Isatuximab Triplet Highly Active in Relapsed/Refractory Myeloma

Paul G. Richardson, MD

Data from the phase III ICARIA-MM trial showed that the CD38-directed monoclonal antibody isatuximab should be used earlier in multiple myeloma treatment rather than reserving it for later use as salvage therapy, explained Paul G. Richardson, MD.

In the study, the addition of isatuximab to pomalidomide (Pomalyst) and low-dose dexamethasone reduced the risk of progression or death by more than 40% versus pomalidomide and dexamethasone (Pd) alone in patients with relapsed/refractory disease.¹

Furthermore, the triplet induced a median progression-free survival (PFS) of 11.5 months versus 6.5 months with Pd alone (HR, 0.596; 95% CI, 0.44-0.81; P = .001) as well as a 1-year overall survival rate of 72% versus 63%, respectively.

“We're very pleased to see that the 3-drug combination outperformed the control group,” said Richardson, clinical program leader, director of clinical research, Jerome Lipper Multiple Myeloma Center, and institute physician at Dana-Farber Cancer Institute. “We saw a doubling in PFS, response rate, quality of response, as well as engenderment of a minimal residual disease negative rate per next-generation sequencing.”

On July 10, 2019, the FDA accepted a biologics license application (BLA) for the triplet regimen in the relapsed/refractory setting; the agency is scheduled to make a decision on the BLA by April 30, 2020.

Moreover, melflufen, a targeted chemotherapeutic, may become an additional agent for patients with relapsed/refractory disease, according to data from the phase I/II O-12-M1 trial (NCT01897714), in which the agent showed preliminary durability in combination with dexamethasone.²

In an interview with OncLive, Richardson, who is also the RJ Corman Professor of Medicine at Harvard Medical School, reviewed the results of the phase III ICARIA-MM trial as well as preliminary data regarding melflufen in relapsed/refractory multiple myeloma.

OncLive: Could you provide background on the ICARIA-MM trial?

Richardson: Isatuximab is a CD38-targeted antibody, which is of great interest because it has demonstrated single-agent activity as well as excellent safety and efficacy data when used in combination in the relapsed/refractory setting. In our phase Ib trial, the median PFS was in excess of [17] months, which for such a sick population is very encouraging. Regarding its preclinical profile, it has potent activity in the ectoenzymatic pathway. The agent targets apoptosis, and, at the same time, has less complimentary activation; this may make it easier to administer. [These data have] led to a very strong rationale to bring it into the randomized phase III setting.

This is the first trial of its kind in this setting where we compared a CD38-targeted antibody plus pomalidomide/dexamethasone with pomalidomide and dexamethasone alone. About half of the patients whose disease worsened after receiving pomalidomide and dexamethasone went onto daratumumab (Darzalex)-based therapy. That’s good news because it meant they were able to go onto CD38-based treatment.

Interestingly, there's a trend toward improved survival in favor of the 3 drugs. This suggests that keeping daratumumab or isatuximab in reserve does not make sense. In relapsed/refractory disease, you need to use your best options earlier rather than later. We also built in other secondary endpoints, including time to next therapy, which was strikingly in favor of the 3 drugs over the 2. That’s an important clinical endpoint for our patients.

We also looked comprehensively at safety and quality of life (QoL). There were no new safety signals of concern. There was a little bit of neutropenia, which is manageable. As with all antibodies, you have to be careful about chest infections. There was no loss of QoL or detriment to the QoL measures with the use of 3 drugs.

Is there a rationale to hold daratumumab or isatuximab as salvage therapy?

The reason to be more careful would be [for tolerability]. If, for example, you thought your patient might be better able to tolerate the 2 drugs first, you might do that and then add the third drug if you had to. However, the data from the ICARIA-MM trial suggest that may not be the wisest move. In reality, using all 3 drugs earlier may result in better outcomes. In our trial, we had a broad age range; over one-third of patients were over the age of 65 and 70, so it was well representative of an older population.

