In a late-breaking abstract at this month’s American Society of Hematology (ASH) Meeting, Johnson & Johnson (J&J) will present data from the Phase III ALCYONE trial of Darzalex in patients with newly diagnosed multiple myeloma who are ineligible for transplant. This data will set the stage for Darzalex’s approval as a frontline therapy for multiple myeloma, the next logical step in its development, as it has already secured significant market share (estimated to be approximately 20% in the second line and increasing) in the relapsed/refractory patient segment in the US.

Regimens for frontline treatment of multiple myeloma are typically chosen based on stem cell transplant (SCT) eligibility. Patients who are SCT-eligible generally have a better performance status and are able to tolerate more intensive treatments, while patients who are SCT-ineligible are generally older and may have one or multiple comorbidities such as renal insufficiency or cardiovascular disease.

The ALCYONE trial evaluated Darzalex in combination with the drug triplet of Velcade + melphalan + prednisone (VMP) in SCT-ineligible patients only. In this study, treatment with D-VMP resulted in a 50% decrease in the risk of progression or death at a median follow-up of 16.5 months (p< 0.0001). Survival data are not yet available. If approved, D-VMP will be competing against the triplet regimen of Velcade + Revlimid + dexamethasone (VRD), which is currently the most frequently prescribed regimen in this setting, according to GlobalData’s primary research.

Despite key opinion leader (KOL) enthusiasm over the incorporation of Darzalex into frontline treatment, there remain several challenges in its anticipated battle with VRD. First, the cost of D-VMP will be an estimated $75,000 higher than that of VRD in the first year of treatment. This difference will be compounded in the near future when both Velcade and Revlimid will be available in generic form. While cost is generally less of a concern in the US market, European KOLs have expressed doubts over the feasibility of administering quadruplet regimens upfront from an economic perspective. Second, US KOLs have expressed doubts over the tolerability of quadruplet regimens in SCT-ineligible patients, who are typically less able to tolerate intensive treatments. They instead envision that quadruplet regimens will have better uptake in the SCT-eligible population, while SCT-ineligible patients may see Velcade being replaced by Darzalex in the future, making way for a Darzalex + Revlimid + dexamethasone (DRD) regimen as standard-of-care (SOC) in the front line.

Last, VMP is a seldom-used regimen that is considered to be inferior to VRD in the US. US KOLs question whether D-VMP can demonstrate superior efficacy to VRD without a head-to-head study. This is less of an issue in other markets, as VMP remains the SOC for frontline treatment of SCT-ineligible patients in Europe, where simply adding Darzalex to the current SOC will be less of a concern from a clinical point of view.

If D-VMP is approved, Darzalex will be part of the first quadruplet combination to enter the multiple myeloma market. This will be a major advantage for a drug that has already significantly impacted the current treatment algorithms, as US KOLs foresee a shift from triplet to quadruplet combination regimens in the frontline setting in the next five years.