ASH Convention Post # 2 – Current Clinical Controversies and Future Research Priorities for the Treatment of Multiple Myeloma

That is the title of my first symposium at the conference of the American Society of Hematology (ASH), Friday, December 9, 2011, three hours. It seemed to be intended for clinical practitioners – doctors who treat myeloma patients and need to stay up to date in this rapidly-changing field.

I attended with all of the attention and understanding of an electrical engineer – or lawyer – doesn’t matter, I’m not a doctor. The session was a flood of information and I was not able to keep up, which is on me, not the presenters. With that disclaimer, here is what I got out of it:

Dr. Paul Richardson, Dana-Farber, Chairperson of the Symposium:

Frontline treatment still divides patients in to two groups – transplant-eligible or not eligible.

Revlimid/Velcade/Dexamethasone (RVD) has proven to be very effective. Cyclophosphamide/Velcade/Dex may be just as good as a frontline therapy, but all four drugs together were not as good because of toxicities. Cyclophosphamide (Cytoxan) is an alkylating agent like melphalan. “Frontline” means the first therapy for a newly-diagnosed patient.

Almost every myeloma patient relapses, whatever the therapy. With good front-line therapies now, the real challenge is to treat patients with relapsed and refractory disease. His slide contained at least 30 different combinations of drugs available to the practitioner. Doxorubicin (Doxil) has become an important option, in combination with other novel drugs, although the supply is questionable.

Ongoing studies add a number of new agents, or agents new to myeloma, to the existing drug combinations.

In one specific case involving an 84-year-old woman, the opinion of the doctors in the audience about the importance of achieving a complete response (CR) or very good partial response (VGPR) varied widely. The largest group thought it was “somewhat” important, but some thought it wasn’t important at all, and some thought it was very important.

Question from the floor: Why do we treat the elderly different from young people? This patient had been treated with a melphalan combination, but Dr. Richardson responded that he would not have treated her differently from a younger patient, and would have given her the same front-line therapy, but tailored to her tolerance of it.

Dr. Philip McCarthy, Jr.:

Maintenance Therapy Post-transplant

Zometa is preferable to Aredia and other bisphosphonates because it does seem to have a modest anti-myeloma effect.

A recent study using thalidomide as a maintenance after stem-cell transplant (SCT) did not show much benefit for progression-free survival (PFS) or overall survival (OS).

Another study has shown a very significant benefit from Velcade maintenance after SCT.

Revlimid maintenance has shown significant PFS, and at this point in the study, one of two studies is also showing a significant OS.

Conclusion: Revlimid is appropriate for prolonging time to progression (TTP), event-free survival (EFS), and overall survival (OS). Velcade as well. Also, to a lesser degree, Zometa.

Case: 72-year-old widowed woman, working in doctor’s office. Scapular pain. IgA myeloma. Four therapies were presented to the group, which voted with tiny handheld wireless voting pads. The the top choice was a melphalan/prednisone/thalidomide combination, and the second choice a Rev/Velcade/dex combination. Blogger’s comment: Why do doctors persist in giving OLD therapies to OLD people, when novel therapies are proven to be better? There seems to be incredible inertia in the medical field, especially among clinicians.

Comment by a panel member: PET/CT, though expensive, can be helpful in some cases, but not so much when other diagnostics already show active disese.

Maria-Victoria Mateos, M.D., Ph.D.:

Discussion of two classes of novel agents: Proteasome inhibitors (e.g. Velcade) versus immunomodulatory agents (e.g. Rev/thal). In both classes, new agents are being introduced and may help patients for whom first-line therapy has failed.

Carfilzomib/Rev/Dex produced a very high rate of complete or very good response. Several other proteasome inhibitors are coming along.

Pomalidomide seems to provide a benefit to 25-34% of patients for whom Rev and thalidomide are no longer of benefit. There are also combinations of pomaldomide with clarithromycin and other agents.

Bottom line: Both classes benefit from continuing research and innovation.

Andrzej J. Jakubowiak, M.D., Ph.D.:

Dr. Jakubowiak discussed novel mechanisms for overcoming myeloma’s resistance to current therapies. This went very fast, but is also very exciting. He mentioned nine different drugs which have shown benefit when used in combination with Revlimid or Velcade, and a tenth was mentioned by another panelist.

Drugs synergistic with Velcade: Elotuzumab, Perifosine, Vorinostat, Panobinostat, more.

Synergistic with Revlimid: Vorinostat, panobinostat, more.

Also the efficacy of the traditional therapy melphalan/prednisone/thalidomide (MPT) is improved with Vorinostat or panobinostat. Resistance to Rev/Velcade/Dex (RVD) can also be overcome with Vorinostat.

Plitidepsin suppresses proliferation and anti-apoptosis genes. In other words, it affects the genes which cause the myeloma cell to grow rapidly, and the genes that prevent the cell from dying when it knows that it’s goofy and should die. An engineer’s view. That’s really cool stuff.

Elotuzumab works by yet another mechanism, and has shown a significant benefit in combination with both Revlimid and Velcade.

Bottom line: Some of these new therapies are very promising, when used in combination with existing drugs, and ongoing trials will tell us which will provide the most help and for whom.

My Take:

I attended ASH two years ago, when Revlimid and Velcade were relatively new and were the subject of every talk. Now they are unquestionably the standard, and the buzz is about new agents for use in combination with them, to make them work better and longer.