In terms of specific subgroups of patients, including those with high-risk cytogenetics and the over 90% of patients who were lenalidomide (Revlimid)-refractory, those patients did particularly well with the 3 drugs over the 2. This drug does not exacerbate chronic obstructive pulmonary disease (COPD) or asthma. Daratumumab, because of its complimentary activation, has been associated with some pulmonary issues. For our patients with asthma or COPD, of whom there were over 10% in the trial, they did remarkably well.

Over 70% of patients were double-refractory, so this was truly a heavily pretreated relapsed/refractory population. Patients in whom lenalidomide has failed them represent an exquisite unmet medical need and were clearly well-represented in the trial. Everyone was exposed to lenalidomide, but over 90% were refractory to lenalidomide.

What differentiates this triplet from other available triplet regimens available?

The triplet works in high-risk patients and it works quickly, which is important. It works in patients with renal disease, and it can be given to patients who have some degree of pulmonary risk, which may make this a more attractive option. It has the advantage of a weekly schedule for the first month and then every 2 weeks thereafter, so it’s a little bit more convenient. There is also a relatively short infusion time; it’s only a couple of hours once things are settled in. I have to stress, however, that we saw some very exciting data with daratumumab in terms of the efficacy and safety of subcutaneous administration. The issue of the duration of infusion time is less of a challenge now, which is good news.

The advantage of isatuximab is that it has this antiapoptotic mechanism [via] an ectoenzymatic engagement of the epitope where the CD38 is expressed, which may make it particularly attractive for a patient who has had multiple lines of treatment, including daratumumab. If you're revisiting CD38 in combination, you might want to think about isatuximab.

We know that if daratumumab fails a patient and you immediately go to isatuximab monotherapy, that may not be terribly successful. [That approach is] safe, but the early trials in Europe did not suggest significant benefit. The converse is that the combination of the drug with other agents has more appeal, especially based on the data from the ICARIA-MM trial.

What are the immediate next steps of research following these data?

Isatuximab is being studied in numerous other phase III trials in earlier lines of therapy and in combination with other drugs in later stages of disease. The agent has great promise because it works very well with other drugs. We see a very favorable safety profile [with isatuximab], so we're looking forward to being able to develop it further and use it with other drugs.

You also presented an analysis of time to next treatment in melflufen and dexamethasone-treated patients with relapsed/refractory disease. Could you shed some light on those findings?

We were able to observe prolonged survival in patients who received prior melflufen as part of the O-12-M1 study. This trial is different from the HORIZON trial which we presented at the 2018 ASH Annual Meeting showing a really striking response rate in penta-refractory, triple-class—resistant patients. The data showed some degree of durability; however, the data are early. The data come from our earlier experience from the O-12-M1 study, which was performed some time ago. In that study, we defined the dose of 14 mg per month with dexamethasone. We're pleased to see that there are really durable responses with that combination. We also saw an encouraging survival signal.

The exciting thing about melflufen is that it provides an important new option beyond what we currently have. We know that chemotherapeutics are important. It's important to make sure that we have all assets available to our patients. Melflufen constitutes a very exciting, and perhaps less appreciated, area in our new spectrum of options for our patients.

References

1. Richardson PG, Attal M, Rajkumar SV, et al. A phase III randomized, open label, multicenter study comparing isatuximab, pomalidomide, and low-dose dexamethasone versus pomalidomide and low-dose dexamethasone in patients with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2019;37(suppl 15; abstr 8004). doi: 10.1200/JCO.2019.37.15_suppl.8004.
2. Bringhen S, Richardson PG, Voorhees PM, et al. Analysis of time to next treatment (TTNT) in melflufen and dexamethasone-treated patients (pts) with relapsed/refractory multiple myeloma (RRMM). J Clin Oncol. 2019;37(suppl; abstr 8043). doi: 0.1200/JCO.2019.37.15_suppl.8043.