Investigating a Venetoclax-Based Triplet Therapy for Patients With Relapsed/Refractory Myeloma

In a phase Ib trial of patients with relapsed/refractory multiple myeloma, targeting BCL2 and MCL1 with a triplet combination of the BCL2 inhibitor venetoclax plus bortezomib and dexamethasone led to high response rates with a “manageable safety profile,” according to a study published in Blood.

In the open-label, single arm, multicenter M12-901 study, Philippe Moreau, MD, head of the hematology department at the University Hospital Hôtel-Dieu in Nantes, France, and co-authors enrolled 66 patients (median age = 64 years; range = 38-79 years) from eight sites between November 2012 and May 2016. Patients were excluded if they received prior treatment with bortezomib within 30 days of the first dose of venetoclax; experienced grade 3/4 peripheral neuropathy; or had systemic infection, fever, or neutropenia within one week of the first venetoclax dose. All patients had received prior myeloma treatment (median prior lines of therapy = 3; range = 1-13 therapies), and 39 patients (59%) had undergone hematopoietic cell transplantation.

Most patients (n=53; 80%) had previously received bortezomib (26 [39%] of whom were refractory), and 48 patients (73%) had received lenalidomide (35 [53%] of whom were refractory). Patients had the following cytogenetic abnormalities: t(11;14) (n=9; 14%), t(4;14) (n=5; 8%), del(17p  (n=15; 23%), del(13q) (n=30; 45%), and hyperdiploidy (n=30; 45%).

Patients received:

  • bortezomib 1.3 mg/m2 administered via subcutaneous injection on days 1, 4, 8, and 11 during cycles 1-8 and on days 1, 8, 15, and 22 during cycles 9-11
  • dexamethasone 20 mg administered orally on days 1, 2, 4, 5, 8, 9, 11, and 12 during cycles 1-8 and on days 1, 8, 15, and 22 during cycles 9-11
  • venetoclax 50 mg administered alone during a 1-week lead-in period, followed by doses ranging from 100 to 1,200 mg

After 11 cycles, patients could remain on venetoclax monotherapy.

At data cutoff (August 19, 2016), the median time on study was 5.9 months (range = 0.3-29 months) for all patients. Those who were refractory to prior bortezomib appeared to have a shorter time on study than those who were not refractory to prior bortezomib (2.8 months and 9.1 months, respectively).

Forty-six patients (70%) discontinued the study because of disease progression (n=36), adverse events (AEs; n=5), or withdrawal of consent (n=2; the other three were not specified). AEs that led to treatment discontinuation were respiratory and cardiac failure (n=2), lung adenocarcinoma (n=1), Guillain-Barré syndrome (n=1), and sepsis (n=1); none was deemed related to venetoclax, the authors noted.

Six patients (9%) receiving venetoclax required dose reductions related to AEs, and 27 patients (41%) temporarily interrupted treatment because of AEs. Five deaths were reported: four related to disease progression and one related to respiratory syncytial virus infection.

The most common all-grade AEs were diarrhea (46%), constipation (41%), and nausea (38%), and the most common grade 3/4 AEs were thrombocytopenia (29%), anemia (15%), and neutropenia (14%). Serious AEs (occurring in ≥2 patients) included pneumonia (n=5), sepsis (n=3), pyrexia (n=3), influenza (n=3), febrile neutropenia (n=3), thrombocytopenia (n=2), cardiac failure (n=2), lower respiratory tract infection (n=2), acute kidney injury (n=2), respiratory failure (n=2), embolism (n=2), and hypotension (n=2).

The maximum tolerated dose (primary endpoint) of venetoclax was not determined; the researchers selected 800 mg as the recommended phase II dose because “overall response and very good partial response or better (≥VGPR) response rates increased with increasing venetoclax dose through 800 mg across all patients.”

Forty-four patients (67%) responded to treatment, with a median response duration of 9.7 months (range = 7.4-15.8 months). Twenty-eight patients (42%) achieved ≥VGPR, including three stringent complete responses (CRs), 10 CRs, and 15 VGPRs. Six patients (9%) had stable disease and 14 experienced disease progression as best response.

Response rates were greatest in patients who were not refractory to previous bortezomib treatment and had received one to three prior lines of therapy (overall response rate = 97%; ≥VGPR=73%), compared with patients who were refractory to prior bortezomib or had received four to six prior lines of therapy (p values not reported; TABLE).

“Only one-third of the patients refractory to bortezomib had an overall response, suggesting that venetoclax cannot fully overcome resistance to bortezomib and potentially requires additional MCL1 downregulation by bortezomib for broader activity in the non-t(11;14) population,” the authors wrote, adding that prior therapy with lenalidomide had a lesser effect on response rates.

The study is limited by its small patient population, single-arm design, and limited follow-up.

AbbVie and Genentech, the manufacturers of venetoclax, provided financial support for the study.

The authors report financial support from Celgene, Janssen-Cilag, Takeda, Novartis, Amgen, AbbVie, Servier, Merck, and BeiGene.


Reference

Moreau P, Chanan-Khan A, Roberts AW, et al. Promising efficacy and acceptable safety of venetoclax plus bortezomib and dexamethasone in relapsed/refractory MM. Blood. 2017 August 21. [Epub ahead of print]

TABLE. Overall Response Rates*
All Patients (n=66) Bortezomib Prior Therapies Bortezomib Non-Refractory and 1-3 Prior Therapies (n=30)
Refractory (n=39) Non-Refractory (n=26) 1-3

(n=37)

4-6

(n=20)

>6

(n=9)

Overall response rate 67% 90% 31% 89% 50% 11% 97%
Stringent complete response (CR) 5% 8% 8% 10%
CR 15% 20% 4% 24% 5% 23%
Very good partial response (PR) 23% 36% 4% 33% 15% 40%
PR 24% 26% 23% 24% 30% 11% 24%
*One patient’s information regarding bortezomib-refractory status was missing.

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