Novel Combination Therapies Show Promise in Managing Early Relapse in Multiple Myeloma

Ajai Chari, MD

Although it is still true that not every case of relapsed multiple myeloma (MM) warrants immediate therapy, there is building evidence that novel combination therapies could be effective in treating early relapsed MM, according to data presented by Ajai Chari, MD, at the 2021 International Congress on Hematologic Malignancies.

“We see diminishing returns in relapsed disease,” explained Chari, the director of clinical research for the multiple myeloma program at Mount Sinai’s Ichan School of Medicine in New York, New York. “We can use hazard ratios to help guide therapy and selecting the proper treatment backbone is essential.”

Overall, the literature shows that the experimental treatment arms performed better than their control doublets. Chari explained that treatment backbones must be selected with prior treatments, patient demographics, and disease burden all taken into consideration.¹

Novel treatments utilizing a lenalidomide backbone showed an improved progression free survival (PFS) compared to the lenalidomide plus dexamethasone (Rd) control arms in phase 3 clinical trials. In the TOURMALINE-MM1 trial (NCT01564537), PFS in the experimental proteasome inhibitor ixazomib (Ninlaro) plus Rd arm was 21.0 months versus 14.7 months with Rd (HR, 0.74; CI 95%, 0.59-0.94).²

In ASPIRE (NCT01080391), PFS was 26.1 months in the carfilzomib (Kyprolis) plus Rd group (Kd) compared with 16.6 months for Rd alone (HR, 0.66; CI 95%, 0.55-0.78).³ Data from ELOQUENT-2 (NCT01239797) showed that PFS was 19.0 months with elotuzumab (Empliciti), an anti-CS1 humanized monoclonal antibody, plus Rd group versus 14.9 months in Rd (HR, 0.71; CI 95%, 0.59-0.86).⁴ Finally, in the POLLUX trial (NCT02076009), the experimental arm of daratumumab (Darzalex) plus Rd showed a PFS of 45.5 months compared with 17.5 months for Rd (HR, 0.44; CI 95%, 0.34-0.55).⁵

Treatments using a proteasome inhibitor backbone also produced better PFS in the experimental arms of phase 3 clinical trials compared to the bortezomib plus dexamethasone (Vd) control arms. Data from the BOSTON trial (NCT03110562) found PFS in the selinexor (Xpovio) plus Vd arm to be 13.9 months, while it was 9.5 months in Vd (HR, 0.70; CI 95%, NA).⁶ Results from BELLINI (NCT02755597) showed a PFS of 23.2 months in the group receiving venetoclax(Venclaxta) plus Vd, as opposed to 11.4 months with Vd (HR, 0.63; CI 95%, 0.44-0.89).⁷

“Based on the randomized studies, the CD-38 and Kd regimens seem quite compelling, with a PFS of over 20 months,” Chari said. “Given a choice, I’d probably use CD-38 and Kd [first], but while also recognizing that not every patient is appropriate for the carfilzomib backbone—particularly someone with uncontrolled blood pressure, a cardiac history, or the very old. Those patients might be better suited to do a CD-38 with pomalidomide and dexamethasone combination.”

However, Ajai warned that cross-trial comparisons can be fraught due to differing patient populations, disease burdens, and prior therapy exposures. As a result, the outcomes of identical control arms can significantly vary between trials. Patient access to certain treatments at relapse also remains an issue.

In general, novel therapies improved outcomes for those with high-risk disease, but did not outperform the same techniques used in standard-risk patients.

PFS in the experimental arms declined in patients with lenalidomide-refractory disease in all the phase 3 studies examining the use of proteasome inhibitor backbones. PFS in lenalidomide-refractory patients was 9.5 months (HR, 0.61; CI 95%, 0.49-0.77) in OPTIMISMM (NCT01734928), 7.8 months (HR, 0.31; CI 95%, 0.24-0.39) in CASTOR (NCT02136134), and 8.6 months (HR, 0.53; CI 95%, 0.44-0.65) in ENDEAVOR (NCT01568866).^8-10 These PFS figures all exceeded their control counterparts, but all fell short of the same therapy in standard-risk patients.

References

1. Chari A. Managing early relapse in multiple myeloma. Poster presented at 25th Annual International Congress on Hematologic Malignancies; February 28, 2021. Accessed March 1, 2021. https://bit.ly/3uN3PMG
2. Monreau P, Masszi T, Grzasko N, et al. Oral ixazomib, lenalidomide, and dexamethasone for multiple myeloma. N Engl J Med. 2016;374:1621-1634. doi:10.1056/nejmoa1516282
3. Siegel DS, Dimopoulos MA, Ludwig H, et al. Improvement in overall survival with carfilzomib, lenalidomide, and dexamethasone in patients with relapsed or refractory multiple myeloma. J Clin Oncol. 2018;36(8):728-734. doi:10.1200/jco.2017.76.5032
4. Dimopoulos MA, Lonial S, Betts KA, et al. Elotuzumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended 4-year follow-up and analysis of relative progression-free survival from the randomized ELOQUENT-2 trial. Cancer. 2018;124(20):4032-4043. doi:10.1002/cncr.31680
5. Bahlis NJ, Dimopoulos MA, White DJ, et al. Daratumumab plus lenalidomide and dexamethasone in relapsed/refractory multiple myeloma: extended follow-up of POLLUX, a randomized, open-label, phase 3 study. Leukemia. 2020;34(7):1875-1884. doi: 10.1038/s41375-020-0711-6
6. Dimopoulos MA, Delimpasi S, Simonova M, et al. Weekly selinexor, bortezomib, and dexamethasone (SVd) versus twice weekly bortezomib and dexamethasone (Vd) in patients with multiple myeloma (MM) after one to three prior therapies: Initial results of the phase III BOSTON study. J Clin Oncol. 2020;38(suppl 15):8501. doi:10.1200/jco.2020.38.15_suppl.8501
7. Kumar SK, Harrison SJ, Cavo M, et al. Updated results from BELLINI, a phase 3 study of venetoclax or placebo in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma. J Clin Oncol. 2020;38(suppl 15):8509. doi:10.1200/jco.2020.38.15_suppl.8509
8. Richardson PG, Oriol A, Beksac M, et al. Pomalidomide, bortezomib, and dexamethasone for patients with relapsed or refractory multiple myeloma previously treated with lenalidomide (OPTIMISMM): a randomised, open-label, phase 3 trial. Lancet Oncol. 2019;20(6):781-794. doi:10.1016/s1470-2045(19)30152-4
9. Weisel KC, Sonneveld P, Mateos MV, et al. Efficacy and safety of daratumumab, bortezomib, and dexamethasone (D-Vd) versus bortezomib and dexamethasone (Vd) in first relapse patients (pts) with multiple myeloma (MM): four-year update of CASTOR. Blood. 2019;134(suppl 1):3192. doi:10.1182/blood-2019-123527
10. Dimopoulos MA, Monreau P, Palumbo A, et al. Carfilzomib and dexamethasone versus bortezomib and dexamethasone for patients with relapsed or refractory multiple myeloma (ENDEAVOR): a randomised, phase 3, open-label, multicentre study. Lancet Oncol. 2016;17(1):27-38. doi:10.1016/s1470-2045(15)00464-7