Venetoclax-Based Triplet Demonstrates Early Efficacy in t(11;14)-Positive RRMM

Jonathan Kaufman, MD

In patients with (11:14)-positive relapsed/refractory multiple myeloma, adding venetoclax (Venclexta) to the combination of carfilzomib (Kyprolis) and dexamethasone led to increased response rates vs carfilzomib plus dexamethasone alone, phase 2 study (NCT02899052) results show.¹

The findings were presented by Jonathan Kaufman, MD, at the 2023 International Myeloma Society Annual Meeting.

Preliminary evidence of longer progression-free survival (PFS) was also observed with the triplet therapy vs doublet, and enrollment for the randomized part 4 portion of the trial is ongoing.

Patients receiving the triplet at any dose (n = 39) achieved an investigator-assessed objective response rate (ORR) of 92% (95% CI, 79%-98%) with a 21% stringent complete response (sCR) rate, a 10% CR rate, a 51% very good partial response (VGPR) rate, and a 10% PR rate. Those given the doublet (n = 19) achieved an ORR of 63% (95% CI, 38%-84%) with 5% of patients experiencing a CR, 37% achieving a VGPR, and 21% having a PR.

When ORRs were evaluated via dosing, patients given 400 mg of venetoclax with carfilzomib and dexamethasone (n = 19) achieved an ORR of 89% (95% CI, 67%-99%) encompassing sCRs (11%), CRs (5%), VGPRs (63%), and PRs (11%). Those treated with 800 mg of venetoclax with carfilzomib and dexamethasone (n = 20) achieved an ORR of 95% (95% CI, 75%-100%) including sCRs (30%), CRs (15%), VGPRs (40%), and PRs (10%).

“Importantly, that improvement in response rate and deep responses translated to what appears to be an improvement in PFS,” said Kaufman, the medical director and section chief of the Ambulatory Infusion center at the Winship Cancer Institute and a professor in the Department of Hematology and Medical Oncology at the Emory University School of Medicine. However, in the presentation of the data, he noted that the trial was not designed or intended to evaluate if there were statistical differences in PFS.

Patients who received the triplet achieved a median PFS of 32.2 months vs 14.2 months for those given the doublet (HR, 0.490; 95% CI, 0.193-1.243) at a median follow-up of 22.6 months (range, 1.8-69.7) vs 16.8 months (range, 0.0-35.4), respectively. The median duration of response (DOR) was 41.5 months (95% CI, 23.9–not estimable [NE]) vs 16.3 months (95% CI, 6.5-NE) and the median time to response (TTR) was 1.0 month (95% CI, 1.0-1.1) vs 1.3 months (95% CI, 1.0-4.2), respectively. The median time to progression (TTP) was 32.2 months (95% CI, 17.1-NE) in the triplet arm vs 17.2 (95% CI, 5.8-NE) in the doublet arm.

When evaluating by dose level, the median PFS in the triplet arm with 400 mg of venetoclax was 32.2 months (HR vs the doublet, 0.495; 95% CI, 0.165-1.484) and the median PFS was 42.4 months in the 800 mg arm (HR vs the doublet, 0.483; 95% CI, 0.165-1.416). Median DORs in the 400 mg and 800 mg venetoclax arms were 31.3 months (95% CI, 14.8-NE) and 41.5 (95% CI, 16.1-NE) at median follow-ups of 22.4 months (range, 1.8-34.7) and 24.9 months (range, 2.2-69.7), respectively.

“When you look at the overall survival [OS] curves, there is no evidence that the combination of venetoclax/carfilzomib/dexamethasone is associated with a decrease in survival compared with carfilzomib and dexamethasone alone,” Kaufman said.

The median OS was not reached (NR) in both the triplet and doublet arms (HR, 0.553; 95% CI, 0.128-2.387) at the May 16, 2023, data cutoff.

