Melflufen/Dexamethasone Improves PFS in Transplant-Naïve Relapsed/Refractory Multiple Myeloma

Melphalan flufenamide (melflufen) plus dexamethasone demonstrated an improvement in progression-free survival vs pomalidomide/dexamethasone in patients with transplant-naïve relapsed/refractory multiple myeloma, according to phase 3 data of the OCEAN (OP-103) study (NCT03151811) that were presented at the 18th Annual Internal Myeloma Workshop.¹

Investigators reported that the median PFS as assessed by independent review committee (IRC) for patients in the melfufen group was 6.8 months (95% CI, 5.0-8.5) compared with 4.9 months (95% CI, 4.2-5.7) for patients in the pomalidomide group (HR, 0.79; 95% CI, 0.64-0.98; P = .03). The median follow-up was 15.5 months and 16.3 months for the melflufen and pomalidomide groups, respectively.

“The results from this study show that melflufen [plus dexamethasone] is a better treatment for this patient group than pomalidomide [plus dexamethasone] in patients who have not received a prior transplant, however [the regimen may be] better for…patients who have received a prior transplant,” study presenter, Fredrik Schjesvold, MD, PhD, head of the Oslo Myeloma Center at the Department of Hematology, Oslo University Hospital and KG Jebsen Center for B Cell Malignancies, University of Oslo, explained in a presentation on the findings.

The randomized, open-label, phase 3 comparison study enrolled 495 patients with relapsed/refractory multiple myeloma. In order to be eligible for the study, patients needed to be aged 18 years or older, have had 2 to 4 previous lines of therapy including lenalidomide (Revlimid) and a proteasome inhibitor. Additionally, patients were required to be refractory to lenalidomide and their last line of therapy, as well as having an ECOG performance score of 0 to 2.

Patients were randomized 1:1 to receive either intravenous melflufen at a dose of 40 mg on day 1 of each cycle plus 40 mg of oral dexamethasone once weekly, or 4 mg of oral pomalidomide on days 1 through 21 of each cycle plus 40 mg of oral dexamethasone once weekly.

Patients in the melflufen group (n = 246) had a median age of 68 years (IQR, 60-72) and the majority of the cohort was male (57%). The median age for patients in the pomalidomide group (n = 249) was also 68 years (IQR, 61-72), with 56% of patients being male.

The primary end point of the study was PFS as assessed by IRC per International Myeloma Working Group (IMWG) criteria. Key secondary end points included overall response rate (ORR), overall survival (OS), and safety.

The ORR was 33% (95% CI, 27%-39%) for patients in the meflufen group compared with 27% (95% CI, 22%-33%) for patients in the pomalidomide group. A total of 7 and 3 patients in the melflufen and pomalidomide groups, respectively, achieved a complete response (CR).

In a subgroup analysis, patients in the melflufen group who did not receive a prior autologous stem-cell transplant (ASCT) experienced a PFS benefit. Specifically, median PFS was reported as being 9.3 months (95% CI, 7.2-11.8) vs 4.6 months (95% CI, 3.5-6.3) for the melflufen and pomalidomide groups, respectively (HR, 0.59; 95% CI, 0.44-0.79; P < .001).

OS favored melflufen in patients who had not received a prior ASCT, while patients with a prior ASCT experienced better responses from pomalidomide. Overall, OS data were immature and not statistically significantly different, with melflufen achieving a median OS of 19.8 months (95% CI, 15.1-25.6) compared with 25.0 months (95% CI, 18.1-31.9) for pomalidomide (HR, 1.10; 95% CI, 0.85-1.44; P = .47).

Any grade treatment-emergent adverse effects (TEAEs) were observed in 99% and 98% of patients and grade 3 or higher AEs were observed in 90% and 77% of patients in the melflufen and pomalidomide groups, respectively. Grade 3 or higher non-hematologic TEAEs observed in more than 2% of patients in the melflufen and pomalidomide groups, respectively, included pneumonia (4% vs 8%), muscular weakness (2% vs 2%), hyperglycemia (2% vs 3%), asthenia (2% vs 2%), COVID-19 pneumonia (2% vs 2%), and hypertension (2% vs 2%). Common grade 3/4 TEAEs of special interest in both groups included thrombocytopenia (76% vs 13%), neutropenia (64% vs 49%), infection (13% vs 22%), and infective pneumonia (5% vs 12%).

In total, 46% and 43% of patients in the melflufen and pomalidomide groups, respectively, died. Specifically, deaths occurring after 30 days from the last dose of treatment were reported in 36% of patients in the melflufen group and 30%of patients in the pomalidomide group.

Melflufen plus dexamethasone previously received accelerated approval by the FDA in the United States for the treatment of adult patients with relapsed/refractory multiple myeloma who received 4 or more prior lines of therapy and whose disease is refractory to 1 or more proteasome inhibitor, 1 or more immunomodulatory drug, and 1 or more anti-CD38 monoclonal antibody.

Notably, the regimen received a partial clinical hold from the FDA on July 8, 2021 based on data from the OCEAN trial.² Although the trial had met its end point of PFS, its secondary end point of OS appeared to favor the control arm.

References

1. Schjesvold F, Dimopoulos MA, Delimpasi S, et al. OCEAN (OP-103): a Phase 3, randomized, global, head-to-head comparison study of melflufen and dexamethasone (Dex) versus pomalidomide (Pom) and dex in relapsed refractory multiple myeloma (RRMM). Presented at: International Myeloma Workshop; September 8-11, 2021; Vienna, Austria. Accessed September 11, 2021.
2. Updated results from phase 3 OCEAN study shows melflufen met primary endpoint of superior PFS – Overall survival data lead to partial clinical hold. News release. Oncopeptides AB. July 8, 2021. Accessed July 8, 2021. https://bit.ly/3qUzUR2