Cowan Highlights Practice-Changing Combo Regimens in Multiple Myeloma

Andrew J. Cowan, MD

Combination regimens, especially in the form of triplet and quadruplet regimens, are the future of multiple myeloma treatment, explained Andrew J. Cowan, MD, citing the results of the phase III CASSIOPEIA and MAIA trials as examples.

The randomized, phase III CASSIOPEIA trial compared the safety and efficacy of daratumumab (Darzalex), bortezomib (Velcade), thalidomide, and dexamethasone versus bortezomib and thalidomide/dexamethasone alone in transplant-eligible patients with newly diagnosed multiple myeloma. Results showed that a complete response or better was achieved by 39% of patients on the daratumumab arm versus 26% in those who did not receive daratumumab.¹

“This is exciting because this is the first time we have seen quadruplets used, published, and showing positive data in newly diagnosed, transplant-eligible patients. I suspect that going ahead, this will become standard of care for [this population],” Cowan said. “It's pretty clear to me that the path forward is quadruplets for multiple myeloma.”

Secondly, in the phase III MAIA study, researchers found that patients who received the triplet therapy of daratumumab (Darzalex), lenalidomide (Revlimid), and dexamethasone (DRd) had a 44% reduction in the risk of progression or death compared with lenalidomide/dexamethasone alone.² In June 2019, the FDA approved DRd for the treatment of patients with newly diagnosed multiple myeloma who are ineligible for autologous stem cell transplantation.

Not all combination trials have demonstrated similar results. For example, in the phase III BELLINI trial,³ the triplet therapy of venetoclax (Venclexta) with bortezomib and dexamethasone had a higher proportion of deaths compared with placebo plus bortezomib/ dexamethasone in patients with relapsed/refractory multiple myeloma, causing the FDA to put the trial on a partial clinical hold. However, Cowan says there is too little research about venetoclax to eliminate it from the myeloma paradigm.

In an interview with OncLive^® during the 2019 State of the Science Summit™ on Hematologic Malignancies, Cowan, an assistant professor of medicine at University of Washington School of Medicine and hematologic oncologist at Seattle Cancer Care Alliance, discussed pivotal trials in multiple myeloma and potential for new treatments in the future.

OncLive: What factors do you consider when determining whether patients with myeloma are eligible or ineligible for transplant?

Cowan: One important thing about it is you don't have to be dogmatic about who is transplant eligible and ineligible. There are many factors you need to consider. Overall, level of frailty and index of comorbidities are important to consider; age is potentially less important. We have certainly seen data of patients who would be considered advanced age and can tolerate transplant well. I don't think age should be the sole predictor or reason why a person should or should not have a transplant.

That being said, as we age, most people do develop more comorbidities that would, in general, limit their ability to undergo transplant. While age is not an absolute reason not to do a transplant, it tends to track with other comorbidities as well.

Patient preference is important; there are simply some patients who are not interested in a transplant. There are a variety of reasons for that, but all of the above factors need to be taken into consideration. You need to have a thorough discussion with patients discussing the data. The most recent data was from the IFM 2009 trial, which showed an improvement in progression-free survival (PFS) with the use of a transplant by about 14 months. It is not a cure for multiple myeloma, so anytime you're faced with a discussion like that, there are some nuances that have to be discussed.

How do the treatment strategies differ between transplant-eligible and -ineligible populations?

The treatment strategies differ only in whether or not we include transplant. Increasingly, 3-drug regimens are the mainstay of treatment for patients, whether they are transplant ineligible or not. Certainly, for more frail patients or patients who are in the advanced stage, using lenalidomide/dexamethasone or bortezomib/dexamethasone alone would be more appropriate.

Again, you don't have to be dogmatic about it. With the results of the MAIA trial that were presented at the 2018 ASH Annual Meeting and were recently published, we now have a new regimen that is very exciting and promising. That [studied] daratumumab, a CD38-directed monoclonal antibody, in combination with lenalidomide and dexamethasone. It's nice to have more options for patients with newly diagnosed myeloma. One nice thing about daratumumab that's comparable with bortezomib is we don't need the neuropathy that we do with bortezomib. It's nice to have that as an option for patients who are frailer.

