Phasing Out Doublet Regimens in Relapsed/Refractory Multiple Myeloma

Barry Paul, MD

Various triplet and quadruplet strategies that have moved through the pipeline are replacing the role of doublet regimens for patients with relapsed/refractory multiple myeloma, according to Barry Paul, MD.

“The role of [doublets] is extraordinarily limited in multiple myeloma today,” said Paul. “Doublets would be reserved for patients who are extremely frail or who have severe comorbidities that would make it challenging to give them a 3-drug combination.”

One triplet regimen that has shown benefit in the relapsed/refractory setting is the combination of daratumumab (Darzalex), carfilzomib (Kyprolis), and dexamethasone (KdD). Results of the phase III CANDOR trial demonstrated a 37% reduction in the risk of disease progression or death with KdD compared with carfilzomib and dexamethasone (Kd) alone in patients with relapsed/refractory multiple myeloma.

Additionally, data showed that the median progression-free survival (PFS) was not reached with KdD versus 15.8 months with Kd (HR, 0.63; 95% CI, 0.46-0.85; P = .0014). The median overall survival (OS) was not reached in either arm after a median follow-up of 17 months (HR, 0.75; 95% CI, 0.49-1.13; P = .08).

"This suggests the combination has efficacy,” said Paul. “I was personally excited about the fact that the regimen had efficacy in patients who were refractory to lenalidomide (Revlimid). That's a good sign that giving a non-immunomodulatory drug (IMiD) —based regimen to a patient who was refractory to an IMiD [could] have good efficacy."

In an interview during the 2020 OncLive^® State of the Science Summit™ on Multiple Myeloma, Paul, a physician in the Plasma Cells Disorders Group, Levine Cancer Institute, Atrium Health, discussed some of the newer data to emerge regarding relapsed/refractory multiple myeloma.

OncLive: What key trials have shaped the role of carfilzomib in this space?

Paul: Carfilzomib plays a key role in this space; however, that role is evolving as carfilzomib is being used more in the frontline setting. How we are approaching [the treatment of patients with] relapsed/refractory disease is a moving target.

Once a patient is refractory to a certain agent, we won't use it in subsequent settings. If patients are getting carfilzomib upfront and they become refractory to it, we won't use a carfilzomib-based regimen in that first relapse. Assuming patients have not progressed on carfilzomib, there are excellent data [to suggest that] patients who are refractory to other proteasome inhibitors, such as bortezomib (Velcade), [can derive benefit] from carfilzomib.

The ENDEAVOR trial certainly demonstrated a PFS and OS benefit for patients [receiving carfilzomib versus bortezomib] who are not refractory to proteasome inhibitors. That trial showed an OS advantage with carfilzomib [when put head-to-head with] bortezomib.

Could you discuss the data looking at optimal dosing strategies with carfilzomib?

The ARROW study showed that giving once-weekly carfilzomib at 70 mg/m2 has superior efficacy to twice-weekly carfilzomib at 27 mg/m² given on days 1, 2, 7, 8, 14, and 15.

You would think that there would be increased toxicity [with the once-weekly regimen], but it is quite the opposite. There was more toxicity with the twice-weekly dosing versus the once-weekly dosing. [However], one caveat to that is that more patients who had the once-weekly dosing had to have a dose reduction based on some degree of minor toxicity.

This is great evidence to use the once-weekly dosing regimen of carfilzomib. It is obviously more convenient for patients and allows them to have more freedom in their life.

What questions remain unanswered in relapsed/refractory multiple myeloma?

Everyone makes the assumption that if you are resistant to carfilzomib, you are inherently resistant to other proteasome inhibitors. We don't have evidence yet to that effect. It would be interesting to know, if a patient is absolutely refractory to carfilzomib, [whether] they will [or will] not have a response to bortezomib or ixazomib (Ninlaro). That question needs to be addressed.

Similarly, the trials of [triplet] versus [doublet] regimens are challenging to interpret in a setting where we rarely use [doublets] anymore. Unfortunately, doublet therapy was considered the standard of care when these trials were designed. Now the standard of care has advanced, and one can make the case that [newer trials are not investigating] the standard of care versus standard therapy plus a novel agent.

What were the updated data of the CANDOR trial?

The CANDOR trial looked at the combination of KdD versus Kd alone in patients who had progressed on 1 to 3 prior lines of therapy. A PFS advantage, as well as a trend toward an OS advantage, was observed in the patients who received the [triplet regimen]. Interestingly, a significantly increased rate of minimal residul disease negativity [was seen with the triplet], suggesting that it [generates] a deeper response.

That being said, it will be challenging to extrapolate the data as drugs such as carfilzomib and daratumumab move into the frontline setting. It will leave a void for patients with relapsed/refractory [disease] and will be something to consider down the road.

If approved, how do you see isatuximab fitting into the treatment landscape?

The ICARIA-MM study looked at isatuximab with pomalidomide (Pomalyst) and dexamethasone compared with pomalidomide/dexamethasone alone in patients with relapsed/refractory multiple myeloma.

Patients who [were previously exposed to] pomalidomide [were excluded]; however, patients could have had lenalidomide or thalidomide (Thalomid). Interestingly, they could not [have been exposed to] daratumumab, which is the other CD38-targeting therapy.

ICARIA-MM showed a PFS and OS advantage for patients who received the isatuximab-containing triplet, with minimally increased toxicity. There was a concern regarding an increased risk of secondary primary malignancies in the isatuximab-containing arms, so that is something to [be cognizant of] going forward.

The trial is going to be a challenge because we don't yet know if isatuximab has a different activity than daratumumab. Whether isatuximab will have activity in daratumumab-refractory patients is unknown. I would hope it does, but I am not enthusiastic it will.

With the influx of combinations available or under investigation, how are you approaching treatment selection in practice?

It is a moving target based on [patient-related factors], comorbidities, and prior therapies. Every patient is unique and there is no one-size-fits-all algorithm.

Some patients had very long remissions with therapy that was the standard of care 5 to 10 years ago. That is great for those patients, because they achieved good remissions from a not-so-great regimen. It speaks to the [amount] of agents we have available now.

Conversely, there are also patients who have rapidly progressed and thus have been treated relatively recently. Those patients have likely seen more efficacious drugs and combination therapies, but they are significantly more challenging to treat because they have more aggressive, refractory disease.

Cellular therapy will play an important role for these patients moving forward. As of now, it is important to think about patients categorically. What have they been exposed to? What have they responded to? We have to make educated decisions based on those factors, the available data, and anecdotal evidence. Of course, not every patient fits the profile for every clinical trial.

Usmani SZ, Quach H, Mateos M-V, et al. Carfilzomib, dexamethasone, and daratumumab versus carfilzomib and dexamethasone for the treatment of patients with relapsed or refractory multiple myeloma (RRMM): primary analysis results from the randomized, open-label, phase 3 study CANDOR (NCT03158688). Blood. 2019;134(suppl_2):LBA-6. doi: 10.1182/blood-2019-132629.