Expert Explains Latest Developments in Multiple Myeloma

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.

OncLive: What are some recent trials that have been practice changing in relapsed/refractory 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.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 FDA just approved a new dose for carfilzomib based on the ARROW study findings. What did that trial show?

What other agents are moving through the pipeline?

What impact does it seem to have in patients with penta-refractory disease?

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 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.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.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.

What CAR T-cell therapy developments are in the pipeline?

Other compounds that are early in development are bispecific T-cell engagers (BiTEs). Amgen has a BiTE that is going to be developed in myeloma. The potential advantage to BiTEs compared with CAR T-cell therapy is that there may be less toxicity associated with the BiTE technology and hopefully with the same or similar efficacy.The farthest along does seem to be bb2121. What is being looked at in the near future will be moving CAR T-cell therapy earlier in the course of therapy. Many of the studies currently designed are for patients who are refractory to all other standard agents. There are studies that are starting to enroll patients with high-risk myeloma.

Could checkpoint inhibitors still have a role in myeloma?

Two next-generation sequencing assays were recently FDA approved in myeloma. How has that impacted the paradigm?

We know that our current standard therapies do not produce survival durations that we hope for in the high-risk population. The possibility of moving CAR T-cell therapy earlier in the course of therapy may reduce toxicity when the disease is better controlled with increased efficacy.Investigations are ongoing with checkpoint inhibitors, particularly atezolizumab (Tecentriq). There is a current study with atezolizumab, daratumumab, and pomalidomide that is enrolling. It slowed a bit when the FDA halted the trials with checkpoint inhibitors, but that study has now re-opened and will move forward. Checkpoint inhibitors in myeloma may or may not be effective drugs. Combining the drug with daratumumab makes a lot of sense because if you can eliminate some of the immune protection provided to the malignant cell with the checkpoint inhibitor, that may allow a drug like daratumumab to stimulate the immune system and work even better.There is still a story to be told regarding the detection of MRD. The sequencing assays seem to provide an early signal for overall survival (OS). That would be important. If the FDA comes to accept MRD negativity as a surrogate for OS advantage, that would make the use of MRD testing much more common, particularly in clinical trials.

There are potential roles for this in the everyday patient setting, although it does require sequential bone marrow sampling over time. If you did the repeat bone marrow sampling in patients who are in a complete response (CR), you may be able to detect them coming out of that CR earlier and potentially change their therapy. That may or may not have impact on the survival of these patients. That story will have to be worked out, but that is one potential application for such technology.

References

1. Chari A, Martinez-Lopez J, Mateos MV, et al. Daratumumab (dara) in combination with carfilzomib and dexamethasone (D-Kd) in lenalidomide (len)-refractory patients (pts) with relapsed multiple myeloma (mm): subgroup analysis of MMY1001. J Clin Oncol. 2018;36(suppl; abstr 8002).
2. Mateos MV, Moreau P, Berenson JR, et al. Once-weekly vs twice-weekly carfilzomib (K) dosing plus dexamethasone (d) in patients with relapsed and refractory multiple myeloma (RRMM): Results of the randomized phase 3 study A.R.R.O.W. J Clin Oncol. 2018;36(suppl; abstr 8000).