Novel Agents Rouse Responses in Relapsed/Refractory Multiple Myeloma

Thomas G. Martin, MD

In just the past 5 years, incredible progress has been made in multiple myeloma, evidenced by the emergence of novel CD38 antibodies, BCMA-directed treatments, and cereblon E3 ligase modulators (CELMoDs), according to Thomas G. Martin, MD.

“We have a lot of options that are coming up. It’s really quite [exciting] to be treating patients with multiple myeloma because now we can tell patients that we have options,” said Martin.

In an interview with OncLive® during an Institutional Perspectives in Cancer webinar on Multiple Myeloma, Martin, a clinical professor of medicine in the Adult Leukemia and Bone Marrow Transplantation Program, associate director of the Myeloma Program at the University of California, San Francisco (UCSF), and co-leader of the Hematopoietic Malignancies Program at UCSF Helen Diller Family Comprehensive Cancer Center, discussed the importance of targeted therapy in multiple myeloma, in addition to ongoing research.

OncLive®: Could you discuss the importance of targeting CD38 in multiple myeloma?

Martin: These past 5 years have been amazing in terms of development of CD38 antibodies. First was daratumumab (Darzalex), which began its career in the relapsed/refractory setting, showing overall response rates of about 30%. Back then, this was unheard of for a monoclonal antibody. We’re still getting data right now [regarding its use] in early relapse patients. So, daratumumab has been combined with a variety of agents, initially showing an advantage when combined with the lenalidomide (Revlimid) and dexamethasone and bortezomib (Velcade) and dexamethasone. Now, more recently, in combination with carfilzomib (Kyprolis) and dexamethasone, as well as pomalidomide (Pomalyst) and dexamethasone. These combinations are extremely potent. When these combinations are given to patients with 1 to 3 prior lines of therapy, it can lead to a remission of more than 18 months and sometimes more than 30 months, which is pretty amazing.

The next antibody is isatuximab (Sarclisa), which is another CD38 antibody that was recently approved due to its ability to show a benefit in combination with pomalidomide and dexamethasone. [The addition of isatuximab] nearly doubled the progression-free survival (PFS) from around 6 months to 11.5 to 12 months. So, this is a great combination. We also saw data on the combination of isatuximab plus carfilzomib and dexamethasone at the 2020 European Hematology Association Annual Congress, showing a large advantage in PFS and overall response rates (ORRs) versus carfilzomib and dexamethasone alone.

Daratumumab also has shown amazing effects in the frontline setting. We don’t have data yet for isatuximab in the frontline setting, but daratumumab has been approved for use with a number of [frontline] regimens. The PERSEUS trial assessed the 3-drug induction regimen of lenalidomide, bortezomib, and dexamethasone (RVd) versus RVd plus daratumumab in the frontline setting. We all hope that this is going to be what we use as frontline therapy, which is showing quiteimpressive responses in the randomized phase 2 GRIFFIN study. We now want to see that response in the PERSEUS study, which is the licensing trial [for that quadruplet regimen]. CD38 antibodies have come a long way.

We have a fair number of next-generation CD38 antibodies that are coming down the pike as well. We have a couple from Takeda, such as TAK-079, which binds only to the cells that have a large amount of antigen or CD38 receptors on the surface. It may bind more preferentially to cancer cells versus normal or red blood cells. We’ll have to see how those next-generation molecules do. I suspect they’ll do quite well; we are anticipating the data. There’s also a CD38 [antibody] that has an interferon structure built into it, in addition to [an antibody] with a penta structure. There are a variety of agents that are coming out that could potentially make treatment better and more potent.

Could you shed light on some of the BCMA-targeted agents you are excited about?

In the antibody domain, we just had our first BCMA-targeted therapy approved by the FDA. It’s really amazing that we’re here so quickly. This was the approval of belantamab mafodotin-blmf (Blenrep). It’s a BCMA-targeted antibody-drug conjugate (ADC) that has multiple mechanisms of action, including the classic [mechanism of an ADC] where the antibody binds to the cell surface of BCMA and then gets internalized. The poison attached to the antibody is cleaved and that poison causes cellular apoptosis. It also has a fragment crystallizable domain that allows for enhanced antibody dependent cellular cytotoxicity. It also blocks BCMA, and that may give a proapoptotic signal. It works by a less investigated mechanism, [leading to] immunogenic cell death. We’ll see how [belantamab mafodotin] affects the immune system in more studies going forward.

[Belantamab mafodotin] received accelerated approval based on results from the phase 2 DREAMM-2 study, where patients were randomized to 2 different doses of belantamab. About 100 patients were in each arm; one arm received 3.4 mg/kg and the other received 2.5 mg/kg. Belantamab is given intravenously (IV) every 3 weeks, which is easy to administer. There is also a very low incidence of infusion-related reactions, at about 20%. It’s typically given without premedications, but if patients have an infusion reaction, they can get medications for that. This usually only occurs in the first infusion.

Between those 2 doses, the response rate was very similar; the ORR was 31% with the 2.5 mg/kg dose and 34% for the 3.4 mg/kg dose. The adverse effects (AEs) were interesting. Thrombocytopenia stood out because it’s linked to the antibody, monomethyl auristatin F (MMAF). Though, the rate was only 35% in the 2.5 mg/kg arm, whereas it was over 50% in the 3.4 mg/kg arm. It was because of toxicity that the 2.5 mg/kg dose was selected for further study. Interestingly, it does have this unique AE that’s also related to the [antibody] MMAF. We believe it can get to the surface of the eye, causing keratopathy. This is noted by an ophthalmologist. As such, this drug has to be given alongside a good ophthalmologist, who will [monitor] the surface of the eye.

