On August 24th, Genmab announced that the ALCYONE trial, which compared the combination of daratumumab (Darzalex®) with VMP (Velcade®/melphalan/prednisone) to VMP alone, hit the primary endpoint for treatment of myeloma as a frontline therapy. The progression-free survival (PFS) for the VMP alone was 18.1 months versus “not reached” with the addition of daratumumab. Showing the added value of daratumumab is very important in Europe, where VMP is a standard frontline regimen.

Ramifications for US patients

The result is also more broadly important, as it illustrates both the tolerance and benefit with a 4-drug upfront combination, and the potential similar benefit which may be achieved by adding daratumumab to other 3-drug combinations, such as CyBorD (Cytoxan/bortezomib [Velcade]/dexamethasone, the US equivalent of VMP); VRD (Velcade/Revlimid®/dexamethasone), or KRd (Kyprolis®/Revlimid/dexamethasone). Other trials with these alternate 4-drug combinations are ongoing or upcoming.

These new frontline data have several implications:

  • An “IMiD-free” frontline regimen is a conceptual game-changer for myeloma therapy specialists. Although VMP is not used in the US, a daratumumab/CyBorD regimen can be considered a potentially very active 4-drug combo, which includes no IMiD and only two of the more expensive novel agents. It is always good to have a back-up regimen for patients for whom an IMiD-containing treatment might not work well or might not be tolerable.
  • A “dara-triplet” in frontline also becomes a potential option for discussion. The POLLUX and CASTOR trials, with daratumumab combined with Rd and Vd respectively, raised the bar for expectations in the early relapse setting. A recent meta-analysis identified daratumumab/Rd as the best option for early relapse patients.  The high response rates and achievement of MRD (minimal residual disease)-negative status for relapse patients raise hopes for excellent results as frontline therapy. Could dara/Rd or dara/Vd challenge the current VRd standard of care?  Or even challenge the dara/VMP or dara/CyBorD options? In other words, might 3 drugs be equivalent to or even better than the more complex and more expensive 4-drug options? Many things to ponder!
  • Daratumumab administration is an issue because of the real-world impact of long infusion times, especially in the first cycle. Since infusion times for the first dose can be as much as 12 hours (or more) in the UK and many US clinics, inpatient administration becomes necessary. This is costly and challenges the capabilities of infusion centers. For this reason, the introduction of subcutaneous administration will be welcomed once it is fully tested and approved as an alternative administration method. Trials with subcutaneous daratumumab are ongoing in Europe and in the US. The challenge is to find the ideal volume of the drug that is both tolerable and retains the full treatment benefit. 
  • The cost of this treatment is absolutely the elephant in the room for all discussions about new combinations for myeloma therapy. Can the reimbursement system withstand the costs of a 4-drug combination which might include 3 very expensive agents? How many patients could conceivably handle a five-figure co-pay?  Isn't that untenable for nearly everyone?

The bottom line

These are hopeful but challenging times for myeloma doctors, their patients, and patients’ loved ones. We all must assess the value of the rapidly emerging new therapies and combinations, balancing effectiveness, quality of life, and cost, to decide which approach is best. It is certainly one of the most difficult tasks we face.

But evaluating these choices fully armed with the facts is proof positive that knowledge is power. Stay tuned!

Image of Dr. Brian G.M. DurieDr. Brian G.M. Durie serves as Chairman of the International Myeloma Foundation and serves on its Scientific Advisory Board. Additionally, he is Chairman of the IMF's International Myeloma Working Group, a consortium of nearly 200 myeloma experts from around the world. Dr. Durie also leads the IMF’s Black Swan Research Initiative®.

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