Immunotherapy Treatment Options Continue to Grow in Relapsed/Refractory Multiple Myeloma

Sham Mailankody, MBBS

Although not yet approved for patients with relapsed/refractory multiple myeloma, chimeric antigen receptor (CAR) T-cell therapies have shown great promise, in addition to the various immunotherapy treatment options already available, according to Sham Mailankody, MBBS. Immunotherapy with checkpoint inhibitors, however, has encountered a rockier road in multiple myeloma.

Favorable Outcomes With Triplet Combinations

During a presentation at the 2nd Annual Live Medical Crossfire: Hematologic Malignancies meeting presented in New York, NY, Mailankody, a medical oncologist/hematologist at Memorial Sloan Kettering Cancer Center, discussed current treatment options and shifting preferences, especially toward triplet combinations, as well as emerging immunotherapy treatment options.Currently, several doublet and triplet treatment options are recommended by the National Comprehensive Cancer Network for patients with relapsed/refractory multiple myeloma. Recent data, however, show superior outcomes with triplet combinations.

The phase III TOURMALINE study, for example, showed improved PFS rates with a triplet combination of the proteasome inhibitor ixazomib (Ninlaro), lenalidomide (Revlimid), and dexamethasone compared with placebo, lenalidomide, and dexamethasone in patients with relapsed/refractory multiple myeloma.¹

Of the randomized 772 patients, the median PFS was 20.6 months in the ixazomib arm versus 14.7 months in the placebo arm (HR, 0.74; 95% CI, 0.587-0.939; P = .01). Additionally, the rate of serious adverse events was similar between both arms (47% vs 49%, respectively).

Likewise, the phase III CASTOR study randomized 498 patients with relapsed/refractory multiple myeloma to receive daratumumab (Darzalex), bortezomib (Velcade), and dexamethasone or bortezomib and dexamethasone alone.² After a median follow-up period of 7.4 months, the median PFS was not yet reached for the daratumumab arm versus 7.2 months for the doublet combination (HR, 0.39; 95% CI, 0.28-0.53; P <.001). Higher rates of thrombocytopenia and neutropenia, however, were noted in the daratumumab group.

“Continuing with the theme…the 3 drugs here are better than the 2 drugs for PFS,” Mailankody said.

In the single-arm phase Ib EQUULEUS study, daratumumab plus pomalidomide (Pomalyst) and dexamethasone showed promise in patients with relapsed/refractory multiple myeloma with ≥2 prior lines of therapy (n = 103) with an ORR of 60%.⁵ Of the responders, 29% were MRD-negative.

Early Data Show Promise for CAR T-cell Therapies

Based on this trial, the FDA approved the combination for patients with relapsed/refractory who have received ≥2 prior lines of therapy including a proteasome inhibitor and lenalidomide.In the CRB-401 phase I study of bb2121 CAR T-cell therapy, 21 adults with relapsed/refractory multiple myeloma received bb2121 in 4 cohorts in the dose-escalation portion of the trial.³ The overall response rate (ORR) in 18 evaluable patients receiving doses ≥150 x 10⁶ was 94%. Additionally, 56% (n = 10) of patients achieved a complete response. Of the responders, 9 out of the 10 were minimum residual disease (MRD)—negative.

Bb2121 is a second-generation CAR T-cell therapy, developed by bluebird bio, targeting B-cell maturation antigen (BCMA) to redirect T cells to recognize and kill malignant myeloma cells, Mailankody explained.

“[These data are from the 2017 ASH Annual Meeting], showing very high response rates for patients who were treated at ≥150 x 10⁶. A side point that at the 50 x 10⁶ mark, there is very little or no activity,” he added. From the preliminary findings, doses of 150 to 450 x 10⁶ CAR T cells were selected for an expansion phase.

Based on updated data presented at the 2018 ASCO Annual Meeting, evaluable patients had a median progression-free survival (PFS) of 11.8 months at active doses ≥150 x 10⁶.⁴ Of those who achieved MRD-negativity (n = 16), a median PFS of 17.7 months was seen.

