Therapeutic Activity of Combining BCL-2 and HMG-CoA Reductase Inhibition in Systemic Light-Chain Amyloidosis

Introduction:

Overexpression of BCL-2 in association with t(11;14) in multiple myeloma (MM) and systemic light-chain amyloidosis (AL) makes it a therapeutic target for the BCL-2 inhibitor venetoclax; response rates of 60-80% in t(11;14) have been reported in MM (Kumar S, Blood 2017 & Vaxman I, Expert Rev Hematol 2018). Addition of HMG-CoA reductase inhibitors (statins) may augment venetoclax activity (Lee JS, Sci Transl Med 2018). We now report ex-vivo functional activity of venetoclax with AL patient CD138-selected plasma cells and provide clinical outcomes of 8 patients with relapsed/refractory AL who were treated with venetoclax and a statin.

Methods:

To construct a functional assay NCI-H929 and KMS-12-PE cells were used as controls and incubated with venetoclax to assess the IC50. Cell viability was measured with CellTiter-Glo and caspase activity with Caspase-Glo 3/7 (Promega, Madison, WI). H929 cells were the negative and KMS cells the positive control. From patient marrows CD138+ cells were isolated (Miltenyi Biotec, Auburn, CA) as previously described (Ma X, Gene Ther 2016) and incubated with 100 nM of venetoclax for 18 hours with controls.

In AL patients, Venetoclax was started at 200 mg daily and escalated to 400 mg daily after 2 weeks if tolerated. Statin (atorvastatin, 10-40 mg daily or simvastatin 40 mg daily) was started concurrently or for lack of response to venetoclax alone. Bone marrow assessment was performed prior to starting venetoclax and response assessment was performed monthly.

Results:

Venetoclax induced apoptosis in a dose escalated manner with KMS-12-PE cells (t(11;14) positive) when compared with H929 cells (Figure 1A-B). CD138-selected plasma cells from 20 patients (17 AL, 2 MM, 1 MGUS) were incubated with venetoclax (100 nM) for 18 hours and had a median caspase 3/7 activity level that was significantly higher in patients with t(11;14) (Figure 1C).

Eight patients were treated with venetoclax in combination with a statin. Baseline characteristics are provided in Table 1. Median age of the cohort was 70 (range, 59 – 77), of which five (63%) were male, and 6 were λ-type (1-kappa, 1-heavy chain). At diagnosis, four (50%) patients had involvement of two or more organ systems (cardiac, renal, gastrointestinal, vascular, and/or neurological). Cardiac involvement was the most common (88%). Seven patients had t(11;14) and/or positive cyclin D1 staining on pre-treatment marrow studies. The median number of prior therapies was 2 (1 – 5), and all except one had been previously treated with daratumumab. Venetoclax-statin combination was started due to hematologic progression (4), organ progression (1), or suboptimal response to prior therapy (3). At a median follow-up of 8 weeks (5 – 25), overall hematologic response rate is 63% (1 CR, 3 VGPR, 1 PR and 1 progression). Cardiac response was seen in 2 patients. One patient who lacked the t(11;14) mutation had early disease progression. One patient with stage-3 cardiac AL amyloidosis experienced cardiac progression without hematologic response on venetoclax alone but responded promptly with both hematologic and cardiac response to addition of simvastatin, 40 mg daily. Statin dose was reduced in 1 patient due to grade 1 myalgia. All responders continue on treatment at their most recent follow-up.

Conclusion:

In this cohort of 8 patients with AL amyloidosis treated with a combination of venetoclax and statin, hematologic response rate was 63% and >VGPR was seen in 50%. The combination was well tolerated. Consistent with the preclinical activity of venetoclax in MM, functional activity of venetoclax was similarly higher in plasma cells from AL patients harboring t(11;14). As t(11;14) is the most common cytogenetic abnormality in systemic AL amyloidosis, venetoclax and statin combination may provide a potent therapeutic alternative for relapsed/refractory AL patients and requires validation in clinical trials.