Of the 8 patients in parts 1 to 3 of the study, 5 discontinued therapy due to progressive disease (PD), and 3 were still receiving treatment. Patients in part 4 of the trial also remained on treatment in the 400 mg venetoclax, carfilzomib, and dexamethasone arm (n = 10; 53%), 800 mg venetoclax, carfilzomib, and dexamethasone arm (n = 8; 67%), and carfilzomib/dexamethasone arm (n = 5; 28%); reasons for discontinuation of treatment primarily included PD.

Study Design

Patients at least 18 years of age with relapsed/refractory multiple myeloma, an ECOG performance score of up to 2, and measurable disease were enrolled in the study. No prior treatment with carfilzomib, venetoclax, or a BCL-2 inhibitor was allowed, patients in parts 1 to 3 received 1 to 3 prior lines of therapy, and those enrolled in part 4 received at least 1 prior therapy.

In the ongoing 4-part study, the nonrandomized initial 3 parts examined dosing strategies with venetoclax 800 mg plus carfilzomib 70 mg/m² and dexamethasone 40 mg determined as the dose to go forward to part 4 of the study; patients in cohorts 3 (n = 2), 5 (n = 3), and 6 (n = 3) of parts 1-3 were treated with the determined dose, and these 8 patients were included in the 800 mg venetoclax arm of the randomized part 4 portion of the trial.

Blood cells | Image Credit: © Катерина Євтехова - www.stock.adobe.com

In part 4 of the trial, patients are all receiving carfilzomib 70 mg/m² and dexamethasone 40 mg. They are being randomly assigned 5:3:5 in a non-stratified matter, according to Kaufman, to receive venetoclax at 400 mg with carfilzomib and dexamethasone, venetoclax at 800 mg with carfilzomib and dexamethasone, or carfilzomib/dexamethasone alone. In a 28-day cycle, venetoclax is administered orally once per day, and carfilzomib as well as dexamethasone are given on days 1, 8, and 15. Investigators noted those 75 years of age or greater could receive dexamethasone at 20 mg.

“Proteasome inhibitors and corticosteroids have been shown to enhance BCL-2 dependency providing the rationale for exploring venetoclax in combination with these agents,” Kaufman wrote in a presentation of the data.

The primary end points of the study are safety and ORR evaluated per investigator assessment in the efficacy population, including those in part 4 of the study and the patients in parts 1 to 3 who received venetoclax at 800 mg. Secondary end points are PFS, OS, TTR, TTP, and DOR.

Baseline Characteristics

Baseline characteristics were well balanced between the 400 mg triplet, 800 mg triplet, and the doublet arm. Most patients were male (53% vs 55% vs 53%, respectively), White (89% vs 90% vs 79%), and had an ECOG score of 1 to 2 (53% vs 50% vs 63%). The median ages were 71 (range, 45-84), 71 (47-78), and 73 (range, 57-83); median time from initial diagnosis was 4.1 years (range, 0.2-17.9), 4.1 years (range, 0.4-12.9), and 3.4 years (range, 0.6-14.1); and International Staging System stages were I (26% vs 45% vs 33%), II (26% vs 30% vs 44%), and III (42% vs 25% vs 11%), respectively.

“It’s important to remember patients who have t(11;14)[-positive disease] will not [be positive for] t(4;14) or t(14;16), so in this study we defined high risk as patients who have deletion 17p and 1q abnormalities,” Kaufman said.

Patients in the 400 mg triplet, 800 mg triplet, and the doublet arm had the following high-risk cytogenetics: deletion 17p (21% vs 20% vs 32%), gain 1q (16% vs 45% vs 11%), or gain 1q and/or deletion 17p (37% vs 55% vs 39%), respectively.

Patients received a median of 2 prior lines of therapy in each arm. Of those who had received a prior proteasome inhibitor in the 400 mg triplet (95%), 800 mg triplet (90%), and the doublet arm (89%), 53%, 70%, and 56% were refractory a proteasome inhibitor. Of patients who had prior exposure to an immunomodulatory drug in the 400 mg triplet (89%), 800 mg triplet (85%), and the doublet arm (89%), 84%, 70%, and 78% were refractory to the drug class with 63%, 65%, and 72% refractory to lenalidomide (Revlimid), respectively. Of those who had received a prior anti-CD38 monoclonal antibody in the 400 mg triplet (21%), 800 mg triplet (30%), and the doublet arm (50%), 21%, 30%, and 44% were refractory to daratumumab (Darzalex), respectively.

