Venetoclax Combination Shows Antitumor Activity in Advanced Myeloma

Asher A. Chanan-Khan, MD

A three-drug combination comprising the novel Bcl-2 inhibitor venetoclax (GDC-0199/ABT-199), bortezomib (Velcade), and dexamethasone demonstrated a clinical benefit in heavily pretreated patients with relapsed/refractory multiple myeloma (MM), according to findings presented at the 13th International Conference on Malignant Lymphoma in Lugano, Switzerland.

The overall response rate (ORR) in 36 patients with MM was 47%, ORR in 6 bortezomib-naïve patients was 83%, and ORR in 20 bortezomib-sensitive patient was 60%; none of the 10 patients that were refractory to prior bortezomib showed a response.

Overall, 19% of patients achieved very good partial response (VGPR) or better; two patients (6%) showed stringent complete response, one patient (3%) achieved a complete response, four (11%) achieved VGPR, and 10 (28%) achieved PR following treatment. Stable disease was seen in 6 patients (17%) and 9 patients (25%) experienced progressive disease. The overall median duration of response was 6.0 months (range, 0.7-9.5) months.

“There is a dire unmet need of new treatments in multiple myeloma; this combination provides broad inhibition, which is important,” said lead study author Asher A. Chanan-Khan, MD, a professor of Medicine at Mayo Clinic in Jacksonville, Florida.

Chanan-Khan headed an international team in evaluating the safety, pharmacokinetics (PK), preliminary efficacy, maximum therapeutic dose, and cytogenetic results of targeting BCL-2 with venetoclax and MCL-1 with bortezomib. The phase Ib study enrolled patients with relapsed/refractory MM and included subsets of patients with chromosomal abnormalities, since these are known to influence sensitivity of MM cells to treatment. Patients with five distinct genetic alterations were enrolled: five patients had t(11:14), three had t(4:14), nine had del7p, 19 had del3q, and 14 patients were hyperdipliod.

Explaining the rationale for the study, Chanan-Khan said that cell survival in MM is promoted by the antiapoptotic proteins BCL-2 and MCL-1; bortezomib inhibits MCL-1 activity by increasing the expression of NOXA, an antagonist of MCL-1, and venetoclax is a selective, orally bioavailable, small-molecule inhibitor of BCL-2, which inhibits apoptosis. Adding venetoclax has been shown to enhance the activity of bortezombib in myeloma cells and xenograph models, further supporting the rationale of this combination.

A total of 38 patients were enrolled; the mean age was 65 years (range, 38-79) and 63% of patients were male. Patients had received a median of five prior lines of therapy (range, 1-15) and 63% had undergone autologous stem cell transplant. Of the 82% of patients previously treated with bortezomib, 26% were refractory, and of the 84% of patients receiving prior lenalidomide, just over half (55%) were refractory. Overall, 68% of patients had received both drugs and 21% of these were refractory to both. ECOG PS was 0 or 1, and 30% of patients had ISS stage III disease.

Venetoclax was administered at 50 to 500 mg daily per designated dose escalation cohorts based upon continual reassessment, bortezomib was given at 1.3 mg/m² subcutaneously, and dexamethasone at 20 mg. All patients also received prophylaxis against tumor lysis syndrome.

Preliminary PK data showed venetoclax coadministered with bortezomib and dexamethasone exposure at steady state was within the exposure range seen when venetoclax is administered as monotherapy in MM patients.

Myeloma protein was decreased by 94.5%, and 63.6% in bortezomib-naïve and -sensitive patients, respectively, following triplet treatment, but increased by 7.1% in bortezomib-refractory patients.

ORR by genetic status was 75%, 33%, 25%, and 64%, respectively, in patients with t(11:14), t(4:14), del17p, and hyperdipliod abnormalities.

Regarding the toxicity profile of the triplet, Chanan-Khan said, “Venetoclax in combination with bortezomib and dexamethasone has an acceptable safety profile in patients with heavily pretreated multiple myeloma.”

A total of 25 patients discontinued the study; two patients discontinued due to adverse events and four of the 19 patients who discontinued due to progressive disease died of their disease.

Nearly all patients (98%) experienced an adverse event (AE) of any grade; constipation was reported by 37% of patients, diarrhea and insomnia were each reported in 32%, and thrombocytopenia occurred in 29% of patients. Dyspnea, asthenia, and peripheral neuropathy were each reported by 26% of patients, peripheral edema in 24%, and anemia in 21%.

Grade 3/4 AEs included thrombocytopenia in 21% of patients, anemia in 13%, and dyspnea in 11%.

Serious AEs occurred in 47% of patients: cardiac failure, embolism, pneumonia, pyrexia, respiratory failure, and sepsis each occurred in 5% of patients.

One dose-limiting toxicity occurred that was linked to dexamethasone.

No cases of tumor lysis syndrome were reported. “Tumor lysis syndrome prophylaxis may not be necessary in future studies of this combination,” said Chanan-Khan.

Beyond MM, venetoclax has also shown promising activity in other hematologic malignancies, including chronic lymphocytic leukemia (CLL), mantle cell lymphoma, and acute myelogenous leukemia. AbbVie and Genentech, the codevelopers of venetoclax, announced in early May that the FDA granted a breakthrough therapy designation to the Bcl-2 inhibitor for the treatment of patients with relapsed/refractory CLL who harbor a del(17p).

Chanan-Khan AA, Touzeau C, Roberts AW, et al. Venetoclax (abt-199/gdc-0199) in combination with bortezomib and dexamethasone in relapsed/refractory multiple myeloma: phase 1b results. Presented at: 13th International Conference on Malignant Lymphoma; June 16-20, 2015; Lugano, Switzerland. Abstract 109.

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