Emerging Therapies Generate Excitement in Myeloma

Thomas G. Martin, MD

Emerging treatments continue to shift the paradigm in multiple myeloma, including those designed to improve the quality of life for these patients.

For example, the January 2017 FDA approval of denosumab (Xgeva) for the prevention of skeletal-related events (SRE) in multiple myeloma can have an impact on patients with renal insufficiency. In the phase III 482 study, denosumab demonstrated noninferiority to zoledronic acid at delaying time of SRE in patients (HR, 0.98; 95% CI, 0.85-1.14; P = .01).

The median time to first on-study SRE was similar between the treatments, at 22.83 months with denosumab versus 23.98 months with the bisphosphonate zoledronic acid. The median progression-free survival (PFS) was 10.7 month higher in the denosumab arm (HR, 0.82; 95% CI, 0.68-0.99; P = .036).

Additional systemic agents—some of which were discussed during the 2017 ASH Annual Meeting—are also moving through the pipeline, including venetoclax (Venclexta) and isatuximab.

OncLive^®: Can you discuss the recent FDA approval of denosumab?

In an interview during the 2017 OncLive^® State of the Science Summit^TM on Hematologic Malignancies, Thomas G. Martin, MD, clinical professor of medicine, Adult Leukemia and Bone Marrow Transplantation Program, associate director of the Myeloma Program, co-leader, Hematopoietic Malignancies Program, Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, discussed emerging advancements in the treatment landscape of multiple myeloma.Martin: I am excited that denosumab has just received FDA approval for the treatment of patients with plasma cell disorders. Bone disease is a significant complication in multiple myeloma. We had several bisphosphonates, [specifically] pamidronate and zoledronic acid, that have proved efficacious in multiple myeloma, and now there is a third agent.

What did you focus on in your presentation on multiple myeloma?

The major advantage of denosumab over the other agents is it is less nephrotoxic, which is a significant problem in patients with multiple myeloma. This adds to the armamentarium to strengthen bones in patients with myeloma, especially in those patients who have renal insufficiency.We have made many advancements in patients with multiple myeloma. However, even though we are getting better response rates for all kinds of regimens that we are using, all patients still relapse. When it comes to relapse, we must think about several factors before therapy is started. There are patient- and disease-related factors.

Regarding patient-related factors and choosing therapy, it is important to consider age, performance status, and how robust patients are. Additionally, it is important to know whether they have other toxicities, such as those that are kidney, liver, or cardiac related.

There are certain regimens that are favored for patients who have renal toxicity. For instance, lenalidomide (Revlimid) is excreted in the kidneys and perhaps there is more toxicity in patients who have renal insufficiency, especially if the dose is not reduced. This needs to be taken into consideration.

There are also disease-related factors, such as determining if it is the first or second relapse, or if they have a refractory relapse, as well as the pace of relapse. There are some patients who relapse very fast where they are doubling the time to weeks or a few months. We need to be aggressive when determining their initial therapy.

On the other hand, we have patients who have a biochemical relapse. In those patients, we have the options of using a better tolerated and less potent regimen. We can also use one drug first and add a second drug if it is well tolerated, and then add a third drug, if needed.

The treatment of [patients with] relapsed myeloma is an art with many different strategies to use. We usually break up patients with relapsed myeloma into 2 groups, including patients who relapse early and those who have had 1 to 3 prior lines of therapy and relapse later.

In the early-relapsed group, the last 2 to 5 years have had many randomized trials showing that triplets are better than doublets. The triplets that have shown an advantage include carfilzomib (Kyprolis), lenalidomide, and dexamethasone; elotuzumab (Empliciti), lenalidomide and dexamethasone; ixazomib (Ninlaro), lenalidomide, and dexamethasone; and daratumumab (Darzalex), lenalidomide, and dexamethasone.

Additionally, triplets with antibodies plus proteasome inhibitors are quite good. In one large trial, it was determined that carfilzomib given at a higher dose of 56 mg/m2 is better than bortezomib (Velcade) in terms of PFS.