Patients in the 400 mg triplet, 800 mg triplet, and the doublet arm were refractory to both a proteasome inhibitor and immunomodulatory drug at rates of 42%, 45%, and 33%, respectively, and were refractory to a proteasome inhibitor, immunomodulatory drug, and anti-CD38 monoclonal antibody at rates of 16%, 10%, and 22%, respectively.

Efficacy

Kaufman noted that there were no new safety signals observed with the addition of venetoclax to carfilzomib and dexamethasone in the safety population, which encompassed all who were enrolled to the study and received at least 1 dose.

Serious treatment-emergent adverse effects (TEAEs) occurred in the 400 mg triplet (37%), 800 mg triplet (40%), and doublet (28%) arms. The most common serious TEAEs were pneumonia (n = 4; 21%) in the 400 mg triplet arm, pneumonia (n = 3; 15%) in the 800 mg triplet arm, and acute kidney injury (n = 2; 11%) as well as COVID-19 (n = 2; 11%) in the doublet arm. One patient died in each arm; Kaufman explained in the presentation that both deaths in the triplet arms were infection related, and the death in the doublet arm was related to cardiac toxicity.

In the 400 mg triplet, 800 mg triplet, and doublet arms, the most common any-grade TEAEs were neutropenia (21% vs 55% vs 11%, respectively), thrombocytopenia (42% vs 60% vs 33%), nausea (58% vs 55% vs 33%), vomiting (5% vs 50% vs 17%), diarrhea (63% vs 75% vs 17%), and fatigue (32% vs 50% vs 22%). Grade 3 or higher TEAEs included anemia (11% vs 10% vs 11%), lymphopenia (16% vs 30% vs 6%), pneumonia (21% vs 15% vs 11%), sepsis (16% vs 15% vs 0%), and cardiac disorders (5% vs 5% vs 6%).

Infections of any grade and grade 3 or higher occurred in the 400 mg triplet (68% and 32%), 800 mg triplet (85% and 25%), and doublet (33% and 11%) arms. Patients experienced serious infections at rates of 26%, 25%, and 11% in the 400 mg triplet, 800 mg triplet, and doublet arms, respectively.

Further Outcomes

Subgroup analysis showed that of those who received the triplet and were daratumumab refractory (n = 10), lenalidomide refractory (n = 25), or had gain 1q and/or deletion 17p risk-factors (n = 18) had similar ORRs at 90% (95% CI, 56%-100%), 96% (95% CI, 80%-100%), and 94% (95% CI, 73%-100%), respectively. Similar ORRs were also recorded for patients who received the doublet and were daratumumab refractory (n = 8), lenalidomide refractory (n = 13), or had gain 1q and/or deletion 17p risk-factors (n = 7). Those rates were 63% (95% CI, 25%-92%), 62% (95% CI, 32%-86%), and 57% (95% CI, 18%-90%), respectively.

Investigator-assessed median PFS in the daratumumab group was NR for those given the triplet compared with 5.8 months for those treated with the doublet (HR, 0.308; 95% CI, 0.066-1.449). In the lenalidomide-refractory groups, median PFS was 32.2 months in the triplet arm vs 8.8 months in the doublet arm (HR, 0.362; 95% CI, 0.131-1.001). Finally, patients with gain 1q and/or deletion 17p risk-factors experienced a median PFS of 42.4 months in the triplet arm vs 17.2 months in the doublet arm (HR, 0.449; 95% CI, 0.111-1.813).

The median OS was NR in all subgroups.

_Reference:

_{Kaufman JL, Gasparetto C, Kovacsovics, et al. First results from the randomized portion of a phase 2 study of venetoclax plus carfilzomib-dexamethasone vs carfilzomib-dexamethasone in patients with t(11;14) relapsed/refractory multiple myeloma. Presented at: 2023 International Myeloma Society Annual Meeting; September 27-30, 2023; Athens, Greece. Abstract OA-29.}