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Plethora of Novel Agents Transforming Outcomes in Multiple Myeloma

Gina Columbus @ginacolumbusonc
Published: Friday, Jul 28, 2017

Rachid Baz, MD
Rachid Baz, MD
Novel combination regimens that include daratumumab (Darzalex), the anti-CD38 monoclonal antibody, are on the rise and producing significantly improved outcomes for patients with multiple myeloma, although therapeutic sequencing challenge exists. 

Findings of an open-label, phase Ib study presented at the 2017 ASCO Annual Meeting demonstrated that the addition of daratumumab to carfilzomib (Kyprolis), lenalidomide (Revlimid), and dexamethasone (KRd) in patients newly diagnosed with multiple myeloma was well tolerated and had durable responses as a frontline regimen. Treatment with daratumumab plus KRd yielded an overall response rate (ORR) of 100% in 21 response-evaluable patients; the 6-month progression-free survival rate also was 100%. 

Rachid Baz, MD, associate member, head of the Myeloma Section at Moffitt Cancer Center, gave his presentation “Too Many Cooks in the Kitchen” with regard to the abundance of available therapies for patients with multiple myeloma during the 2017 OncLive® State of the Science Summit™ on Hematologic Malignancies. In an interview, he spoke to the change in risk factors for select treatments, the impact of daratumumab, and the current sequencing questions among the field. 

OncLive: What was the basis of your discussion on multiple myeloma?

Baz: Over the past few years, we have had a lot of new treatment options for patients with myeloma—certainly, those with newly diagnosed disease. I divided the talk into approaches for patients who are elderly or frail versus patients who are younger or fit. Traditionally, we separated patients based on their eligibility for stem cell transplant, although, we now rely more on frailty than age. 

How do you treat these 2 patient groups differently? 

Historically, we used to avoid alkylating agents, like melphalan, for patients who are eligible for transplant because of concern over difficulty mobilizing stem cells. You consider the elderly patients’ therapy to be traditionally melphalan-based. Now there is considerable evidence that melphalan is not a required treatment for the elderly and frail patients either. 

But the most important determinant of outcomes in patients who are elderly and frail turns out to be fitness or frailty indicators [versus age]. For those patients who are considered to be frail, a doublet, such as dose-adjusted lenalidomide/dexamethasone, or a weekly SC bortezomib (Velcade)/dexamethasone approach would be very reasonable. For a patient who is of intermediate fitness, a bortezomib/ lenalidomide/dexamethasone (VRd) regimen would be appropriate. 

For the young and fit patients, typically the standard of care is bortezomib/dexamethasone/lenalidomide. Some of the emerging trials that are coming up are challenging that data for the future, so [we are] looking at the combination of carfilzomib/lenalidomide and incorporating a monoclonal antibody into upfront treatment. It is an exciting time definitely for patients with myeloma. We have more effective therapies and less toxic therapies, too. 

We have seen a lot of promise with daratumumab for patients with multiple myeloma. What does the future hold for it? 

The key thing is to look at the data in patients with advanced myeloma. Daratumumab, as a single agent, has 30% activity, considerable activity. It has very little toxicity, and importantly, the toxicity is not overlapping with some of the other existing myeloma therapies. When we got to the triplet of bortezomib/lenalidomide/dexamethasone up front for young and fit patients, a quadruplet was too toxic if you added traditional or conventional therapies. However, when you get to monoclonal antibodies being added, it has the potential to make a big difference without adding too much toxicity. There are ongoing studies looking at daratumumab in addition to VRd. 

There are also studies looking at the addition of daratumumab to lenalidomide/dexamethasone up front comparing that to lenalidomide/dexamethasone alone. Even for patients who are considered to be frail, incorporating daratumumab is not likely to add meaningful toxicity; it may have quite a beneficial effect on controlling myeloma. 

What other exciting studies can we expect to read out this year? 

One of them is a comparison of carfilzomib, cyclophosphamide, and dexamethasone (KCd) versus KRd. If you think about the ENDEAVOR study in myeloma—comparing carfilzomib to bortezomib in the relapsed setting—carfilzomib turns out to be more efficacious with less neurotoxicity. It kind of makes sense to incorporate that in the upfront setting. Comparing KCd to KRd would be the new wave. That would be quite a bit interesting. 

There are a couple of studies looking at the addition of elotuzumab (Empliciti) to the VRd backbone; that is interesting, too. 




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