QoL Comes Into Focus in Myeloma Amid Expanding Treatment Options

David Samuel Dicapua Siegel, MD, PhD

Now that several effective therapies have been added to the treatment armamentarium of multiple myeloma, researchers have focused their efforts on improving patient quality of life (QoL), according to David Samuel Dicapua Siegel, MD, PhD.

“We spent many decades without any new drugs in multiple myeloma, so QoL was unfortunately largely ignored because we were just desperately looking for drugs that had activity,” said Siegel. “Now we have a multitude of drugs, and thankfully, many of them are very effective, so it becomes a question of, ‘What is the impact of these drugs on QoL?’”

Data from the ongoing phase II MM-014 trial (NCT01946477) trial showed that the 3-drug regimen of daratumumab (Darzalex), pomalidomide (Pomalyst), and low-dose dexamethasone was safe and effective in patients with relapsed/refractory disease after lenalidomide-based failure. Now, results from a health-related QoL analysis presented at the 2019 ASCO Annual Meeting showed that not only was QoL maintained with the regimen, but it trended toward improvement.¹

“It's nice to know that we're not only able to control the disease way better than we used to, but that we now have tools that don't ‘slam’ the patient while we're doing that,” said Siegel, founding director, Multiple Myeloma Institute, Hackensack University Medical Center.

In addition to daratumumab, carfilzomib (Kyprolis) is another active agent in the space. Although the drug is generally well tolerated, it has been underutilized in the field due to its twice-weekly dosing schedule, according to Siegel. In order to alleviate that burden on the patient, investigators set out to find if a once-weekly dose would be equally as effective as the twice-weekly dose. Results from a posthoc analysis confirmed that once-weekly carfilzomib had a comparable risk-benefit profile to twice-weekly treatment.²

“I believe this gives us the opportunity to get one of the best drugs that we have into patients in a way that they're willing to accept,” added Siegel.

In an interview with OncLive, Siegel highlighted key research in multiple myeloma and the renewed focus on improving QoL.

OncLive: Could you discuss the health-related QoL analysis with daratumumab, pomalidomide, and low-dose dexamethasone?

Siegel: This is one of many very important combinations in multiple myeloma right now and this is the first attempt that looked at QoL related to the administration of daratumumab, pomalidomide, and dexamethasone.

Daratumumab and pomalidomide are two of the most important drugs that have come along in the last decade for the management of multiple myeloma, so the 3-drug combination is very important. However, one of the major issues in multiple myeloma is this impression that you have to change classes of drugs. Lenalidomide (Revlimid) is the most widely used drug in myeloma. Pomalidomide is a very similar molecule to lenalidomide so there's a lot of concern over whether you can go from 1 to the other. The overarching finding of this trial was that you could do it both safely and with a significant degree of efficacy. Now that we have a great regimen and we know where we can use it, what impact does it have on QoL?

This is the first assessment of that, and it was done in a unique setting, which was very early in myeloma treatment; most of the patients were still very healthy. When a patient is very sick from their disease, controlling the myeloma is enough to fairly significantly improve QoL. However, these are patients who have not been dramatically compromised by the myeloma itself; therefore, you would expect that this 3-drug combination—particularly one including corticosteroids—would have a negative impact on functionality and perception of QoL. However, the analysis didn't show that.

For the analysis, we used several tools. One was visual scoring from 1 to 100, [to answer the question], “How do you feel?” The patients who came in feeling fairly well had scores of around 90 and they came out of the trial with scores of about 90. We also had a 5-question panel [which included questions such as]: “How are you interacting with your friends? How mobile are you? What impact does this have on you psychologically? How does [treatment] impact your daily activities?” The bottom line is, [QoL] was stable across all of those parameters. If there was a change, it was a slight improvement. Therefore, we have a 3-drug combination that is highly effective that doesn’t negatively impact QoL. In fact, [the combination] may have even improved their QoL.

In terms of another active drug in multiple myeloma, could you discuss the research pertaining to the dosing schedule of carfilzomib?

Carfilzomib is arguably the most active drug in the multiple myeloma space, and it is generally very well tolerated. I always tell my patients that the biggest toxicity with carfilzomib isn't a complication of the drug, but that it is rather the dosing schedule. Carfilzomib is given 2 days per week; it's a lot of work for the patient to have to repeatedly return for treatment. This study compared once-weekly [administration of carfilzomib] versus a twice-weekly scheduled. [Results showed that the once-weekly dose] was perceived to work better with less toxicities. It’s very nice to be able to use this very active drug on a schedule that is way better for patients. This is important because we can control the disease [with less of a burden on] the patients.

Risk-adapted treatment strategies are starting to emerge in the space. Could you discuss the prospective study evaluating SKY92, a 92-gene prognostic signature?

Myeloma isn't staged the same way that other diseases are. The amount of disease doesn't define how well patients will do [with treatment]; it's all about the biology of the disease. Our ability to predict how patients are going to do remains very limited. We can say that a patient is high-risk, but there's still a lot of variability. It’s very important in multiple myeloma to understand how well a patient is going to do for several reasons. Perhaps, most importantly, the patient wants to know, "Am I going to live for a decade or not?" It’s important at that level. Now, we're starting to have tools that are going to perhaps help us overcome some of those biological features that make patients [react poorly] on treatment.

The SKY92 panel is a 92-gene expression profile. We take RNA from the cancer cells and we dump it on a plate that is dotted with RNA. We can then measure how much is bound to the plate. This 92-gene panel has been demonstrated to very accurately predict outcomes in patients. If you overlay it on some of the more traditional staging methods, even better. The 92-gene panel provides us with a way to more accurately assess probability of patients remaining in remission for certain length of times; it predicts how patients will do.

We have all understood that we need that, and now it needs to be validated. What this study is attempting to do is to demonstrate that the knowledge of that gene expression profile is going to impact both our perception and clinical decision making.

It’s an interesting study. We do the diagnostic bone marrow and we send it for analysis. We don't get the results of that analysis until after we make a decision about how we're going to manage the patient and how we're going to characterize them—whether they are high-risk, intermediate-risk, etc. Then, they hand us the page saying, “No, this is what the gene expression profile demonstrates." Then they ask us the question, "What is your perception of the patient's risk stratification now and how would you change the therapy?"

It’s actually remarkable that there's a substantial number of patients that we have said are standard-risk, who, in fact, have high-risk disease. Perhaps more importantly, there is an even more significant number of patients who we've called high-risk, who turn out to have standard-risk disease. [With this tool, we have] saved these patients from potentially dangerous interventions that might not be warranted.

References

1. Reece DE, Bahlis NJ, Samaras CJ, et al. A health-related quality-of-life (HRQoL) analysis of pomalidomide + low-dose dexamethasone + daratumumab in relapsed refractory multiple myeloma (RRMM) after lenalidomide treatment. J Clin Oncol. 2019;37(suppl 15, abstr 8025). doi: 10.1200/JCO.2019.37.15_suppl.8025.
2. Moreau P, Stewart AK, Dimopoulos MA, et al. Once-weekly (70 mg/m2) versus twice-weekly (56 mg/m2) dosing of carfilzomib (CFZ) for patients (pts) with relapsed and/or refractory multiple myeloma (RRMM). J Clin Oncol. 2019;37(suppl 15, abstr e19505). doi: 10.1200/JCO.2019.37.15_suppl.e19505.