Immunotherapy Combination Treatment Options Growing in R/R Multiple Myeloma Space

Sham Mailankody, MBSS

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

During a presentation at the2nd AnnualLive Medical Crossfire^®: Hematologic Malignancies meeting presented in New York, Mailankody, a medical oncologist/hematologist at Memorial Sloan Kettering Cancer Center, discussed current treatment options and shifting preferences, especially toward triplet combinations, for patients with R/R MM, as well as emerging immunotherapy treatment options.

Favorable Outcomes With Triplet Combinations

Currently, several doublet and triplet treatment options are recommended by the National Comprehensive Cancer Network (NCCN) for patients with R/R MM.1 A recent update to the NCCN guidelines suggests triplet regiments are now standard therapy, while older patients should receive doublet regimens. Recent data show superior outcomes with the triplet combinations.

The phase III TOURMALINE study, for example, showed improved progression-free survival (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 R/R MM.²

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% and 49%, respectively).

Likewise, the phase III CASTOR study randomized 498 patients with R/R MM to receive daratumumab (Darzalex), bortezomib (Velcade), and dexamethasone or bortezomib and dexamethasone alone.³After a median follow-up 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.

&ldquo;Continuing with the theme, the 3 drugs here [in relapsed/refractory multiple myeloma] are better than 2 drugs for PFS,&rdquo; Mailankody said (TABLE).

In the single-arm phase Ib EQUULEUS study, daratumumab plus pomalidomide (Pomalyst) and dexamethasone showed promise in patients with R/R MM with &ge;2 prior lines of therapy, with an overall response rate (ORR) of 60%.⁴Of the responders, 29% were minimum residual disease (MRD) negative. Based on this trial&rsquo;s results, the FDA approved the combination for patients with R/R MM who have received &ge;2 prior lines of therapy, including a proteasome inhibitor and lenalidomide. In ELOQUENT-2, at the 4-year update, patients who received elotuzumab, lenalidomide, and dexamethasone had a 29% reduction in risk of progression/death versus patients who received lenalidomide and dexamethasone (HR 0.71, 95% CI 0.59—0.86) and relative improvement of 50% in PFS (21 vs 14%).⁵

Early Data Show Promise for CAR T-Cell Therapies

In the CRB-401 phase I study of bb2121 CAR T-cell therapy, 21 adults with R/R MM received bb2121 in 4 cohorts in the dose-escalation portion of the trial.⁶The ORR in 18 evaluable patients receiving doses &ge;150 x 106 was 94%. Additionally, 56% (n = 10) of patients achieved a complete response. Of the responders, 9 out of the 10 were 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.

&ldquo;[These data are from the 2017 ASH Annual Meeting], showing very high response rates for patients who were treated at &ge;150 x 106. At the 50 x 106 mark, there is very little or no activity,&rdquo; 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,⁷evaluable patients had a median PFS of 11.8 months at active doses &ge;150 x 106. Of those who achieved MRD negativity, a median PFS of 17.7 months was seen.

Grade &ge;3 treatment-emergent neutropenia was seen in 79%, thrombocytopenia in 51%, anemia in 44%, and cytokine release syndrome in 5%. No grade 4 or fatal cytokine release syndrome events were observed.

&ldquo;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,&rdquo; Mailankody said. &ldquo;The fact that we now have patients who are 1.5 to 2 years out without needing any additional treatment&hellip;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.&rdquo;

A global phase II trial of bb2121 called&nbsp;KarMMa has been initiated following the findings of CRB-401 (NCT03361748).

Questioning Potential With Checkpoint Inhibitors

Recent trials have looked at PD-1 and PD-L1 checkpoint inhibitors in combination with immunomodulatory drugs, such as lenalidomide and pomalidomide. &ldquo;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.&rdquo;

Two studies were recently postponed due to deaths in patients with multiple myeloma utilizing the combination strategy.⁸

In KEYNOTE-183, the combination of pembrolizumab (Keytruda), pomalidomide, and low-dose dexamethasone was being compared with pomalidomide and lowdose dexamethasone alone in 249 patients with R/R MM who had undergone at least 2 lines of prior treatment.

At a median follow-up of 8.1 months, there were 29 deaths in the pembrolizumab arm and 21 deaths in the control arm. The hazard ratio for overall survival (OS) 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 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 and 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.

&ldquo;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. NCCN Clinical Practice Guidelines in Oncology: multiple myeloma. V1.2019. NCCN website. nccn.org/professionals/physician_ gls/pdf/myeloma.pdf. Updated July 20, 2018.
2. Moreau P, Masszi T, Grzasko N, et al; TOURMALINE-MM1 Study Group. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma.N Engl J Med.2016;374(17):1621-1634. doi: 10.1056/NEJMoa1516282.
3. Palumbo A, Chanan-Khan a, Weisel K, et al; CASTOR Investigators. Daratumumab, bortezomib, and dexamethasone for multiple myeloma.N Engl Med.2016;375(8):754-766. doi: 10.1056/NEJMoa1606038.
4. 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.
5. Lonial S, Dimopoulos MA, Weisel KC, et al. Phase 3 ELOQUENT-2 study: Extended four year follow-up (FU) of elotuzumab plus lenalidomide/ dexamethasone (ELd) vs Ld in relapsed/refractory multiple myeloma (RRMM).J Clin Oncol.2017; 35 (suppl; abstr 8028).
6. 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. bloodjournal.org/content/ 130/Suppl_1/740?sso-checked=true.
7. 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.J Clin Oncol.2018;36(suppl; abstr 8007). meetinglibrary.asco.org/record/ 160693/abstract.
8. FDA alerts healthcare professionals and oncology clinical investigators about two clinical trials on hold evaluating Keytruda (pembrolizumab) in patients with multiple myeloma. FDA website. www.fda.gov/Drugs/DrugSafety/ucm574305.htm. Published August 31, 2017. Accessed July 14, 2018.