Which Triple-Drug Regimen is Better For Your First Multiple Myeloma Treatment?

VRd versus KRd

For the last several years, most patients newly diagnosed with multiple myeloma have been put on an initial triple-drug regimen, and usually that regimen is a combination called VRd, which consists of these three drugs: Velcade (bortezomib),  Revlimid (lenalidomide), and low-dose dexamethasone. This first treatment, also referred to as frontline or induction therapy, is prescribed to patients of all ages and risks, whether or not they're considered good candidates for a stem cell transplant. The previous standard regimen was a two-drug regimen which didn't contain bortezomib. The addition of this drug, according to a study published in 2016, gave patients an average additional year of survival.

The newer triple-drug regimen being touted as an alternative frontline therapy for multiple myeloma is called KRd. It's a combination of two of the same drugs that are in VRd: lenalidomide (Revlimid), and dexamethasone . But instead of bortezomib it contains Kyprolis (carfilzomib) as the third drug. Coming into wider use just a few years ago, some doctors initially saw KRd as a new standard of care for multiple myeloma frontline therapy.

But newer doesn't always mean better as the ENDURANCE study has shown. The interim analysis found that the median progression-free survival was 34.4 months for VRd and 34.6 months for KRd. And the overall survival was equally close: 84 percent for VRd and 86 percent for KRd. “Any time you want to change practice, you want to have good quality evidence that shows one of those is better than the other,” Dr. Vincent Rajkumar, a multiple myeloma specialist with the Mayo Clinic in Rochester, Minnesota, told Survivornet. “The real question is, was one triplet better than the other? And no, it was not.”

Both triple-drug treatments have their advocates, and both carry risks and benefits. Determining which one to use is important since initial therapy has the greatest impact on patient outcomes. Here's what you need to know about each:

What They Have in Common
As stated before, both of these regimens share two of their three drugs: lenalidomide (Reylimid) and dexamethasone.

Lenalidomide works by blocking the development of abnormal cells and also stimulating specialized immune system cells to attack the cancerous cells.

Dexamethasone is a corticosteroid which stops white blood cells from traveling to areas where cancerous cells are causing damage, reducing swelling and inflammation, and relieving pain and pressure.

The third component of both regimens is a proteasome inhibitor. In VRd it’s bortezomib (Velcade) and in KRd it’s carfilzomib (Kyprolis). Proteasomes are enzymes that work a bit like garbage disposals; they break down damaged and unwanted proteins in cells into smaller components that are used to create new proteins. Cancer cells are more dependent on this action, so when  proteasomes are blocked or slowed by proteasome inhibitors drugs, the buildup of proteins in the cancer cells can lead to their deaths.

The Facts about VRd

Clinical trials found this triple drug regimen superior to the two-drug regimen that had previously been in widespread use, with increased survival. But the caveat was that the addition of a third drug also added to the regimen's toxicity. The main toxic side effects include peripheral neuropathy (nerve damage in the hands and feet that cause tingling, numbness or pain), blood cell irregularities, fatigue and gastrointestinal distress. According to one clinical trial, as many as three-quarters of patients on VRd may experience a toxic side effect. Doctors can combat these unwanted effects with prophylactic medication and dosage adjustment.

In addition, lenalidomide is a teratogenic, meaning it may cause cancer, so there are concerns that people on this drug combination may be at increased risk of developing another, primary malignancy.

The Facts about KRd
As stated before, KRd is a newer combination therapy on the scene. Doctors were excited about this new combination because some small studies had indicated that the carfilzomib (Krypolis) in KRd was a more effective protease inhibitor against multiple myeloma than the bortezomib (Velcade) in VRd.

But in May 2020 doctors got to see the long awaited interim results on efficacy and toxicity from the phase 3 ENDURANCE trial which compared the efficacy and toxicity of VRd and KRd. More than 1000 patients, median age 65, were enrolled in the study between December 2013 and February 2019. Surprisingly, these interim results did not show a longer progression free survival or overall survival compared to VRd. “The new proteasome inhibitor seemed more potent, and early studies seemed to show better progression free survival and response rates,” says Dr. Rajkumar. But the new study results don’t bear this out.

In addition, the KRd regimen is considerably more expensive than KRd. In the ENDURANCE trial results, KRd cost almost $16,000 more per cycle, and almost $100,000 more for the complete regimen. Doctors are also concerned that KRd may carry the risk of more serious toxicities than VRd, with many of the same side effects, plus additional risks to the cardiovascular system, lungs, and kidneys.

The consensus?
While more trials are underway to add more data to the decision-making process, many doctors now feel it makes sense to keep VRd as the default frontline therapy for multiple myeloma because of its track record, more reasonable cost, and efficacy. “We conclude that VRd remains the standard of care,” says Dr. Rajkumar.

 

 

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