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Sunday, October 11, 2015

Immunization Therapies

I haven't updated my blog in a long time.  I apologize for that.  I don't have a good explanation.  I've just been a bit lazy lately.  On the myeloma front, every thing is still OK with me, so I don't have any news to report.  I am going into the  Farber on Tuesday for my monthly checkup.  I did have Mohs surgery on the squamous-cell carcinoma on my scalp.  Everything went well.  I had 21stiches in my forehead, but it seems to be healing well, and I don't think I will be too disfigured. That's good, not that I care too much about my looks these days.

In my last post, I gave short shrift to the various immunization therapies that are under investigation for MM.  I would like to expand on that in this post.  There are three immunotherapathy drugs that have great potential being tested now:  daratumumab, elotuzumab, and SAR650984.  Each of these does something that has never been done before:  teach the body's own immune system to recognize and attack the myeloma cells.  This post might be a little bit technical, so I won't be upset if you decide to skip some or all of it.

One of the problems with MM therapies is that MM is not a single disease.  It is genetically heterogeneous with multiple clones and subclones evolving over time and under the influence of treatment.  Each patient has a unique genetic risk profile.  This is why it has not been a curable disease to date.  The current advanced treatment therapies, including a proteasone inhibitor (Velcade, Kyprolis), immunomodulatory drug (Revlimid, Thalomid, Pomalyst) and steroid (dexamethasone) have been very successful in extending overall survival (OS) for most MM patients up to 7-10 years.  These treatments have worked well in suppressing the dominant clone.  But in most patients, the disease eventually recurs because of its heterogeneousity.   What could be done to suppress all the remaining recessive clones and subclones so that it will never come back?

Monoclonal antibodies are targeted against proteins on the surface of the MM cells, which are not usually subject to genetic variability, so they are likely to be unaffected by the genetic heterogeneity of the underlying tumor.  This is huge!

Now I want to concentrate on daratumumab (dara).  This drug targets a protein, CD38, which is heavily expressed on malignant MM cells.  In a phase 1-2 study, dara was given to a cohort of patients who had received a median of 4 prior therapies, 79% of whom were refractory to both proteasome inhibitors and immunomodulators.  These patients had a particularly poor prognosis:  the Progression Free Survival (PFS) was 5 months and the OS was 9 months.

In a typical clinical trial with a new drug, a Phase 1 trial will use a single agent with variable dosing to determine a safe dose level and see what effect it might have.  For a good drug candidate, a single agent dose overall response rate (OR) of 20-25% is considered very good, which would allow it to continue trials in combination with other drugs.

In the dara trial, the OR was 36%!  Furthermore, 65% of the patients did not have disease progression after 12 months.  These results are very encouraging!  Because of this, the FDA has recently designated daratumumab as a "breakthrough" drug , allowing its compassionate use for those who have exhausted other lines of therapy.  The FDA is expected to approve dara in the near future. 

I hope to update this blog more often, but we'll see.  I'm not going to promise to adhere to a particular schedule.