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Evidence-Based Oncology January 2019

Clinical: Multiple Myeloma

Updates from the annual ASH meeting, December 2018.

ELOQUENT-3: Adding Elotuzumab to Pomalidomide, Dexamethasone Improves PFS in R/R Multiple Myeloma

David Bai, PharmD

ELOQUENT-3 trial results show that adding elotuzumab to pomalidomide and dexamethasone improved progression-free survival (PFS) and overall response rate (ORR) in patients with multiple myeloma who had relapsed from or were refractory to (R/R) lenalidomide and a proteasome inhibitor. Results were presented December 1, 2018, at the 60th American Society of Hematology Annual Meeting & Exposition and previewed in the New England Journal of Medicine.1

Immunomodulatory agents and proteasome inhibitors are the mainstay for treatment of multiple myeloma. Once patients relapse or become refractory, prognosis becomes extremely poor, with overall survival averaging 9 months. The triplet regimen of elotuzumab in combination with lenalidomide and dexamethasone, which combines an immunomodulatory agent with elotuzumab in patients with multiple myeloma who have progressed after at least 1 previous therapy, was approved in 2015.2

Elotuzumab is a humanized monoclonal antibody that binds to signaling lymphocytic activation molecule F7 (SLAMF7) on the surface of myeloma cells and natural killer cells to initiate natural killer cell–mediated cellular cytotoxicity or macrophage-mediated killing on myeloma cells. Because pomalidomide also affects the immune system, investigators said that a combination of elotuzumab and pomalidomide will work synergistically and enhance cell-mediated killing of myeloma cells. In the phase 2 ELOQUENT-3 study, the efficacy and safety of elotuzumab plus pomalidomide and dexamethasone were compared with pomalidomide and dexameth- asone in patients with relapsed/refractory multiple myeloma who had already received lenalidomide and a proteasome inhibitor.

Patients who were relapsed/refractory to lenalidomide and a proteasome inhibitor were randomized in a 1:1 ratio to receive either elotuzumab plus pomalidomide and dexamethasone (elotuzumab group) or pomalidomide and dexamethasone (control group). Median PFS was 10.3 months in the elotuzumab group compared with 4.7 months in the control group (HR, 0.54; 95% CI, 0.34-0.86; P = .008). The addition of elotuzumab was beneficial across all key patient subgroups, including patients who had received at least 4 previous lines of therapy and patients with at least 1 cytogenetic abnormality (eg, chromosome 17p deletion). ORR was also higher in the elotuzumab group (53%) than in the control group (26%), with 20% of patients in the elotuzumab group having a very good partial response or better compared with 9% in the control group. Median duration of response was not reached in the elotuzumab group; it was 8.3 months in the control group.

Reported adverse events (AEs) were similar between the 2 groups. The most common grade 3-4 AEs in the elotuzumab group and control group, respectively, were neutropenia (13% vs 27%), anemia (10% vs 20%), infections (13% vs 22%), and hyperglycemia (8% vs 7%). AEs that led to discontinuation occurred in 18% of the patients in the elotuzumab group compared with 24% of the patients in the control group.

Elotuzumab in combination with pomalidomide and dexamethasone was shown to be effective and safe and can be considered for patients who have progressed after lenalidomide and a proteasome inhibitor.

REFERENCES:
  1. Dimopoulos MA, Dytfeld D, Grosicki S, et al. Elotuzumab plus pomalidomide and dexamethasone for multiple myeloma. N Engl J Med. 2018;379(19):1811-1822. doi: 10.1056/NEJMoa1805762.
  2. Dangi-Garimella S. FDA’s decision on elotuzumab further expands options in multiple myeloma. The American Journal of Managed Care® website. ajmc.com/newsroom/fdas-decision-on-elotuzumab-further-expands-options-in-multiple-myeloma. Published November 30, 2015. Accessed December 14, 2018.


Carfilzomib-Based Combination Results in Sustained MRD-Negative Complete Response in Multiple Myeloma

Jaime Rosenberg

Upfront treatment with carfilzomib, lenalidomide (Revlimid), and dexamethasone (KRd) with lenalidomide maintenance incorporating a “by-default-delayed” autologous stem cell transplant (ASCT) strategy in newly diagnosed multiple myeloma has demonstrated high rates of minimal residual disease negativity (MRD negative) complete response (CR).

Expanding on these results, researchers at the 60th American Society of Hematology Annual Meeting & Exposition, held December 1-4, 2018, in San Diego, California, presented long-term study results showing that these responses were sustained with a median duration of over 4 years among treatment-naïve patients with multiple myeloma.

Expanding on these results, researchers at the 60th American Society of Hematology Annual Meeting & Exposition, held December 1-4, 2018, in San Diego, California, presented long-term study results showing that these responses were sustained with a median duration of over 4 years among treatment-naïve patients with multiple myeloma.

Following 8 cycles of KRd, patients received 2 years of lenalidomide 10 mg oral maintenance on days 1-21.

The primary objective of the study was to assess the rate of grade ≥3 peripheral neuropathy with secondary objectives of overall response rate (ORR), MRD negative CR, time to progression, and response duration assessed after every cycle during induction and subsequently after every 90 days of maintenance therapy. MRDneg CR was assessed by multi-color flow cytometry after 8 cycles of induction, 1 and 2 years of lenalidomide, and then annually.

Median potential follow-up was 5.7 years. The ORR was 97.8% (95% CI, 88.2%-99.9%) with a median duration of response of 65.7 months (95% CI, 55.6-not reached months). Notably, 28 patients (62.2%) had deep responses of MRD negative CR, and the durability was observed up to at least 70 months with a median duration of over 4 years.

Median time to progression was more than 5.5 years and median overall survival was not reached. However, at 80 months, 84.3% of patients were still alive. “As expected, patients who attained MRDneg CR by cycle 8 had a 78% reduction in the risk of progression,” wrote the researchers.

They added that these deep responses of MRD negative CR and long progression-free durations occurred regardless of age or cytogenic-based risk profile. Toxicities were generally manageable with no grade ≥3 neuropathy or death due to toxicity.

REFERENCES:
Kazandijan D, Korde N, Mailankody S, et al. A phase 2 study of carfilzomib, lenalidomide, and dexamethasone with lenalidomide maitenance (KRd-r) in newly diagnosed multiple myeloma (NDMM): sustained long term deep remissions and prolonged progresion-free duration regardless of age or cytogenetic risk after 5 years of follow up. In: Proceedings from the American Society of Hematology; December 1-4, 2018; San Diego, CA. Abstract 1957.
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