Triplet Regimens Dominate the Relapsed/Refractory Myeloma Treatment Landscape

Kelly Godby, MD

Novel triplet combinations are leading the key developments made in the treatment of patients with relapsed/refractory multiple myeloma in recent years, according to Kelly Godby, MD, who added that despite the impressive responses elicited with these approaches, longer follow-up is needed to determine the overall survival benefit of these approaches.

“We know that triplets are the standard of care in the up-front [setting]. In some areas, even quadruplets seem to be reasonable options. Don't be afraid to use triplets in the relapsed/refractory setting,” said Godby. “In just about every single clinical trial [there is] an overall improvement in progression-free survival (PFS) and objective response rates (ORRs). Even in some of the other studies, you see a median overall survival (OS) advantage, so if you have the right patient who is fit and can tolerate a triplet regimen, that would be preferable to a doublet therapy.”

In an interview with OncLive® during the 2020 International Perspectives in Cancer webinar on Multiple Myeloma, Godby, an associate professor at the University of Alabama at Birmingham discussed several novel triplet regimens under examination in relapsed/refractory multiple myeloma and the challenge of choosing among the available options.

OncLive®: Several novel combinations are emerging for patients with relapsed disease. Would you say the field is shifting toward the use of triplets over doublet regimens?

Godby: A multitude of options are available. One of the trickiest [tasks] for multiple myeloma physicians is determining what to use in the first and second relapse. It's a great problem to have, but not a lot of head-to-head data comparing various regimens are available. [Some notable] clinical trials compared doublets to triplets to get a better sense of not necessarily how to sequence, but whether we should really use triplet therapy instead of doublets. There's always a concern that potential toxicity could outweigh any benefits to our patients.

What are some of the factors that you consider when selecting a treatment for patients with relapsed/refractory disease?

The performance status of the patient is the most important [factor to consider]. Number 2, what are the previous regimens that they have received? What is the most recent line of therapy? What previous toxicities did they [experience] with chemotherapy? What pre-existing medical conditions do they have? All those questions could help narrow down which drugs would be the best for that individual. We try to individualize [treatment] as much as possible. But we always keep in the back of our minds that, 3 drugs are usually superior to 2 drugs, as far as efficacy.

With regard to triplet therapies generating excitement in the space, could you speak to the isatuximab-irfc (Sarclisa) regimen examined in the ICARIA-MM trial?

This is a phase 3 study that [enrolled] 300 patients. It was a 1:1 randomization of isatuximab, pomalidomide (Pomalyst), and dexamethasone versus pomalidomide and dexamethasone. Isatuximab is a monoclonal antibody against CD38, so it's similar to daratumumab (Darzalex). Patients were randomized to receive either receive isatuximab 10 mg/kg weekly for 4 weeks [followed by bi-weekly for 28-day cycle] in combination with standard pomalidomide and dexamethasone versus just pomalidomide/dexamethasone.

All these patients had to have received at least 2 prior lines of therapy, so it made it a little bit unique compared with other studies that have been done. All patients had to have received a previous proteasome inhibitor (PI), as well as an immunomodulatory drug (IMiD). Approximately 93% [of patients] were refractory to lenalidomide (Revlimid) and 75% were refractory to a PI.

The median duration of follow-up was 11.6 months and almost a doubling in median PFS was reported, at 6.4 months in the control arm versus 11.5 months in the investigational arm. The ORR was almost doubled, as well, at 35% versus 60%, respectively. For those who responded [to therapy], there was an increase in minimal residual disease (MRD) negativity, which has become an end point for most studies and the gold standard. Of course, the data are not yet mature and we have yet to really see a median OS benefit.

The main toxicity difference was risk of infection, which is pretty comparable to [what has been seen in] other monoclonal antibody studies. Overall, [the approach] was very well tolerated and infusion reactions were reported in about 38% of those who were on isatuximab, [which is] not surprising. As far as clinical implications, this is the first phase 3 study that examined a monoclonal antibody in combination with pomalidomide. This is a very viable treatment option for our patients who have not yet [been treated with] pomalidomide.

What were the lessons learned from the IKEMA trial with isatuximab?

In the IKEMA study, investigators examined isatuximab, a CD38 monoclonal antibody, in combination with carfilzomib (Kyprolis) and dexamethasone versus carfilzomib and dexamethasone alone. It is also a phase 3 study that [enrolled] 302 patients who were randomized 3:2 and the primary end point of the trial was PFS. The exact same dosing schedule with isatuximab [was used in this trial as was used in the ICARIA-MM trial]. The dosing of carfilzomib was 56 mg/m2 given twice weekly.

