CHMP Recommends Melphalan Flufenamide for Triple-Class Refractory Multiple Myeloma

The European Medicines Agency's (EMA) Committee for Medicinal Products for Human Use (CHMP) has unanimously recommended full marketing authorization approval of melphalan flufenamide (melflufen; Pepaxto) for patients with triple-class refractory multiple myeloma.¹

The recommendation stemmed from findings from the phase 2 HORIZON trial (NCT02963493), which investigated melphalan flufenamide plus dexamethasone in patients with relapsed/refractory multiple myeloma. The EMA also based its decision on data from the phase 3 OCEAN trial (NCT03151811) evaluating melphalan flufenamide with dexamethasone vs pomalidomide (Pomalyst) plus dexamethasone in patients with relapsed/refractory multiple myeloma.

In the HORIZON trial, among evaluable 52 patients with triple-class refractory multiple myeloma who had received at least 3 prior lines of therapies and did not receive an autologous stem cell transplant (ASCT) or progressed more than 2 years after an ASCT, melphalan flufenamide elicited an overall response rate (ORR) of 28.8% (95% CI, 17.1%-43.1%), a duration of response (DOR) of 7.6 months (95% CI, 3.0-12.3), and a median time to response (TTR) of 2.3 months (range, 1.0-10.5).

“[Melphalan flufenamide] helps patients with multiple myeloma, an incurable hematologic cancer. [The] positive CHMP opinion confirms that [melphalan flufenamide] provides benefit to these patients and is foundational for the future of Oncopeptides and our development pipeline,” Jakob Lindberg, chief executive officer of Oncopeptides, stated in a press release. “Based on the scientific evaluation by EMA, our dialogue with the FDA has now been intensified to achieve a clear path forward for patients [in the United States].”

In February 2021, the FDA approved melphalan flufenamide for use in combination with dexamethasone in adult patients with relapsed or refractory multiple myeloma. The combination is indicated for patients who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory drug (IMiD), and 1 CD38-directed monoclonal antibody.²

That regulatory decision was also based on data from the HORIZON trial, where melphalan flufenamide produced an ORR of 23.7% and a median DOR of 4.2 months in heavily pretreated patients with relapsed/refractory multiple myeloma (n = 157).²

However, in July 2021, the FDA issued an alert based on evidence from the OCEAN trial indicating that melphalan flufenamide plus dexamethasone resulted in an increased risk of death.³ The agency ordered Oncopeptides to suspend enrollment, and put a halt to enrollment in other ongoing melphalan flufenamide clinical trials.

In October 2021, Oncopeptides withdrew the multiple myeloma indication for melphalan flufenamide plus dexamethasone in the United States, citing FDA concerns that data from the OCEAN trial did not meet the criteria for a confirmatory trial.⁴ The company said at the time that the findings from OCEAN warranted further evaluation.

“The recommendation for full approval of [melphalan flufenamide] by EMA is really good news for patients with triple-class refractory disease, where the unmet medical need remains high and treatment options often are exhausted,” Pieter Sonneveld, professor of Hematology at the Erasmus University Medical Center in Rotterdam, the Netherlands, and principal investigator of the OCEAN study, said in a press release.

At a data cutoff of February 3, 2021, investigators had enrolled 495 patients into OCEAN. Findings showed the median overall survival (OS) in those who received melphalan flufenamide plus dexamethasone was 19.7 months (95% CI, 15.1-25.6) compared with 25.0 months (95% CI, 18.1-31.9) for those administered pomalidomide/dexamethasone (HR, 1.104; 95% CI, 0.846-1.441).⁵

OCEAN recruited patients who were at least 18 years old with documented progression of multiple myeloma, a life expectancy of at least 6 months, and an ECOG performance of 2 or lower. The trial excluded patients who had primary refractory disease; had evidence of mucosal or internal bleeding; were platelet transfusion refractory; had prior exposure to pomalidomide; had known intolerance to IMiDs; had a known infection that required treatment within 14 days of randomization; or had another malignancy diagnosed or requiring treatment within 3 years of enrollment.

Patients in the experimental arm received 40 mg of melphalan flufenamide on day 1 plus 40 mg of dexamethasone on days 1, 8, 15, and 22 of every 28-day cycle. The control arm was given 4 mg of pomalidomide per day for days 1-21, plus the same schedule of dexamethasone.

The primary end point of OCEAN was progression-free survival (PFS) per independent review committee assessment. Secondary end points included ORR, DOR, OS, safety, and tolerability.

HORIZON enrolled patients with relapsed/refractory multiple myeloma who had received 2 or more prior lines of therapy, including exposure to an IMiD and a proteasome inhibitor. Patients were required to be refractory to pomalidomide and/or daratumumab (Darzalex), and they needed to have triple-class refractory disease, extramedullary disease, and/or high-risk cytogenetic features.

Notably, 97 patients enrolled in the trial had triple-class refractory disease and had received at least 4 prior lines of treatment.

Patients in HORIZON received 40 mg of melphalan flufenamide on day 1, plus 40 mg of dexamethasone on days 1, 8, and 15 of every 28-day cycle. Those aged 75 years or older received 20 mg of dexamethasone. Treatment continued until progressive disease or unacceptable toxicity.

The primary end point of HORIZON was ORR. Secondary end points included clinical benefit rate, PFS, OS, DOR, TTR, time to progression, time to next treatment, safety, and quality of life.

References

1. CHMP issues a positive opinion recommending full approval of Oncopeptides Pepaxti in EU for patients with triple class refractory multiple myeloma. News release. Oncopeptides. June 23, 2022. Accessed June 23, 2022. https://prn.to/3Osh3HI
2. FDA approves Oncopeptides' PEPAXTO (melphalan flufenamide) for patients with relapsed or refractory multiple myeloma. News release. Oncopeptides. February 26, 2021. Accessed June 23, 2022. http://cisn.co/3q2bZgq
3. FDA alerts patients and health care professionals about clinical trial results showing an increased risk of death associated with Pepaxto (melphalan flufenamide). News release. FDA. July 28, 2021. Accessed June 23, 2022. https://bit.ly/3f81zJu
4. Oncopeptides withdraws Pepaxto in US, scale down organization and focus on R&D. News release. Oncopeptides. October 22, 2021. Accessed June 23, 2022. https://bit.ly/3vzvjGc
5. Statistical analysis and findings. FDA. Accessed June 23, 2022. https://bit.ly/3yicW9q