You may have to either reduce the dose or hold the drug for a longer period of time and give it every 4, 5, or 6 weeks in about half of the patients. We have to watch our patients closely on this drug, especially due to this ocular toxicity. Although, it demonstrated some great responses. We’ve had some patients at UCSF with extramedullary disease who’ve had some very nice responses with belantamab. Belantamab is a really nice drug for patients with triple-class refractory disease, who have received immunomodulatory drugs (IMiDs), proteasome inhibitors, and a CD38 antibody, and now need something else. This is [the setting in which] it’s approved.

Selinexor (Xpovio) is the other drug that’s good in that triple-class refractory setting. With selinexor, the response rates are in the 25% range in that group of patients, and it’s given together with dexamethasone. However, patients must be watched closely for AEs. Most of these are gastrointestinal AEs, fatigue, and low sodium. Patients typically require antiemetics and IV hydration.

The other antibodies that are really exciting are the bispecific T-cell engaging antibodies. With these antibodies, 1 arm binds to BCMA and the other arm binds to CD3 on a T cell, which activates the T cell. There are drugs that are targeting other antigens; however, the ones that are furthest along bind to BCMA.

An incredible number of trials are ongoing with these drugs, and they’re all different in the way [each investigational agent] binds BCMA, how tightly, and how many binders there are for BCMA. The [agent] may have 2 or 3 binders on one side, and, on the other arm, it may just be CD3. It may be a weak binder of CD3 or a really tight binder of CD3 and therefore activate the T-cell a little differently. It’s very neat.

During the 2018 ASCO Annual Meeting, Max S. Topp, MD, of University Hospital of Wuerzburg, presented the first dataset on AMG 420, which is a continuously infused bispecific T-cell engager that binds to BCMA and [activates] T cells. At the maximum tolerated dose (MTD), 7 of 10 patients had a response, which in a very refractory group is pretty amazing. However, that drug was scrapped, mostly because of the continuous infusion [aspect of administration]. We need agents that are easier to administer. Now, we have other drugs. We have a drug from Bristol Myers Squibb, CC-93269, which is another T-cell engager. At the 2019 ASH Annual Meeting, Luciano Costa, MD, PhD, of University of Alabama’s Birmingham School of Medicine, presented data on that agent.

The investigators evaluated a step-up from 6 mg to 10 mg, and 8 of 9 patients had response. Then, at the 2020 ASCO Virtual Scientific Program, Saad ​Z. Usmani, MD, FACP, of Levine Cancer Institute, presented data on a drug from Janssen called teclistimab (JNJ-64007957). At the higher dose level, around 270 μg,they treated about 12 patients and showed a response rate of 67%. Notably, some of these patients had durable responses at 18 months [of follow-up].

Are there any safety concerns with these agents?

All the patients who receive these drugs, especially when it comes to the first and second dose, must receive it in the hospital. This is an FDA mandate because these drugs do activate the immune system and can result in cytokine release syndrome (CRS). Over 50% of patients are getting CRS [from these drugs], [resulting in] fever and some hypotension; sometimes patients need oxygen. Though, very few patients have had to go to the ICU.

After the first and second dose, patients then receive therapy in an outpatient setting. I have a couple patients that are on some of these clinical trials that are getting [these agents] as early as 3 months down the road and as late as 1.5 years down the road. These patients aren’t reporting any AEs, which is great. I’m excited about this because after the first couple of doses, the AEs are very limited. Less than 10% of patients experience neurotoxicity. These are symptoms that we’ve also seen with CAR T-cell therapy. We think [these AEs] are due to the immune activation and some mild blood count suppression.

Could you highlight some of the key data on CELMoDs?

We all are very familiar with lenalidomide and pomalidomide. They’ve been big parts of our treatment algorithms for newly diagnosed and relapsed/refractory patients. These CELMoDs are the next-generation IMiDs.

Sagar Lonial, MD, FACP,of Emory University School of Medicine, presented phase 1 data on CC-220 or iberdomide during the 2019 ASCO Annual Meeting. In the multi-cohort trial, the investigators evaluated iberdomide alone, iberdomide plus dexamethasone, as well as some other combinations. In this heavily refractory population, we saw a really amazing ORR of 32% in the dose-escalation phase in 59 patients. In IMiD-refractory patients, the ORR was still really good, at 35%. If they looked at daratumumab- and pomalidomide-refractory patients, the ORR was still right up there, at 30%.

These drugs probably have a similar mechanism [as IMiDs] in that they inhibit Ikaros and Aiolos and cause better degradation than lenalidomide and pomalidomide. They’re also more potent in terms of their stimulation of the local immune system. So, they are working by immune stimulatory mechanisms.

In his presentation, Dr. Lonial said he was very impressed in terms of how well-tolerated these agents were. There was no grade 3 or 4 fatigue or peripheral neuropathy, and [few patients had low blood counts]. Now, we also have data from the 2020 ASCO Virtual Scientific Program on CC-92480, which is another next-generation CELMoD. The investigators had an adaptive Bayesian phase 1 design and tested the drug every 21 days of a 28-day cycle and every 10 out of 14 days of a 28-day cycle. Giving the drug continuously for 21 days worked better, so that’s going to be the schedule that’s evaluated moving forward.

The agent in combination with dexamethasone led to an ORR of 21% in 76 patients. The MTD was 1 mg once daily, and at this higher dose, the ORR was 54.5%. Notably, many patients in the trial had extramedullary disease. This was really a refractory population. One patient in particular had a very large liver lesion and after a few cycles of this therapy, the liver lesion was gone on PET imaging. That’s very impressive for this this type of agent.