Landgren Reflects on Recent Breakthroughs in Multiple Myeloma

C. Ola Landgren, MD, PhD

The field of multiple myeloma has seen no shortage of progress in recent years, from new monoclonal antibodies and administrations thereof, to the emergence of targeted therapies for patients with relapsed/refractory disease, explained C. Ola Landgren, MD, PhD.

“The treatment landscape for multiple myeloma has changed dramatically over the past few years, and it’s changing even faster these days,” said Landgren. “We have multiple new drugs for patients who have relapsed/refractory disease. These drugs are also being approved in the newly diagnosed setting.”

One of the most recent regimens to emerge in the relapsed/refractory setting is the triplet of isatuximab, pomalidomide (Pomalyst) and low-dose dexamethasone. In the phase III ICARIA-MM trial, the triplet induced superior progression-free survival (PFS), response, quality of response, and achievement of minimal residual disease (MRD) negativity when compared with pomalidomide and dexamethasone alone. Based on these results, the FDA accepted a biologics license application (BLA) in July 2019 for the monoclonal antibody in the relapsed/refractory setting.

Although the triplet was believed to confer an advantage over daratumumab (Darzalex)-based regimens due to shorter infusion durations, data from the phase III COLUMBA trial showed that daratumumab can be given subcutaneously rather than intravenously without comprising efficacy. As such, a supplemental biologics license application was submitted for the formulation in July 2019.

Moreover, in the same month, the FDA granted an accelerated approval to selinexor (Xpovio) in combination with dexamethasone for the treatment of patients who have received ≥4 prior therapies and whose disease is refractory to ≥2 proteasome inhibitors, ≥2 immunomodulatory agents, and a CD38-targeted monoclonal antibody.

When it comes to CAR T-cell therapy, Landgren explained that several products are in development in the relapsed/refractory setting. However, despite initial response rates, the median duration of response hovers just around 1 year.

In an interview with OncLive, Landgren, chief of the Myeloma Service at Memorial Sloan Kettering Cancer Center, shared his expert insight on these shifts in multiple myeloma management.

OncLive: How has treatment for patients with multiple myeloma evolved in recent years?

Landgren: In 2019, we had the first approval of a monoclonal antibody in the upfront setting. There are ongoing trials that are using 4-drug combinations in the upfront setting. It's an extremely exciting time to be in the myeloma field. It's fantastic for patients.

Selinexor recently received an accelerated approval for use in the relapsed/refractory setting. Could you discuss the data supporting this approval?

Selinexor was granted an accelerated approval by the FDA in the middle of 2019. This was based on a single-arm study that focused on response rates. Specifically, the drug development program looked at selinexor in heavily pretreated patients. The response rate was approximately 25% in patients who had undergone multiple lines of treatment, which met the primary endpoint of the study.

There are now ongoing studies testing selinexor in combination with other drugs. Per standard criteria set by the FDA, the drug has to meet the primary endpoint for the confirmatory studies. However, it already has accelerated approval, which is fantastic.

What are the clinical implications of this approval?

The clinical implications of the approval are hard to measure. The drug is currently approved for heavily pretreated patients, which will probably be a relatively small group to begin with. For those patients who run out of options, it's an important contribution. Assuming that there are new combination trials with selinexor, the drug may be moved up into earlier lines of treatment. Of course, this will be contingent on the balance between efficacy and adverse events (AEs).

Isatuximab is another promising agent that has emerged in this space. Could you discuss the data from the phase III ICARIA-MM trial and the recent BLA submission for the agent?

Isatuximab is a new drug; it is the second monoclonal antibody that we have that targets CD38. The first drug was daratumumab, which was FDA approved back in November 2015.

We now have a press release and data from meetings of the agent in combination with pomalidomide and dexamethasone versus pomalidomide and dexamethasone alone in the relapsed setting. The [ICARIA-MM] study met its primary endpoint; that has now been submitted to the FDA. The agent is not yet FDA approved, but the expectation is that this will be an approved combination in the coming few months.

If isatuximab is approved, what will it add to the space?

It's hard to know what the expected approval of isatuximab will bring to the table, but having multiple drugs going after the same target is not a new phenomenon. We have 3 FDA-approved proteasome inhibitors (PIs). If isatuximab is approved, it would be the second CD38-targeted monoclonal antibody. It's great to have different options. The dosing schedule is slightly different; there are fewer doses compared with daratumumab. The duration of the infusions is shorter than the full duration for daratumumab.

On the other hand, daratumumab is in development for subcutaneous use. The fact that daratumumab has been developed for subcutaneous administration is huge. The toxicity profile seems to be significantly better with subcutaneous use. Around 50% of patients who receive it intravenously have infusion reactions for the first dose. Approximately 10% of patients who receive it subcutaneously experience infusion reactions. [Subcutaneous use] will lead to fewer patients having these AEs. Additionally, the use of steroids may not be mandatory. We could reduce the doses and potentially get rid of steroids. The 90 minutes of time patients spend receiving rapid infusions on the third dose can be reduced to 5 minutes with a shot; that's fantastic for patients.

However, isatuximab is also on its way toward subcutaneous use. There will be a lot of developments in the coming months. We will have to see what these studies deliver.

Could you expand on the recent regulatory advances with daratumumab?

Daratumumab was initially approved by the FDA in late 2015 as a single agent for patients with late relapses. Data came out less than 1 year ago regarding its use in combination with lenalidomide (Revlimid) and dexamethasone and bortezomib (Velcade) and dexamethasone for patients with 1 to 3 prior lines of therapy. Those study results led to a renewed label that included those combinations.

Now, we also an approval with daratumumab in combination with pomalidomide and dexamethasone for patients with relapsed/refractory myeloma. We have multiple different combinations; there are several under investigation. For example, data from the CANDOR trial with carfilzomib (Kyprolis), daratumumab, and dexamethasone are anticipated to read out in 2019.

Could you discuss the latest research with CAR T-cell therapy?

CAR T-cell therapy was on everybody's lips at the 2017 ASH Annual Meeting and it continued to be on everybody's lips at the 2018 ASH Annual Meeting. It's still on our lips, but we have recovered a little bit from the initial excitement. Fewer products are moving forward in development.

The first peer-reviewed publication came out in 2019 in the New England Journal of Medicine on bb2121, a BCMA-targeted CAR T-cell product developed by bluebird bio. Data indicate that the responses with the agent are quite profound. Patients were tested for MRD, and approximately 16 patients reached the rate of MRD negativity that was stipulated in the protocol. Furthermore, the PFS was around 1 year; patients who achieved MRD negativity had a PFS of approximately 18 months.

It is disappointing to see that the average duration of response is only 12 months; ideally, it would be much longer but it is a complicated therapy. You have to harvest the cells, during which time the patients have to be in the hospital. However, for patients who have no other option, it's great. It will be important to improve the therapy and understand why patients continue to relapse. Of course, we'll also keep a close eye on the monoclonal antibodies and the bispecific antibodies to see how they deliver. Will they be complimentary, or will they challenge the development of CAR T cells? Those are questions we still don't know the answers to. There's much more work to be done before we will know.

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.