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    • Multiple Myeloma News
    • Jan 08, 2020

    1Q Gain Multiple Myeloma is Sensitive to Specific Drug Targeting

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One of these types of genetic mutations is called a gain of 1q, or three or more extra copies of the 1q chromosome. If there are four or more copies of the 1q chromosome, it is considered to be a high risk feature and patients don’t live as long as other types of myeloma. 
 
Dutch researchers have found that multiple myeloma with the 1q gain may respond to an MCL-1 inhibitor called S63845 by testing it in 31 human myeloma cell lines and in 47 bone marrow biopsy samples from myeloma patients. For the first time, they found that myeloma patients with the 1q gain (or amplification) are significantly more sensitive to the inhibition of MCL-1. They also found that having high beta-2 microglobulin and having kidney issues also correlated with increased sensitivity to MCL-1 inhibitor treatment. 
 
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.
 

About Author

Jenny A

Myeloma survivor, patient advocate, wife, mom of 6. Believer that patients can help accelerate a cure by weighing in and participating in clinical trials. Founder of Myeloma Crowd, Myeloma Crowd Radio and the CrowdCare Foundation.

5 Comments

  1. Susan S. January 9, 2020 at 9:05 am

    Jenny,

    Thank you for this update. I have gain 1q and this was described as being a strong negative for me in terms of response to treatment and OS. Good news then for the sizable number of people who share this. Oddly, the mutation present in several biopsies did not appear in the most recent BM biopsy. Probably just hit a pocket that didn’t have it but I will for the moment pretend that it just died from boredom.

    • Jenny A
      Jenny A January 9, 2020 at 11:19 am

      Susan, glad to hear it is not showing up. I suggest you look at your FISH test because one important finding from the COMPASS data was that if you just have 3 copies, it doesn’t behave as high risk, but if you have 4 or more, it does. Important info to have.

  2. Neil White January 10, 2020 at 12:56 am

    Many Thanks for sharing this Jenny. I will follow this with interest, and if you have any more information or links I would be grateful. I have 1gain of one copy of 1q and was diagnosed with MM due to kidney failure in Dec 2015. I’ll share the link on my blog.

  3. Lori Karan January 10, 2020 at 7:14 am

    I have a 1q gain and am at the end of my current clinical trial (CC-200). Is there a trial with these drugs currently available or in the very near future? I am seriously considering no further treatment at this time.

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