What are your thoughts on the venetoclax trials being halted? Could venetoclax still have a role in multiple myeloma therapy?

Venetoclax, which is an oral BCL-2 inhibitor, showed a lot of promise in multiple myeloma when I presented the data at the 2017 ASH Annual Meeting, which showed a 40% overall response rate (ORR) for patients who harbored t(11;14) by fluorescence in situ hybridization. This lets us settle further studies. The BELLINI trial was a randomized study for patients with relapsed multiple myeloma who did not have to have t(11;14), although many did, compared venetoclax with bortezomib/dexamethasone versus bortezomib/dexamethasone alone. This study was halted earlier this year when it was discovered that there was an increased risk of death for patients receiving venetoclax and bortezomib/dexamethasone compared with bortezomib and dexamethasone alone.

Despite the shortcomings we're seeing in the BELLINI trial, this drug has an important role to play for patients with relapsed multiple myeloma. In particular, we should try to focus on those who harbor t(11;14); that is where we have seen the highest response rates. Data showed that those patients did not have a substantial increase of death, admittedly as subgroup analysis, but maybe suggested that a biomarker-driven approach might be more appropriate for using venetoclax.

Personally, I've treated a few patients with venetoclax. Most recently, a patient with t(11;14) and plasma cell leukemia who hadn't responded to anything and has responded beautifully to venetoclax as a single agent. I do think this drug has an important role to play. It will be important to figure out the data and determine what exactly went on in the BELLINI trial, but it would be premature to say this drug doesn't have a role.

What are your thoughts on selinexor and where could it be used?

Selinexor has stumbled a little recently. There was a lot of promise that we saw with selinexor when the data from the STORM trial were presented showing an ORR of 26% amongst heavily pretreated patients, many of whom were refractory. Unfortunately, when these data were presented to the FDA, the application for accelerated approval was declined and the FDA chose to await the results of the phase III BOSTON trial.

Even though there's no single-agent activity of selinexor, there does seem to be some activity when in combination with dexamethasone. The results of the phase III trial will tell us whether this drug has an important role for multiple myeloma. It's premature to, like venetoclax, write it off completely.

What are your thoughts on the use of CAR T-cell therapy in multiple myeloma?

The leader of development would be the product that is being developed by bluebird bio and Celgene, bb2121, which is a BCMA CAR T-cell product that has been studied in a phase I setting. Those data were published a few weeks ago; we saw a median PFS of approximately 12 months. I suspect this will be the first BCMA CAR T-cell therapy that is commercially available for patients with relapsed myeloma.

It's important because it's the first [CAR T-cell therapy in myeloma] and it represents a big improvement for relapsed patients. Many of these patients have failed all prior therapies. I suspect we will see a lot of improvement in the efficacy, hopefully in the durability, of the responses we see with these that make CAR T cells.

References

1. Moreau P, Attal M, Hulin C, et al. Phase 3 randomized study of daratumumab (DARA) + bortezomib/thalidomide/dexamethasone (D-VTd) vs VTd in transplant-eligible (TE) newly diagnosed multiple myeloma (NDMM): CASSIOPEIA Part 1 results. J Clin Oncol. 2019;37(suppl; abstr 8003). doi: 10.1200/JCO.2019.37.15_suppl.8003
2. Facon T, Kumar S, Plesner T, et al. Daratumumab plus lenalidomide and dexamethasone for untreated myeloma. N Eng J Med. 2019;380:2104-2115. doi: 10.1056/NEJMoa1817249.
3. Kumar S, Harrison S, Cavo M, et al. A phase 3 study of venetoclax or placebo in combination with n combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma. Presented at: 2019 European Hematology Association Congress; June 13-16, 2019; Amsterdam, The Netherlands. Abstract LB2601.