Jason Valent, MD
Multiple myeloma treatment continues to evolve with novel triplet combinations, modified dosing strategies, chimeric antigen receptor (CAR) T-cell therapy, and potentially, checkpoint inhibitors, explained Jason Valent, MD.
“The monoclonal antibodies in combination with the novel agents for myeloma have improved response rates in the relapsed/refractory setting,” said Valent.
For example, he said, the addition of daratumumab (Darzalex) to carfilzomib (Kyprolis) and dexamethasone was shown to be effective and tolerable in an analysis of the phase Ib MMY1001 trial.1
Regarding dosing, carfilzomib was shown to be more effective when given once weekly at a dose of 70 mg/m2 versus the standard twice-weekly schedule of 27 mg/m2. This was based on the phase III ARROW trial which indicated a median progression-free survival of 11.2 months versus 7.6 months, respectively.2 The FDA approved this once-weekly dosing option in October 2018.
Though safety issues were previously reported with checkpoint inhibitors Valent said that there may still be a story to be told regarding their application in the paradigm. The same is true for minimal residual disease (MRD) negativity, which he said is prognostic but not yet predictive in myeloma.
In an interview during the 2018 OncLive® State of the Science Summit™ on Hematologic Malignancies, Valent, oncologist, Cleveland Clinic, discussed the current and future landscape of relapsed/refractory multiple myeloma.
OncLive: What are some recent trials that have been practice changing in relapsed/refractory myeloma?
Valent: The first trial centers around the use of daratumumab in combination with carfilzomib. The response rates seen with daratumumab in combination with novel agents has been quite impressive. This study also highlights that type of response rate. The combination of daratumumab with any of the novel agents is a reasonable option to consider in multiple myeloma, particularly in the relapsed/refractory setting. I anticipate that we'll see it moved into the newly diagnosed setting.
The second study is the combination of elotuzumab (Empliciti), another monoclonal antibody, in combination with pomalidomide (Pomalyst) and dexamethasone. [That combination] improves progression-free survival (PFS) in those patients.
The third study highlights how combination therapy, particularly with 3 drugs, is superior when compared with 2 drugs, particularly in relation to PFS. The combination of bortezomib (Velcade), pomalidomide, and dexamethasone was superior to the combination of pomalidomide and dexamethasone alone in the trial.
The FDA just approved a new dose for carfilzomib based on the ARROW study findings. What did that trial show?
The once-weekly dosing of carfilzomib at 70 mg/m2 makes it much more convenient for patients. That's the biggest advantage to that study; it saved patients 1 visit a week. There did not seem to be any increase in the toxicities associated with carfilzomib at the higher once-weekly dosing. Previous studies have used up to 56 mg/m2 twice-weekly, but the 70 mg/m2 dose did not seem to increase the adverse events related to the therapy. It may even reduce some of the toxicities associated with the treatment.
What other agents are moving through the pipeline?
In terms of standard therapies, selinexor is probably one drug that will garner a lot of attention in the next few years. Early on, there was some concern regarding toxicity with some of the dosing schedules that were used. The dose and schedule of administration has become more refined, so selinexor should be moving forward as an effective agent, particularly in relapsed/refractory disease.
What impact does it seem to have in patients with penta-refractory disease?
It is being studied in patients who have been refractory to both proteasome inhibitors, immunomodulatory agents, and daratumumab. It does show efficacy in that large hard-to-treat penta-refractory patient population. There are antibody-drug conjugates (ADCs), particularly a compound from GlaxoSmithKline––a combination of a BCMA-targeted antibody with chemotherapy and an ADC. That seems to be moving forward.