Three early Christmas presents… but what will be the New Year’s resolutions?
November was an amazing month for the myeloma community: FDA approval for three new therapies. The very good, but challenging problem is how to integrate and use these three new agents within the recommended treatment protocols for myeloma patients.
First monoclonal antibody approved
On November 16, 2015, the FDA approved Darzalez™(daratumumab) as a single agent in the treatment of relapsed and/or refractory myeloma. A monoclonal antibody against CD-38, a surface antigen universally present on myeloma cells, it is the first monoclonal antibody approved for myeloma. It is given by infusion and works by helping the immune system attack cancer cells. The drug’s safety and efficacy were demonstrated in two studies. In one study of 106 participants receiving Darzalex, 29 percent of patients experienced a complete or partial reduction in their tumor burden, which lasted for an average of 7.4 months. In the second study of 42 participants receiving Darzalex, 36 percent had a complete or partial reduction in their tumor burden.
Daratumumab will be used in the upcoming IMF Black Swan Research Initiative® cure trial, ASCENT. Along with an aggressive strategy consisting of Kyprolis® (carfilzomib), Revlimid® (lenalidomide), dexamethasone, and autologous stem cell transplant, we believe the anti-CD38 monoclonal antibody will provide that extra bit of treatment that could allow the eradication of many, if not all, resistant clones.
An oral proteasome inhibitor
Next, on November 20, 2015, the FDA approved Takeda Oncology’s Ninlaro® (ixazomib), an oral, once-weekly proteasome inhibitor, for use in combination with lenalidomide and dexamethasone to treat people with multiple myeloma who have received at least one prior therapy. Oral treatments like Ninlaro provide myeloma patients new options for treatment. This opens the door for a fully oral proteasome inhibitor-based triplet combination therapy. Having worked in multiple myeloma for decades, I’ve seen notable progress yet significant unmet needs remain. With the new approval, we have another attractive and rather well-tolerated option for many patients living with multiple myeloma.
The safety and efficacy of Ninlaro were demonstrated in an international, randomized, double-blind clinical trial of 722 patients whose multiple myeloma came back after, or did not respond to, previous treatment. Study participants received either ixazomib in combination with lenalidomide and dexamethasone or placebo plus lenalidomide and dexamethasone. Those taking ixazomib in comibation with lenalidomide and dexamethasone lived longer without their disease worsening (average 20.6 months) compared to participants taking the other regimen (14.7 months).
A monoclonal antibody
Finally, on November 30, 2015, the FDA approved Bristol-Myers Squibb’s Empliciti™ (elotuzumab), a monoclonal antibody, for use in combination with lenalidomide and dexamethasone to treat multiple myeloma patients who have received at least one prior therapy. Eloztuzumab is a new class of agent which recruits the activity of natural killer (NK) cells to attack myeloma. The FDA approval is a very important new addition to the myeloma arsenal.
Clinical trials of elotuzumab showed that the drug works more effectively in combination with the immunomodulatory agent Revlimid and the steroid dexamethasone than alone. In a phase III study of 646 patients, Dr. Sagar Lonial of Emory University found that progression-free survival (PFS) increased by nearly 5 months in patients who had received 1-3 prior therapies and who were treated with elotuzumab combined with Revlimid®/ dexamethasone.
According to the study, the benefit was durable: PFS in the elotuzumab/Revlimid/dex-treated arm was 68% at one year and 41% at two years, compared to 57% at one year and 27% at two years in the Revlimid/dex-treated patients. “It was particularly striking that the difference between the elotuzumab and control groups seems to get bigger over time, which really speaks to the power of this immune-based approach,” said Dr. Lonial.
So how do we use these 3 new drugs? Our New Year’s Resolution must be to figure that out!
For daratumumab, the answer is the most straight-forward since it is very active as a single agent in the relapsed/refractory setting. It is an obvious choice as a salvage agent when other therapies have failed. The key additional question will be: How much can daratumumab improve outcomes when used in combination earlier in the disease? The $64,000-question is what will be the added value combined with Velcade/Revlimid/dexamethasone or Kyprolis/Revlimid/dexamethasone (proposed) and/or Velcade/thalidomide/dexamethasone (IFM/Hovon trial starting), all in the frontline setting. This is where using MRD-negative as an early endpoint will indicate potential progression-free survival (PFS) and overall survival (OS) benefit. This new approach will demonstrate the benefit of 3- or now 4-drug combinations within 1 to 2 years, versus having to wait for 7 to 10 years or longer to evaluate full long-term outcomes.
For ixazomib and elotuzumab, the issues are more complex. Yes, both work better as a triplet with Rd versus Rd alone. But when is the optimal time to introduce those triplet therapies? Many patients will have had Rd as a doublet or as part of a triplet upfront. If that is failing, certainly ixazomib or elotuzumab can be added. However, in some instances a proteasome inhibitor (PI) combination with other agents included may be preferred.
Ideally, over time ixazomib will be excellent for PI-based maintenance since it is well tolerated and helpful in patients with the high-risk t (4; 14) translocation. In addition, it is likely that both ixazomib and elotuzumab will be part of triplet combination options in the frontline setting. Both have value for the extension of remissions in a well-tolerated fashion.
But what to do for now? Our New Year’s resolutions must be to fully endorse the notion that “knowledge is power” and to have detailed discussions with your doctor to assess best options in your own case.
Stay tuned as the IMF rolls out its full educational program for 2016, which will certainly include how to best utilize all the novel agents: new and newest!
Dr. 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®.