In preparing for my “Best of ASH 2014” presentation, I noted there were plenty of new drug presentations, but not as many as were presented at the American Society of Hematology (ASH) annual meeting in 2013. This raised the questions: “What is the driving force behind new drug development in myeloma?” and “Where exactly are the new ideas coming from?” Do we expect new drugs to keep coming?

We have been fortunate to have FDA and ongoing global approvals for five novel agents in myeloma: thalidomide, bortezomib (Velcade®), lenalidomide (Revlimid®), carfilzomib (Kyprolis®), and pomalidomide (Pomalyst®/ Imnovid®). How did this happen and what does this tell us about what to expect in the next 5-10 years?

It is helpful to think back to 1995 when pamidronate (Aredia) was approved for the treatment of bone disease in myeloma: the first drug approved specifically for myeloma in many years. Aredia is a bisphosphonate, a class of drugs developed to clean clogged pipes because it binds to calcium deposits. Aredia was approved by the FDA for treatment of high blood calcium in 1991. Since pamidronate binds calcium, researchers realized it could also be helpful in areas of myeloma bone damage, as well as in osteoporosis and other types of bone damage. This is typical for drug development. Uses evolve over many years. A more potent bisphosphonate, zoledronic acid (Zometa®), was approved for use in myeloma in 2002. The common trend is to improve drugs which are known to work. In addition, a completely different drug, denosumab (high-affinity antibody for RANK-Ligand), is now being assessed for its value in treating myeloma-related bone disease.

If we turn to bortezomib (Velcade), we find a similar pattern. Bortezomib is a proteasome inhibitor. Much of the early research leading to its use as a myeloma treatment occurred in the 1970s and 1980s when proteasomes were discovered and the impact of blocking the elimination of damaged proteins was first appreciated. It was felt that inhibitors could be useful in the treatment of viral diseases. Discoveries related to proteasome chemistry led to the 2004 Nobel Prize in Chemistry for Avram Hershko, Aaron Ciechanover, and Irwin Rose. An important paper showing that proteasome inhibitors are effective anti-tumor agents was published by Julian Adams in 1999. Julian subsequently collaborated with Dr. Michael Kauffman at Millennium Pharmaceuticals in the clinical development of Velcade, which proved to be remarkably effective in myeloma. This final step in the drug development process was both tenacious and skillful. At this stage, many investigators were involved and many brave patients agreed to take the drug, not knowing if it would be effective: true pioneers moving into unknown territory! This subsequently paved the way for another proteasome inhibitor, carfilzomib (Kyprolis), more recently approved for myeloma.

The story about IMiD (immunomodulatory drug) development is particularly fascinating. Thalidomide, developed in the early 1960s as a sedative for use during pregnancy, was found to cause birth defects and was not FDA approved. However, it was subsequently found to be excellent treatment for a type of leprosy and had special limited approval for use in that setting. Fast forward to the late 1990s when Beth Wolmer, the wife of a myeloma patient in Little Rock, Arkansas, desperate to find a treatment for her husband, asked Dr. Bart Barlogie to try thalidomide to “shut down the blood supply” to the myeloma. Since this was a possibility based upon anti-angiogenesis research in Dr. Judah Folkman’s laboratory at Children’s Hospital in Boston, Dr. Barlogie agreed to try thalidomide. Unfortunately, it did not work for Beth Wolmer’s husband. But the silver lining to this story is that another desperately ill myeloma patient had a dramatic response. As the saying goes – the rest is history! Thalidomide was approved for use in myeloma. Its molecular variants, lenalidomide (Revlimid) and pomalidomide (Pomalyst/ Imnovid) have been more recently approved as more effective and better tolerated analogues.

So what does this pattern of discovery and drug development mean for new drugs in 2015 and beyond? Firstly, refinements of prior drugs are the simplest strategy and this will continue to be a useful approach. Revlimid is more effective and has less nerve toxicity than thalidomide. Pomalidomide is the most effective IMiD currently available, and is also the best tolerated. The oral proteasome inhibitors ixazomib and oprozomib, currently in development, have the major advantage of being administered by mouth versus Velcade and Kyprolis, which are given by injection.

Secondly, the value of new types or classes of drugs is less certain. The anti-CD 38 monoclonal antibodies daratumumab and SAR650984 are very promising, and daratumumab even has “breakthrough” status for review at the FDA. But how long will remissions last? How big an impact will these antibodies have for prolonging survival for myeloma patients? It is too soon to know. As I have said in the past, it is important to remember that new drugs are new: there are many unknowns! Fortunately, there are multiple monoclonal antibodies in development and there is thus an opportunity to assess which is best, or which is the best niche for each. In addition, many other classes of agents are in early to midterm development. Thus the relative merits of different classes of new agents can be assessed.

Thirdly, accurate tools and methodologies are required to show precisely if one therapy is better than another. For this aspect of drug discovery and development, the IMF’s International Myeloma Working Group (IMWG) has made, and is continuing to make, a major impact. The IMWG Uniform Response Criteria are essential. Assessment of outcomes for relapsed/ refractory patients is key to providing a benchmark for the FDA. Does a new agent meet an “unmet need” – meaning can a new agent really improve the outcomes for patients who have received all prior therapies? Increasingly, this is an all-important yardstick. An expensive new drug must provide significant benefit with acceptable side effects.

The good news is that decades of basic research have created many promising leads. Many basic and clinical researchers have contributed. Only time will tell which leads will pay off. The enthusiasm, expertise, and expectations are in place. Let’s hope that accelerated research and development will start to cure myeloma patients in the next 5-10 years!       

Dr. Durie sincerely appreciates and reads all comments left here. However, he cannot answer specific medical questions and encourages readers to contact the trained IMF InfoLine staff instead. Specific medical questions posted here will be forwarded to the IMF InfoLine. Questions sent to the InfoLine are answered with input from Dr. Durie and/or other scientific advisors and IMWG members as appropriate, but will not be posted here. To contact the IMF InfoLine, call 800-452-CURE, toll-free in the US and Canada, or send an email to infoline@myeloma.org. InfoLine hours are 9 am to 4 pm PT. Thank you.

Comments

Dr. Durie,
Thank you for answering my prior question about the monoclonal antibodies and maintenance. I am now 6 weeks out of transplant and my bone marrow biopsy showed zero myeloma and my m- protein down from
. 49 to . 23. My wonderful Dr. At COH Dr. Krishnan is suggesting 2 cycles of Carfilzomib/ Rev/Dex with Rev
At 25 mg. and then Rev. 10mg for another year or so. I have heard of an increase in secondary cancers from prolonged Rev. I have also heard the theory to stay on Dex continually to ward off progression. What are your thoughts on staying on Dex indefinitely vs 1 year?

Dear Joan, Glad to receive your feedback. The proposal from Dr. Krishnan seems very reasonable – a very good strategy to achieve the best results. For someone in your situation, the risks of any type of second cancer are extremely low in contrast to the expected benefit with Revlimid. I believe that the Revlimid is a better option versus Dex used indefinitely. The Dex can always be available as needed along the way. I hope this helps. Yours sincerely, Dr. Brian Durie

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