at delaying the time to the first SRE (HR, 0.98; 95% CI, 0.85-1.14; P = .01).

The median progression-free survival (PFS) was 10.7 months higher for patients receiving denosumab (HR, 0.82; 95% CI, 0.68-0.99; P = .036). There was also a nonstatistically significant trend in overall survival (OS) favoring the denosumab arm (HR, 0.90; 95% CI, 0.70-1.16; P = .41).

The adverse events (AEs) in this study were consistent with the known safety profile for denosumab. The most common AEs were diarrhea at 33.5% versus 32.4% and nausea at 31.5% versus 30.4%, in the denosumab and zoledronic acid arms, respectively.

Daratumumab Plus VMP

“Ultimately, this study demonstrated that denosumab could be used safely in patients with renal insufficiency and is one of the preferred treatment for these patients,” explained Berdeja.In a phase III study, patients with newly diagnosed multiple myeloma were randomized to the anti-CD38 monoclonal antibody daratumumab (Darzalex) plus bortezomib (Velcade), melphalan, and prednisone (VMP) versus VMP alone. The combination of daratumumab with VMP significantly improved PFS, which was driven by more patients achieving deep responses, including significantly higher complete response rates and tripling the minimal residual disease (MRD)-negativity rate. The findings were presented at the 2017 ASH Annual Meeting.²

“What is very intriguing about this study is that the overall response rates were significantly better, but the death of patients was also better than expected,” said Berdeja.

In this trial, 706 patients with transplant-ineligible newly diagnosed multiple myeloma were enrolled. At a median follow-up of 16.5 months, the hazard ratio for PFS was 0.5, representing a 50% reduction in the risk of progression or death in the daratumumab plus VMP arm. The MRD-negativity rate was 22.3% versus 6.2% in the daratumumab plus VMP and VMP-alone arms, respectively.

ASPIRE Trial

Based on these data, the FDA granted a priority review designation to the regimen in January 2018 and will make a decision on the application by May 21, 2018, under the Prescription Drug User Fee Act.The ASPIRE trial investigated the addition of carfilzomib (Kyprolis) to lenalidomide (Revlimid) and dexamethasone for patients with relapsed/refractory multiple myeloma. This combination led to a statistically significant 21% reduction in the risk of death compared with lenalidomide and dexamethasone.³

Patients randomized to the carfilzomib arm had a median OS of 48.3 months versus 40.4 months in the lenalidomide plus dexamethasone arm, with the hazard ratio being 0.79 for the carfilzomib combination arm (95% CI, 0.67-0.95; P = .0045). The median PFS for patients receiving the carfilzomib combination was 26.1 months compared with 16.6 months (HR, 0.66; 95% CI, 0.55-0.78; P <.001). These findings were presented at the 2017 ASH Annual Meeting and published in the Journal of Clinical Oncology.

AE rates were similar between the treatment groups, including all-grade AEs (98.0% in both groups), grade ≥3 AEs (87.0% with carfilzomib vs 83.0% for the control group), serious AEs (65.6% vs 56.8%), discontinuation due to AEs (33.4% vs 30.1%), and grade 5 AEs (11.5% vs 10.5%).

PAVO Study

“As we learn more about how we use these drugs, intervening quickly can make a difference in mitigating this potential toxicity, but it was mostly well tolerated,” Berdeja explained.The phase Ib PAVO study of subcutaneous delivery of daratumumab in patients with relapsed/refractory multiple myeloma suggested that the subcutaneous administration of daratumumab plus recombinant human hyaluronidase enzyme (rHuPH20) was well tolerated with lower than expected rates of infusion-related reactions in all groups.⁴

In this dose-escalation study, 53 patients were enrolled in part 1, 8 of those patients receiving 1200 mg of daratumumab and 45 receiving 1800 mg. In part 2 of the study, 25 patients received 1800 mg of daratumumab subcutaneously.

In part 1, 100% and 73% of patients discontinued treatment in the 1200 mg and 1800 mg dose cohorts, respectively. In part 2, none discontinued treatment with shorter follow-up. Infusion-related reactions were reported in 13%, 24%, and 4% of patients in the 1200 mg, 1800 mg, and 1800 subcutaneous doses, respectively.

“Hopefully, we will have subcutaneous daratumumab, so patients do not need to be in the clinic for 10 hours for their first infusion,” Berdeja concluded.

References

1. Raje NS, Roodman D, Willenbacher W, et. al. Impact of denosumab (DMB) compared with zoledronic acid (ZA) on renal function in the treatment of myeloma bone disease. J Clin Oncol. 2017;35(suppl; abstr 8005).
2. Mateos MV, Dimopoulos MA, Cavo M, et al, Phase III randomized study of daratumumab plus bortezomib, melphalan, and prednisone (D-VMP) versus bortezomib, melphalan, and prednisone (VMP) in newly diagnosed multiple myeloma (NDMM) ineligible for transplant (ALCYONE). In: Proceedings from the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract LBA-4.
3. Siegel DS, Dimopoulos MA, Ludwig H, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma [published online January 18, 2018]. J Clin Oncol. doi: 10.1200/JCO.2017.76.5032.
4. Chari A, Nahi H, Mateos MV, et al. Subcutaneous delivery of daratumumab in patients with relapsed or refractory multiple myeloma: PAVO, an open-label, multicenter, dose escalation phase Ib study. In: Proceedings from the 59th ASH Annual Meeting and Exposition; December 9-12, 2017; Atlanta, GA. Abstract 838.