FDA panel opposes continued approval of melphalan flufenamide in relapsed/refractory multiple myeloma

Committee member Christopher Li eu, MD, of the University of Colorado, said, “I voted no. Post-hoc analysis really should be used for hypothesis generation as opposed to labeling and indication for use. There’s certainly a need for better drugs. We all feel that, but we shouldn’t be using drugs that might be harming patients. To me, the answer is simple. You have an analysis which may support the use in a specified patient population that could show a benefit, and a confirmatory study should be performed in this population, but the data do not support the use of this agent currently.”

Additionally, committee member and a patient of multiple myeloma himself, David E. Mitchell expressed, “Frankly, this could be a life-or-death decision for me and others like me, but after listening closely to both the sponsor and FDA presentations, I conclude that melphalan flufenamide has demonstrated a lack of confirmed benefit, inferior overall survival [OS], and a potential for harm. Post-hoc analysis shouldn’t be used to confirm a drug.”

The drug received accelerated approval for use in combination with dexamethasone in 2021; however, data from the confirmatory phase III OCEAN trial (NCT03151811) did not meet the primary or secondary end points of improved progression-free survival (PFS) and OS vs pomalidomide (Pomalyst) and dexamethasone according to FDA standards. In the meeting, committee members reviewed the benefit-risk ratio of melphalan flufenamide for patients with relapsed or refractory multiple myeloma who have received at least 4 prior lines of therapy and whose disease is refractory to at least 1 proteasome inhibitor, 1 immunomodulatory agent, and 1 CD38-directed monoclonal antibody. The regulatory agency based its concerns for continued approval on the potential detriment in OS, failure to demonstrate PFS improvement, and lack of an appropriate dose with the alkylating cytotoxic agent.

Preliminary results from the trial showed that the median OS was 19.7 months (95% CI, 15.1-25.6) with melphalan flufenamide/dexamethasone vs 25.0 months (95% CI, 18.1-31.9) with pomalidomide/dexamethasone (HR, 1.104; 95% CI, 0.846-1.441), highlighting a detriment in survival in the investigative arm vs the control arm. Updated results showed a continued detriment in OS, with a median OS of 20.2 months (95% CI, 15.8-24.3) with melphalan flufenamide vs 24.0 months (95% CI, 19.1-28.7) with pomalidomide (HR, 1.144; 95% CI, 0.913-1.435).

Although Oncopeptides, showed data illustrating that the OS results could have been adversely affected by patients with a time to progression within 36 months of transplant, the FDA contended that subgroups were not prospectively included in the statistical analysis plan with control of Type I error, and subgroup analyses cannot be used to conclude a treatment benefit in a subpopulation––in this case, patients without autologous stem cell transplant (ASCT) or post-ASCT progression after 36 months. Notably, the FDA encouraged Oncopeptides to pursue a prospective trial in this population to confirm the potential benefit therein.

Additionally, the FDA showed that the median PFS in the primary analysis was 6.9 months (95% CI, 5.1-8.5) with melphalan flufenamide/dexamethasone vs 4.9 months (95% CI, 4.2-5.9) with pomalidomide/dexamethasone, failing to demonstrate statistical superiority (HR, 0.817; 95% CI, 0.659-1.012; P = .0644). Oncopeptides asserted that updated findings showed that treatment with melphalan flufenamide was superior to pomalidomide with regard to PFS in this population (HR, 0.792; 95% CI, 0.640-0.979; P = .0311). The analysis was conducted by a blinded independent review committee after determining that data from 29 patients needed to be reassessed. However, the FDA maintained that the trial failed to demonstrate PFS benefit and further emphasized that worse OS negates any real or perceived PFS improvement.

The final point that was made was that the fixed 40-mg dose evaluated in the trial was poorly tolerated and led to high rates of dose modification. Specifically, 78% of patients experienced at least 1 dose modification, 47% experienced at least 1 adverse effect (AE) leading to dose reduction, and 26% experienced at least 1 AE leading to drug discontinuation.