VenDd Elicits Durable MRD Negativity in Myeloma

Multiple myeloma shows hematologic malignancies that involve abnormal cell proliferation in the bone marrow—the combination of venetoclax (Ven), a potent BCL-2 inhibitor. Daratumumab (D) and dexamethasone (d) demonstrated a high overall response rate (ORR) and favorable safety in a Phase 1/2 study.

Nizar J Bahlis and his research group spearheaded the study that aimed to focus on minimal residual disease (MRD) negativity analyses in the Phase 1/2 trial of VenDd at 400 and 800 mg dose levels, comparing them with bortezomib plus Dd (DVd) in t(11;14)-positive RRMM patients.

In the Phase 1/2 multicenter study, Parts 1 (nonrandomized) and 3 (randomized among Ven [400 mg] Dd, Ven [800 mg] Dd, and DVd arms) compared the efficacy of VenDd versus DVd in patients with RRMM harboring the t(11;14) genetic abnormality. The presence of t(11;14) was determined by central laboratory plasma-cell enriched fluorescence in situ hybridization. Eligible patients had received at least one prior line of therapy (LOT), including exposure to a proteasome inhibitor and an immunomodulatory drug.

Patients in the investigational arm (VenDd) underwent 28-day cycles (C), receiving oral Ven at either (400 mg or 800 mg) once daily.  They received D (either 16 mg/kg intravenous [IV] or 1800 mg subcutaneous [C1–2: Days 1, 8, 15, 22; C3–6: Days 1 and 15; C7+: Day 1]) Dosing of d (40 mg weekly; oral/IV). In the DVd arm, patients were dosed according to the label.

MRD negativity (<10-5) was assessed in bone marrow aspirates using next-generation sequencing (clonoSEQ®, Adaptive, Seattle, WA). Evaluation points for MRD status included the time of suspected complete response (CR)/stringent CR (sCR) and at 6- and 12-month intervals post-confirmation of CR/sCR. Patients with missing or indeterminate assessments were categorized as MRD-positive.

In Part 1 of the study, 5 patients received Ven (400 mg) Dd, while 19 patients received Ven (800 mg) Dd. In Part 3, 21 patients were in the Ven (400 mg) Dd group, 10 in the Ven (800 mg) Dd group, and 26 in the DVd group. The combined enrollment for Parts 1 and 3 was 80 patients, with 55 receiving VenDd (24% high-risk cytogenetics, 53% with 1 prior LOT, 2% with prior anti-CD38 monoclonal antibody [mAb], and 76% lenalidomide-refractory), and 26 receiving DVd (23% high-risk cytogenetics, 38% with 1 prior LOT, 4% with anti-CD38 mAb, and 92% lenalidomide-refractory).

The median (range) follow-up for survivors was longer with VenDd (28.2 months [1.0–55.7 months]) compared to DVd (16.9 months [0.0–34.1 months]). VenDd achieved a 96% ORR, 93% ≥ achieving an excellent partial response (VGPR), 67% ≥ achieving CR, with a median progression-free survival (PFS) not reached (95% confidence interval [CI]: 35.0–not estimable [NE]). DVd achieved a 65% ORR, 39% ≥ VGPR, 19% ≥ CR, and a median PFS of 15.5 months (7.5–NE). The 33-month PFS rate was 73.4% (95% CI: 56.4–84.6) for VenDd versus 38.8% (16.3–61.1) for DVd. MRD negativity rates were 38% with VenDd and 8% with DVd.

In various subgroups, including several prior LOTs, lenalidomide refractory status, and high-risk cytogenetics, MRD negativity rates were higher with VenDd compared to DVd (see Table). Among 8 VenDd-treated patients assessed for the duration of MRD negativity, 6 were MRD negative for >6 months, with 2 achieving MRD negativity for >12 months. No DVd-treated patients had durable MRD negativity for >6 months. No new safety signals were observed.

The study concluded that VenDd therapy exhibited elevated rates of MRD negativity and sustained MRD negativity when contrasted with DVd in patients diagnosed with t(11;14)-positive RRMM. This association with higher MRD negativity was linked to an extended PFS observed with VenDd. The study is sponsored by AbbVie. 

Source: https://ash.confex.com/ash/2023/webprogram/Paper180766.html

Clinical Trial: https://clinicaltrials.gov/study/NCT03314181

Bahlis NJ, Quach H, Baz R., et al.” Venetoclax in Combination with Daratumumab and Dexamethasone Elicits Deep, Durable Responses in Patients with t(11;14) Relapsed/Refractory Multiple Myeloma: Updated Analyses of Minimal Residual Disease Negativity in Phase 1/2 Study”. Presented at ASH 2023 ( Abstract: 338)