Novel Agents and Combos Continue to Transform Myeloma Paradigm

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.

In the latest update of CALGB [(Alliance) 100104] trial comparing lenalidomide with placebo, the median PFS was 57 months compared with 29 months in the placebo group. Lenalidomide remains the mainstream of maintenance therapy and is approved for this indication.

Certainly, there is more work to be done in the maintenance setting to see if other monoclonal antibodies and proteasome inhibitors should be added or could replace current treatment.

What are the frontline options for transplant-ineligible patients?

The newest development in this space was the MAIA trial, which led to the FDA approval of daratumumab/lenalidomide/dexamethasone for induction compared with lenalidomide/dexamethasone alone. The treatment was continued until progression of disease with tolerable toxicities and a great improvement in PFS.

Now, the greatest challenges are deciding whether patients who are ineligible for transplant should be treated with RVd or daratumumab/lenalidomide/dexamethasone, and which patients should resort to lenalidomide/dexamethasone. The regimens have different adverse event profiles and durations of treatment, so everything must be considered when discussing options with patients.

Is it possible that triplet regimens will become irrelevant, now that they are being compared with quadruplet approaches?

We could guess that quadruplets will become the new standard of care, but it will be a little more complicated than just saying triplet versus quadruplet. MRD will play a role.

One trial compared early- versus delayed-transplant. Interestingly, patients who achieved MRD-negativity had good outcomes whether or not they received transplant. If that is the case with quadruplets, we may also find that those who are treated with triplets and achieve MRD-negativity do as well as patients who are treated with quadruplets. It is not an easy answer.

Could you discuss the optimal way to assess for MRD?

Currently, we have 2 different methods to test for MRD. Europeans have generally embraced molecular flow cytometry. The advantage with that method is that it doesn't require an initial specimen or development of the primer.

Next-generation sequencing (NGS) appears to be more reproducible, but it has its own shortcomings. Nonetheless, NGS doesn't require as much standardization as flow cytometry; NGS does take longer than flow cytometry as well.

In the relapsed/refractory setting, how does daratumumab fit best?

Currently, daratumumab is used in first relapse more than any other drug in multiple myeloma. In the United States where lenalidomide maintenance is continued until disease progression, daratumumab/lenalidomide/dexamethasone has limited application in the relapsed/refractory setting. Instead, that combination would mostly be for patients who were on observation or a proteasome inhibitor—based therapy.

Recently, daratumumab/carfilzomib/dexamethasone showed high response rates and a favorable side effect profile. That combination will probably be used more often going forward.

As daratumumab [continues to gain approvals in the] frontline setting, we will have to revisit what the sequencing of regimens should be at first and second relapse.

What other factors do you consider when determining the optimal sequence of treatment?

The list of options for first relapse is getting longer. Certainly, efficacy data drive most of the decision, but tolerability and logistics of treatment, as well as disease [characteristics] should also be taken into account.

Is it the patient's first treatment? Do they have residual AEs, like peripheral neuropathy? These factors may also dictate which treatment a patient will receive at first or second relapse.

Finally, some patients who started off with standard-risk disease can transform and have an aggressive relapse and would, in turn, have to be treated more aggressively.

Are there certain agents that are better suited for those more aggressive populations?

There is a tendency to use carfilzomib for patients with high-risk disease; although, those data are not perfect as it mostly comes from subset analyses and phase II trials. Combination regimens would certainly be a priority for these patients, and perhaps extended therapy with a MRD-negativity goal.

What agents are being explored in the heavily pretreated population?

This year we had approval of selinexor for patients with triple-class refractory disease. Patients in the study that led to the approval were very heavily pretreated, with several lines of prior therapy; over half of those patients had high-risk cytogenetics.

Response rates were 26% in patients treated with selinexor and the median duration of response was about 4 months. Selinexor had to be combined with dexamethasone, as dexamethasone potentates the effect of selinexor.

Certainly, selinexor is a viable option; however, potential toxicities such as high rates of fatigue, hypernatremia, and nausea should be carefully considered. Nausea and hypernatremia are not toxicities that multiple myeloma specialists generally have to manage. If the AEs can be managed with dose reductions and supportive care, patients can truly benefit from selinexor.

References

1. Voorhees PM, Kaufman JL, Lauback JP, et al. Depth of response to daratumumab (DARA), lenalidomide, bortezomib, and dexamethasone (RVd) improves over time in patients (pts) with transplant-eligible newly diagnosed multiple myeloma (NDMM): Griffin study update. Presented at: 2019 ASH Annual Meeting; December 7-10; Orlando, FL. Abstract 691.
2. Karyopharm announces FDA approval of XPOVIO™ (selinexor) for the treatment of patients with relapsed or refractory multiple myeloma. Karyopharm. Published July 3, 2019. https://bit.ly/2XMo1k0. Accessed July 3, 2019.