MCL-1 is a protein that is made from the MCL gene and it belongs to the Bcl-2 family. If this gene is mutated, then it can stop cancer cells from dying when they should. This prosurvival mechanism commonly occurs in blood cancers, including multiple myeloma. Because MCL1 is one of the genes located on 1q21, the researchers hypothesized that amplification of 1q21 would lead to increased MCL-1 expression and make MCL-1 easier to target.
The researchers tested all samples with three types of therapy: 1) S63845 (the MCL-inhibitor), 2) Venetoclax (a Bcl-2 inhibitor) and 3) A-1331852 (a BCL-XLi inhibitor). They tested them alone and then in combination. When used alone, the S63845 killed the most myeloma cells compared to the other two treatments. This indicated that the 1q gain myeloma was particularly solely dependent on MCL-1 expression for survival.
When they combined the drugs together, they found that when venetoclax or A-1331852 (BCL-XLi) was added to MCL-1i treatment, more myeloma was killed compared with single-inhibitor treatment, but the best combination seemed to be the S63845 with the BCL-XL inhibitor and not with venetoclax.
The researchers went one step further to see whether high or low BCL-2 or BCL-XL protein levels made a difference in the sensitivity to S63845. High levels of these proteins made the MCL-1 cells more resistant. In their panel, BCL-XL expression was the strongest predictor for sensitivity. This is why the combined dual combinations of S63845 and the BCL-XL inhibitor worked best together for the 1q gain patients. Interestingly, this dual combination did not help the 11;14 myeloma patients.
Because a variety of genetic myeloma samples were used in the study, researchers noticed a 2.4 fold increased sensitivity for the 1q gain patients compared to the other genetic types. In looking at the samples, patients who had BOTH the 1q gain AND high beta-2 microglobulin had the highest sensitivity to S63845. Having high beta-2 microglobulin at diagnosis is a know high risk feature for myeloma patients. Patients can have high beta-2 microglobulin because of kidney issues that are common in myeloma. The number of bone lesions, anemia or a high percentage of plasma cells in the bone marrow was not related to the MCL-1 sensitivity.
Previous research in mice showed that inhibiting MCL1 could have damaging effects on some cell types, including stem cells, B cells and healthy plasma cells, however when S63845 was tested in mice, the dose used was lethal to the myeloma but well tolerated by the mice.
This is new evidence that each patients’ myeloma genetics matter and that new therapies could effectively target the specific type of myeloma. There are between 34-43% of newly diagnosed multiple myeloma patients with the 1q gain. At relapse, 1q amplification occurs in 72% of myeloma patients.
This may be an effective therapy and combination therapy for 1q gain patients, and especially those with high beta-2 microglobulin, who are higher risk patients. This is yet another example that high risk myeloma may not always be considered high risk if the proper and specific treatment is found for it.