This study permitted patients who had received at least 1 previous treatment. About 44% had received at least 1 previous therapy and 35% [received] 2 or more. Additionally, about 10% of the patients were 75 years or older, which is important in clinical trials because often that is a patient population that's underrepresented. Ninety percent [of patients] had previously received bortezomib (Velcade) and 80% had previously received lenalidomide. One-third [of patients] were refractory to lenalidomide.

The median duration of follow-up was approximately 21 months and the median PFS was not yet reached on the triplet arm versus 19.5 months on the doublet arm. There was a 47% decrease in the risk of progressive disease or death on the quadruplet arm. The ORRs were not too dissimilar, [approximately] 80%, but what you did see was that those who did respond to the triplet experienced an almost a two-fold increase in MRD negativity. The median OS is not yet reached, so the data are not mature.

Major toxicities, once again, are very similar to what was seen in the previous study with an increased risk of infection. The concerns with carfilzomib always [have to do with the] increase in acute kidney injury (AKI), hypertension, or congestive heart failure (CHF); with the addition of the monoclonal antibody, you really didn't see a difference [with this] between the 2 arms. As far as clinical implications, this will probably lead the way potentially for the approval of isatuximab in combination with carfilzomib and dexamethasone [in these patients].

Another triplet was examined in the CANDOR trial. What were the data observed with the addition of daratumumab (Darzalex) to the standard backbone?

CANDOR is very similar to the last study. This time, the monoclonal antibody is daratumumab (Darzalex) in combination with carfilzomib and dexamethasone versus carfilzomib and dexamethasone. The phase 3 study included 466 patients and the randomization was 2:1. The daratumumab was the traditional dose of 16 mg/kg weekly and then every other week for 16 weeks and every 4 weeks [thereafter]. The exact same dosing as what was used in the IKEMA trial was used for carfilzomib, at 56 mg/m2 twice a week. The patients in the study had 1 to 3 prior lines of therapy; about 45% only received 1 previous line, and about 90% have previously seen bortezomib and 42% lenalidomide. One-third were refractory to either bortezomib or lenalidomide. 

On this study, 25% of patients were older than the age of 75 years; this is an important patient population [that should be] included in clinical trials because they tend to be underrepresented. The median duration of follow-up was 17 months. The median PFS was not yet reached on the triplet arm versus on the doublet arm; it was 15.8 months. The ORR was 9% better in the triplet arm, at 84% versus 75%. Once again, with the triplets, you're seeing those patients who responded are far more likely to reach MRD negativity, so 12% versus 1%, respectively, at the 12-month mark. This led to the 37% decrease in the risk of progression or death on the triplet arm.

Major toxicities were similar, as I stated in the previous study, with the increased risk of infection. No increased risk between the 2 arms with AKI or CHF was reported. The most common cause for a fatal event was infection. This just gives us another option, another way to treat our patients. This is really going to be the test going forward: How do you determine which triplet to give in the relapse setting?

Could you discuss the promise of selinexor (Xpovio) in relapsed/refractory myeloma?

[In the] BOSTON trial, we're looking at a drug that was already approved, selinexor, for patients with penta-refractory multiple myeloma. The agent has a novel mechanism of action, so this study is a little unique. Selinexor is actually an oral selective inhibitor of nuclear export. This phase 3 [trial] included 402 patients who underwent a 1:1 randomization to either selinexor plus bortezomib and dexamethasone or bortezomib and dexamethasone alone. The primary end point of the trial was PFS.

The patients on this study had received 1 to 3 previous lines of therapy. However, if patients had previous exposure to a PI, at the bare minimum, they needed to have achieved a partial response in order to be eligible for the study. The median PFS was about 4 months longer in the triplet arm, at 13.93 months versus 9.46 months [with the doublet]. The ORR was also higher in the triplet arm compared with the doublet arm, at 76.4% versus 62.3%, respectively.

The major toxicity [with this approach] is completely different than what we see with the monoclonal antibodies with either an IMiD or PI backbone. We see a higher incidence of thrombocytopenia on the triplet arm and we also see higher incidences of nausea, fatigue, decreased appetite, and cataracts. I participated in the STORM trial and [these adverse effects (AEs)] were fairly common with selinexor. Notably, there weren’t necessarily more infectious AEs. More neutropenia was reported, but there weren’t grade 3 infections because of that.

My conclusion from this is that it gives us this idea of recycling classes of drugs. This gives us a drug with a unique mechanism of action in order to try patients who are early in relapse, as well. Overall, [the agent] seems fairly well-tolerated, especially now that selinexor is being given once weekly.

Where is research headed?

All the CAR T-cell studies and bispecific T-cell engagers are exciting. This ability to harness the immune system and use it to go back and attack the cancer is really opening up doors for our patients. Unfortunately, we didn't have the same success with checkpoint inhibitors that you're seeing in many of the solid tumors and other hematologic malignancies, so that was a little heartbreaking. However, now we also have an opportunity to harness the immune system but in a different way, it’s exciting for our patients.