Novel Agents and Combos Continue to Transform Myeloma Paradigm

Jessica Hergert
Published: Monday, Dec 16, 2019

Agne Paner, MD

Agne Paner, MD

Choosing an optimal treatment strategy remains an ever-growing challenge across settings and patient populations in multiple myeloma, as novel agents and 3- and 4-drug regimens continue to be explored and added to the armamentarium, said Agne Paner, MD.

For example, updated results of the phase II GRIFFIN study, which were presented at the 2019 ASH Annual Meeting, showed that adding daratumumab (Darzalex) to lenalidomide (Revlimid), bortezomib (Velcade), and dexamethasone (D-RVd regimen) improves response rates and depth of response over time compared with RVd alone in patients with newly diagnosed multiple myeloma.1

Results showed that the 12-month progression-free survival (PFS) rates were 96.9% with the addition of daratumumab and 95.3% with RVd alone, and the 24-month PFS rates were 95.8% and 89.8%, respectively. Moreover, the 12- and 24-month overall survival (OS) rates were 99.0% and 95.8% with D-RVd versus 97.9% and 93.4% with RVd alone.

"The GRIFFIN study gives us very encouraging data, and there are other ongoing phase III trials exploring this combination further," said Paner.

Additionally, patients in the study were twice as likely to achieve minimal residual disease (MRD)-negativity with D-RVd versus RVd alone—an aspect of research that is gaining more traction.

“MRD in multiple myeloma has proven to be a strong prognostic indicator; however, there are questions to be answered,” said Paner. “How do we standardize molecular flow cytometry–based MRD testing? What level of sensitivity should be used? How do we guide therapy based on the response to treatment? Should patients who achieve MRD-negativity receive less therapy while those patients with MRD-positive disease receive treatment intensification?”

New agents are also being introduced to the space, such as the XPO1 inhibitor selinexor (Xpovio), which was granted accelerated approval by the FDA in July 2019 for patients with relapsed/refractory multiple myeloma, who have received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors, ≥2 immunomodulatory agents, and a CD38-targeted monoclonal antibody.

In an interview during the 2019 Onclive® State of the Science Summit™ on Hematologic Malignancies, Paner, an assistant professor and director of the Multiple Myeloma and Amyloidosis Program at Rush University Medical Center, discussed the treatment paradigm in multiple myeloma and promising agents on the horizon.

OncLive: Could you discuss the current frontline treatment options in multiple myeloma?

Paner: The frontline standard of care for multiple myeloma is the 3-drug regimen RVd, based on the SWOG S0777 trial that showed improvement in PFS and OS with RVd compared with lenalidomide/dexamethasone alone. There is ongoing work to see how we can improve upon that.

There are also ongoing phase II trials investigating the second-generation proteasome inhibitor carfilzomib (Kyprolis) in combination with lenalidomide and dexamethasone (KRd). Additionally, there are 2 ongoing phase III trials trying to answer the questions as to whether RVd or KRd should be induction therapy. While these studies are ongoing, we are already getting some phase III data on quadruplet regimens as induction therapy.

Recently, the FDA approved the combination of daratumumab/bortezomib/thalidomide (Thalomid)/dexamethasone for induction of transplant-eligible patients. This combination had shown higher rates of sCR after consolidation after autologous stem cell transplant (ASCT). However, in the United States, thalidomide is usually substituted for lenalidomide.

We have also seen the surge of the daratumumab/carfilzomib/lenalidomide/dexamethasone regimen. There are multiple ongoing phase II trials where MRD is employed as an endpoint or a guide to change therapy.

What therapeutic updates have impacted the maintenance setting?

The TOURMALINE-MM3 study showed that weekly ixazomib (Ninlaro) over the course of 2 years is better than placebo as a maintenance therapy, with a PFS benefit of about 6 months. The results were statistically significant, but it is harder to say if they are clinically significant. The option is well-tolerated and doesn't cause risk of secondary primary malignancies; however, it doesn't quite compare with the results of lenalidomide maintenance.

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