ASH Conference Post # 3 – Myeloma Questions and Controversies: New Developments in 2011 that Impact Diagnosis, Prognosis and Treatment

The International Myeloma Foundation (IMF) presented their usual excellent review of current clinical practice in myeloma. Most of the attendees were hematologists. 20% of the audience managed more than 50 patients annually, and another 30 percent managed more than ten.

Dr. Vincent Rajkumar:

Diagnosis and and Prognosis:

The doctor who suspects myeloma should do SPEP, immunofixation, immuglobulins, and free light chains. All of them are necessary, because none of those tests will catch all presentations of myeloma.

Doing a free light chain test on urine eliminates the need for the 24-hour urine test.

Myeloma is not in Stage 1 (active) until at least one of the CRAB symptoms is present. Calcium, Renal (kidney), Anemia, or Bone. But if the percentage of plasma cells in the bone marrow is high, say 60%, the disease should be treated as if it is active myeloma. All such patients will progress.

Prognosis depends on tumor burden, aggressiveness, patient performance (age), and other health factors, such as kidney health. Tumor aggressiveness is usually estimated by cytogenetic tests. Response to initial therapy is also an important prognostic factor, though sometimes a patient who responds most rapidly will also have the fastest relapse.

75% of all myeloma patients are normal-risk and have a median survival of 7-10 years or more. High risk, defined by cytogenetics, have a median survival of 2-3 years.

Dr. Jesus San Miguel:

Asked if a cure is possible in MM: The audience was evenly divided. How important is CR?: Nearly everyone thought it was important. He believes that the better the quality of response, the longer the survival.

Q: If a patient achieved a CR on the transplant conditioning regimen, should the transplant still be done? 73% of the doctors in the audience said yes. Hmmm.

Trials are now addressing the question of transplant upfront versus transplant at the time of relapse from initial therapy.

He believes that intensive frontline therapy, such as SCT, is preferable to a more gentle treatment with one therapy at a time. Your blogger knows that this is a hot topic of controversy.

Can novel or intensive approaches overcome high-risk prognosis? 71% said YES! He said they were wrong. The outcome can be improved, but the prognosis cannot be overcome. Trick question? Maintenance therapy after SCT can also improve the outcome, but high-risk patients will not achieve the same OS as standard-risk.

Allogeneic transplants, using stem cells from a donor instead of the patient’s own stem cells, may be an answer for patients who achieve CR and then relapse almost immediately. A study is needed. Last thought: Myeloma is not a single disease. Individualized treatment is needed.

There is no problem giving a transplant to a patient between 65 and 70 if the patient is sufficiently fit.

Dr. Antonio Palumbo:

Treatments for elderly patients. Options:

The new combination of Melphalan/Prednisone/Velcade got the most votes for initial therapy. The actual patient got a “perfect” CR. Now what? 53% say complete six cycles of MPV. He actually was given nine. What now? 35% said no maintenance, others split among different types of maintenance. How long do we continue it? (6 mo to 24 mo, or until progression or unacceptable toxicity). Doctors chose maintenance until progression or until unacceptable toxicity.

He believes in aggressive therapy up front, while the elderly patient is still strong, and then maintenance to maximize progression-free survival (PFS) and overall survival (OS).

Dosage may have to be reduced for elderly patients, because therapy may be more toxic to them. Once weekly should be the standard for Velcade, not twice. Is he still giving Velcade twice a week to other patients? Ouch, says your blogger. Subcutaneous injection was not mentioned but may be preferable, also says your blogger.

Elderly patients who achieve CR and have no other serious ailments, have a 70% chance of survival to five years.

MPT is the current standard of care. He talked a lot about melphalan, and thinks that two- and three-drug combinations with melphalan are the standard of care for the elderly.

For unfit patients, 37% of myeloma patients, the “standard” therapies are often too toxic. He gave a chart of reduced dosages, and it was clear that the practitioner is left to make the choices.

I’m glad he is not my doctor. I think that doctors in the USA are more likely to offer the novel therapies to elderly patients like me, rather than sticking them with elderly therapies.

Phillippe Moreau:

Consolidation and Maintenance after transplant, for young (less than 65) patients

The audience voted on several maintenance options, including none at all, and most chose consolidation plus maintenance. Consolidation is usually a brief, fairly aggressive therapy given after the SCT, to further reduce the tumor burden, and maintenance is a long-term treatment, often using a small dose of a single therapeutic agent such as Revlimid or Velcade.

The audience was asked what is the best available consolidation therapy? One of the choices was a second SCT. Result: The audience thought that a triplet therapy such as Velcade/thalidomide/dexamethasone (VTD) or Revlimid/Velcade/dex (RVD) was best. Bottom line: No current studies exist for guidance.

After two cycles of consolidation, what maintenance is appropriate? Possible answers included none, Revlimid, or Velcade. The audience chose Revlimid maintenance.

Recent studies show that Revlimid maintenance offers a substantial improvement in progression-free survival, and one study also shows an improvement in overall survival. Thalidomide may be a different story – no study shows a long-term improvement in overall survival with thalidomide maintenance, but most show toxicity in the form of peripheral neuropathy.

Conclusions: Consolidation questions require trials. Maintenance looks good but may not result in improved overall survival.

Dr. Robert Orlowski:

What about patients who have tried most available therapies?

Patient example: Many many failed therapies. Dr Orlowski presented eight possible treatment choices. The audience chose carfilzomib with Revlimid and Dex. He said that a combination including pomalidomide was second choice, though I didn’t see that on the list of choices.

He used the term “A Cornucopia of New Drugs,” including the “novel” drugs, which are now standard treatment, and including drugs that have new and different mechanisms of action. There is even an investigational oral proteasome inhibitor, which works like Velcade but can be taken at home.

He made quick mention of many new agents such as perifosine and vorinostat. Efficacy of proteasome inhibitors can be improved by adding HDAC inhibitors. Elotuzomab is a synthetic monoclonal antibody which shows promise.

We don’t really know why Revlimid stops working for many patients.

Rev/Dex or Vel/Dex remain the standard of care. However, novel agents like carfilzomib and pomalidomide are “on the cusp” of availability. More-novel agents like ARRY530 may be on the way. Cyclophosphamide is an old drug that has become new again in combination with newer agents.

We need research telling us why myeloma becomes resistant to therapies. Then we can tailor treatment to the specific myeloma.

That was the end of the session. If you got this far, you should give yourself a little treat – not an unhealthy one, mind you, but maybe a modest piece of dark chocolate, or a few dried apricots, or perhaps a short nap. You deserve it.