Emerging Approaches Offer Hope in Heavily Pretreated Myeloma

Suman Kambhampati, MD

When patients with multiple myeloma become refractory to lenalidomide (Revlimid) or bortezomib (Velcade), or have penta-refractory disease, there have been limited options left for treatment, according to Suman Kambhampati, MD. Recent studies presented at the 2018 ASCO Annual Meeting indicate that meaningful changes may be on the horizon.

Notably, the anti-BCMA CAR T-cell therapy bb2121 had a median progression-free survival (PFS) of 11.8 months and a median duration of response of 10.8 months for patients with relapsed/refractory heavily pretreated multiple myeloma, according to updated findings from the multicenter phase I CRB-401 study presented at ASCO.¹ The complete response (CR) or stringent CR rate was 50%, with an additional 36.4% of patients having a very good partial response. The objective response rate was 95.5%.

Another abstract presented at ASCO showed that administering carfilzomib (Kyprolis) once weekly at 70 mg/m2 with dexamethasone resulted in a prolonged PFS compared with the standard twice-weekly schedule in patients with relapsed/refractory multiple myeloma, according to results from the phase III ARROW study.² The median PFS was 11.2 months (95% CI, 8.6-13.0) with once weekly carfilzomib and dexamethasone compared with 7.6 months (95% CI, 5.8-9.2) for the standard twice-weekly schedule of carfilzomib at 27 mg/m² with dexamethasone (HR, 0.69; 95% CI, 0.54-0.83; P = .0029)

OncLive: Please provide some background to your presentation on multiple myeloma.

In an interview during the 2018 OncLive State of the Science Summit, A Summer of Progress: Updates from ASCO 2018, Kambhampati, the co-medical director of the Blood Cancer Program at Sarah Cannon Research Institute, highlighted some of the latest developments in the treatment of patients with relapsed/refractory multiple myeloma.Kambhampati: For myeloma, the theme here, or the big unmet need, is how to treat patients who have lenalidomide- or bortezomib-refractory disease. Also, we struggle with disease that becomes refractory to all agents, which is something we call penta-refractory disease. At the 2018 ASCO Annual Meeting, we saw tremendous data with the bb2121 CAR T cells, showing that patients can achieve progression-free survival of approximately 1 year. What we are seeing is the impact of CAR T-cell therapy in immunotherapy in myeloma.

Along those lines, we saw some interesting abstracts of drugs we already use in clinics, but it involved changing the dose or schedule and seeing how that could impact responses. For example, with carfilzomib, we saw that by changing the frequency of administration from twice weekly to once weekly, the patients had the convenience of coming in just once a week. Also, the results were slightly better with no added toxicity. We have, in our practice, looked at changing the carfilzomib dose and frequency by using a higher dose and administering it once weekly. That has been better for our patients because a lot of them come from far away.

Do you envision that CAR T-cell therapy will eventually move up to earlier settings, possibly in combination with other therapies?

What does the future hold for the next 5 years in myeloma treatment?

Other interesting abstracts were venetoclax (Venclexta) plus carfilzomib and dexamethasone. That is one drug that clearly has been shown to improve chemotherapy sensitivity, and we saw a very similar theme emerge in myeloma in many subtypes. Something that's also intriguing is the daratumumab plus carfilzomib/dexamethasone in lenalidomide-refractory patients. This was a very useful abstract and something we could translate into clinical practice quickly. Given the trend that we are seeing in relapsed/refractory disease, it's very conceivable that CAR T cells will be tested against stem cell transplant. The reason I say this is because the deep and durable responses we are seeing in very refractory patients suggest it is working. Data indicate we can achieve better responses when their immune system is still pretty robust. Therefore, it is very possible that CAR T cells will be tested soon in the more upfront stages of myeloma. The future for the next 5 years is to make the treatments less toxic. We are now treating patients nonstop for many years. Over time, the cumulative toxicities of steroids and other agents make it difficult for them to stay compliant and be in a position to receive continuous therapy. This obviously impacts the outcome.

This is something the field is demanding—better and less toxic medicines. Also, we would like to introduce better therapies early in the disease course, at a nominal cost—not a back-breaking cost that will bankrupt the system. Without some cost containment, these ideas still look pretty ambitious for many patients.

References

1. Noopur, R; Berdeja, J; Lin, Y; et all. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. J Clin Oncol. 2018;36(suppl; abstr 8007).
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 ARROW. J Clin Oncol. 2018;36(suppl; abstr 8000).