Precision Medicine at IMW 2017
Day 3 at IMW is now behind us!
The busy day started with presentations and a panel discussion on precision medicine, a topic near and dear to the MMRF. The MMRF has the only end to end model for precision medicine in MM, powered by the MMRF CoMMpass Study, which is the largest genomics data set of any cancer, was featured prominently in the session on precision medicine (see below). A quick summary of meeting sessions is below, followed by detailed notes for those who want deeper, more specific information on any of the topics.
What new genomic tests are available for patients? MM cells have a lot of gene mutations; hundreds or even thousands of genes can be abnormal, and the number and identity of these mutations can be different in different MM cells in the same patient. No one mutation causes MM, and the mutations in a cell’s genome may change over the course of the disease. Two new DNA analysis methods, cell-free DNA (cfDNA) and circulating tumor cell DNA (ctcDNA) can analyze DNA from MM cells in your blood. These new tests, when available, will make it much easier for your doctor to follow your disease just by taking a few tubes of your blood instead of doing a bone marrow biopsy.
What’s new for relapsed/refractory patients? This session focused on upcoming and promising treatments for relapsed refractory multiple myeloma (RRMM). There are many new drugs and drug combinations currently under investigation in the clinic, several in the MMRC.
Are three drugs always better than two? Two prominent clinicians were asked to debate the question of whether triplet therapy (three drug combination) is always better than doublet therapy (two drug combination) for RRMM. There have been many studies showing an increase in PFS in RRMM patients with triplet vs doublet, including our own CoMMpass Study. But, triplet therapy can be more toxic, more expensive, and may not increase overall survival, which is why studies like CoMMpass are critical to answering these important questions. By following so many patients for several years, one of our goals is to understand which benefit may be overtreated, ie, who may only need two drugs in combination to effectively treat their disease.
Precision medicine highlights:
- Myeloma is a cancer with very complicated gene patterns. MM is composed of different cell “clones”, each having a different gene pattern which may make them more or less sensitive to different treatments. These patterns can change during treatment and at relapse. New techniques are becoming available to define these patterns which will help doctors decide which treatment may work best with each patient’s disease.
- The MMRF CoMMpass Study has provided the largest set of genomic data of any cancer. New analyses of this data have begun to pinpoint the most common gene mutations found in MM cells. This information will be used to design new clinical trials for MM with drugs that target those mutations. Already, mutation reports are being sent to the doctors of relapsed CoMMpass patients to tell them about new drugs and clinical trials that the patient may be eligible for, based on their mutations. This type of cutting-edge clinical decision making will become more common in the future as new targeted therapies enter the clinic.
- Histone deacetylase inhibitors (HDACi) like Farydak (panobinostat) are a class of drugs that work well in combination with proteasome inhibitors (PI), since they work at a different point in the same pathway that Velcade inhibits. They have been underutilized due to concerns with side effects but new combination approaches with IMiDs and newer PIs (Kyprolis and Ninlaro) have decreased the side effects while making them more effective. New HDACi’s have shown additional activity which make them even more effective; these drugs damage the DNA of cancer cells to kill them, and now also can stop MM cells from repairing the damaged DNA, making HDACi more deadly to MM cells. Studies also show that HDACi can stimulate the immune system which may help explain their activity during maintenance in combination with Revlimid.
- Researchers have been able to find and analyze DNA from MM cells that circulates in the blood. This is known as “cell free DNA” (cfDNA) since it is not contained inside a cell. This test requires 2-4 tubes of blood, and if early studies are confirmed, this blood test may someday be able to take the place of a bone marrow biopsy, allowing your doctor to monitor your disease more easily and more often.
- Another blood test can detect and isolate single MM cells that are circulating in the blood and use them for DNA testing. Similar to the cfDNA test, this circulating tumor cell DNA (ctcDNA) test may someday replace the bone marrow biopsy to allow your doctor to monitor your MM.
- Data from the UK Myeloma XI study was presented further supporting the use of Revlimid as maintenance therapy post-transplant. In this study, after ASCT, patients were either given Revlimid (3 weeks on, 1 week off) or were simply observed. Those patients who received Revlimid showed an increase in progression free survival (PFS – time before the disease came back) similar to earlier trials, and the longer the patient received Revlimid, the better the response was. This was true for both high and low risk patients. Side effects were as expected and there was no increase in the appearance of second primary malignancy (SPM).
- A second study called the CALM study did see a small increase in (SPM) with Revlimid maintenance. Other studies have also documented small increases in SPM with Revlimid use. As with other MM therapies, the decision on whether to use the drug should take into account how effective the drug is and what the risks of side effects are.
- Categories of new drugs currently in clinical trials
- Immune therapies –monoclonal antibodies, CAR-T, antibody drug conjugates, BiTEs
- New drugs in proven drug classes
- PIs – marizomib, oprozomib
- Alkylating agents
- New drugs with novel mechanisms
- XPO1 inhibitors (Selinexor)
- CDK inhibitors dinaciclib, palbociclib
- MEK inhibitor trametinib
- BTK inhibitors in combination with PIs an IMiDs
- AKT inhibitors as single agents and in combination
- Proteasome inhibitor nelfinavir
- Drugs that show promise for double, triple, quadruple refractory patients
- To overcome PI resistance: Clarithromycin, nelfinavir, oprozomib
- To overcome IMiD resistance: CC-122 and CC-220, HDAC6 inhibitor ricolinostat
There are a plethora of new options to treat relapsed/refractory disease. Visit the MMRF website (www.themmrf.org) to learn more. Below is a brief summary:
Just one more day left!