There were many updates presented at the 2017 ASH Annual Meeting. Some of the updates showed that not only was there a PFS advantage to triplets but also an overall survival (OS) advantage. For instance, carfilzomib, lenalidomide, and dexamethasone, as well as a regimen of elotuzumab, lenalidomide, and dexamethasone show a survival advantage to triplet versus doublet therapy.

We also had an update at the meeting of daratumumab with lenalidomide and dexamethasone, which shows the longest PFS in any early-relapse study. With about 33 months of follow-up, 58% of patients are still in remission. That is a dramatic response. The PFS for this study might end up being 36 or 40 months. That is quite a bit longer than any other relapse therapy making it a great regimen to consider.

There were also data in the first relapse that we should treat patients with stronger medicines. In that population, we may be able to induce a minimal residual disease (MRD) state or a complete remission (CR). Daratumumab, lenalidomide, and dexamethasone, as well as daratumumab, bortezomib, and dexamethasone have both shown the ability to induce MRD-negative states, which is phenomenal.

When someone has relapsed in 1 to 3 prior lines of therapy, there are many different regimens to choose from. Therefore, it is important to have experience with all of them. Many of my patients choose an oral regimen for convenience because they are far away from the treatment center. For younger patients, I try to give them the most potent therapy right away. There are no data to suggest that the harder you treat the patient, either in the frontline setting or after first relapse, does not induce a more potent relapse.

For patients who had more than 3 prior lines of therapy or are potentially refractory to therapy, I suggest giving potent secondary agents, such as pomalidomide (Pomalyst). Pomalidomide is usually given with dexamethasone and a third agent, such as carfilzomib, daratumumab, or ixazomib. In a phase II trial, it was shown that pomalidomide in combination with cyclophosphamide was better than the combination of pomalidomide and dexamethasone. It is a general rule that a triplet using pomalidomide and dexamethasone is better than just pomalidomide and dexamethasone at this current time.

We have some novel agents that are being tested in clinical trials. One is a CD38 antibody, isatuximab, which is currently in a phase III randomized trial. There is also a new drug called venetoclax, which is a BCL-2 inhibitor. Now, there are randomized trials in patients receiving venetoclax. The randomized trials are in the earlier relapsed space, but it is going to show significant benefit in patients who have a specific chromosomal abnormality of 11;14 translocation. It is going to end up being the treatment of choice for patients who relapse and have 11;14 translocation. That is my prediction.

Since triplet regimens are showing an improvement compared with doublet therapies, are we investigating 4-drug regimens?

There is a lot of excitement for cellular therapies. Patients who are refractory to all the drugs I talked about have cellular therapies that are looking efficacious. Over the next 2 to 5 years, we are going to have many more studies to combine these drugs with cellular therapies.One question that always comes up is, “Will quadruplets overcome triplets?” At the current time, we do not have data that quadruplets are better than triplets. In the past, they have not been better than triplets; however, we now have different classes of drugs. Three drugs that are active as single agents can be put together with dexamethasone to make a quadruplet. We are excited to see the results of these studies in the frontline and relapse settings.

What is the mechanism of action of isatuximab? Are there any promising data?

I do suspect that quadruplets are going to induce more patients to achieve CR and MRD-negativity, which will give us the longest PFS and OS.Isatuximab is an anti-CD38 antibody in the same space of drugs as daratumumab. The mechanism of action is similar. Isatuximab was selected for its ability to preclinically induce apoptosis in the test tube. Daratumumab was selected for its ability to induce complement-dependent cytotoxicity. Isatuximab is currently in a phase III randomized trial investigating pomalidomide and dexamethasone with or without isatuximab.

I suspect that the triplet regimen will show an advantage to the doublet. This is going to add to our armamentarium, whether it is going to be used in patients who have failed daratumumab or other antibody therapy, that is for future studies to determine.