“The mere fact that we are able to get 16 out of 43 patients to MRD-negative levels with a single CAR T-cell [treatment] in this setting is certainly quite remarkable,” Mailankody said. “The fact that we now have patients who are 1.5 to 2 years out without needing any additional treatment…is quite remarkable. I think it speaks to why there is so much enthusiasm and so many different trials from different companies that are ongoing in this space currently.”

Questioning Potential With Checkpoint Inhibitors

A global phase II trial of bb2121 called KarMMa has been initiated following the findings of CRB-401 (NCT03361748).“As everyone in oncology is aware right now, we have checkpoint blockades, with the most prominent being PD-1 and PD-L1—targeted drugs, that can stimulate the immune system,” Mailankody said.

Recent trials have looked at PD-1 and PD-L1 checkpoint inhibitors in combination with immunomodulatory drugs, such as lenalidomide and pomalidomide. “As the name suggests, lenalidomide and pomalidomide have significant effects on the Tregs [regulatory T cells] suppression, natural killer and natural killer T-cell activation, and Th1 cytokine production. It would make rational sense to combine immunomodulatory drugs with checkpoint blockade for these reasons.”

Two phase III studies, however, were recently postponed due to deaths in patients utilizing the combination strategy.⁶

In the KEYNOTE-183 trial, the combination of pembrolizumab (Keytruda), pomalidomide, and low-dose dexamethasone was being compared with pomalidomide and low-dose dexamethasone alone in 249 patients with relapsed/refractory multiple myeloma who have undergone at least 2 lines of prior treatment.

According to an FDA analysis, at a median follow-up of 8.1 months, there were 29 deaths in the pembrolizumab arm versus 21 deaths in the control arm. The hazard ratio for overall survival for the pembrolizumab group compared with the control arm was 1.61 (95% CI, 0.91-2.85), translating to a >50% increase in the relative risk of death.

There were 301 patients included in the safety and efficacy analysis of c comparing pembrolizumab, lenalidomide, and low-dose dexamethasone with lenalidomide and low-dose dexamethasone. At a median follow-up of 6.6 months, there were 19 deaths in the pembrolizumab group compared with 9 in the control arm (HR for OS, 2.06; 95% CI, 0.93-4.55). The relative risk of death in the pembrolizumab was more than double that of the control arm.

“Both of these studies were put on pause and are no longer requiring patients. Which has led to a re-evaluation of the role of checkpoint blockade in myeloma.”

References

1. Moreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374(17):1621-1634. doi: 10.1056/NEJMoa1516282.
2. Palumo A, Chanan-Khan a, Weisel K, et al. Daratumumab, bortezomib, and dexamethasone for multiple myeloma. N Engl Med. 2016;375(8):754-766. doi: 10.1056/NEJMoa1606038.
3. Berdeja JG, Lin Y, Raje N, et al. Durable Clinical Responses in Heavily Pretreated Patients with Relapsed/Refractory Multiple Myeloma: Updated Results from a Multicenter Study of bb2121 Anti-Bcma CAR T Cell Therapy. Presented at: ASH Annual Meeting and Exposition; Dec. 9-12, 2017; Atlanta, GA. Abstract 740.
4. Raje NS, Berdeja JG, Lin Y, et al. bb2121 anti-BCMA CAR T-cell therapy in patients with relapsed/refractory multiple myeloma: updated results from a multicenter phase I study. Presented at: ASCO 2018 Annual Meeting; June 1-5, 2018; Chicago, IL. Abstract 8007. meetinglibrary.asco.org/record/160693/abstract.
5. Chari A, Suvannasankha A, Fay JW, et al. Daratumumab plus pomalidomide and dexamethasone in relapsed and/or refractory multiple myeloma. Blood. 2017;130(8):974-981. doi: 10.1182/blood-2017-05-785246.
6. FDA Alerts Healthcare Professionals and Oncology Clinical Investigators about Two Clinical Trials on Hold Evaluating KEYTRUDA^® (pembrolizumab) in Patients with Multiple Myeloma. Posted August 31, 2017. www.fda.gov/Drugs/DrugSafety/ucm574305.htm. Accessed July 14, 2018.