Promising New Drugs For Myeloma: Will The Future Come Soon Enough?
Each year at the Annual Meeting of the American Society of Hematology we hear about dozens of new drugs that are able to annihilate multiple myeloma cells in the test tube and in animal models. Unfortunately, at the same meeting, we also sit through presentations and walk by posters of drugs that looked hot in the laboratory but then fail to work when given to real patients with myeloma.
This is not new. It has been the story with myeloma for ages. The myeloma cells are smart and are seemingly able to easily overcome any adversity that comes their way in the form of pesky new drugs. For those of us dealing with this disease on a daily basis, we need some good news.
What are the most promising drugs today that can outsmart the myeloma cells? Will they work in patients who have failed other therapies? Will they have a reasonable safety profile? Will a future filled with many active treatments and options happen soon enough?
If I were a patient with myeloma and none of the current treatments were working for me, I would need to have at least some idea which drugs are the most promising, so that I could hunt for the best clinical trial. However, an Internet search turns up so many possibilities that it is hard for even trained hematologists to determine the best options among the array of clinical trials.
In this column, I will highlight drugs that are unquestionably active in myeloma. These are new treatments that are not commercially available, but in my opinion clearly work in myeloma, even in patients who have failed other treatments. I will also discuss other promising drugs where the data suggest that there is at least a reasonable probability that they actually work in patients.
Note that by highlighting these drugs, my intention is not to suggest that the other agents being studied are unimportant. In fact, deciding the best treatment option or a clinical trial for a given patient is a complex process that requires a great deal of thought and depends on many variables.
My goal is to simply inform, and to illustrate the rationale for my hope and enthusiasm.
In the first category are compounds that have shown clearcut activity in myeloma in terms of reducing monoclonal (M)-protein levels by 50 percent or more when used on their own (single-agent activity). Of countless drugs that have been looked at and not yet approved for commercial use, only pomalidomide and carfilzomib have shown significant single-agent activity in multiple clinical trials. They seem to work in situations where other myeloma treatments have stopped working. They are both in advanced stages of development (i.e., Phase 3 trials are underway).
Pomalidomide: Pomalidomide (also called CC-4047) is a new immunomodulatory analogue of thalidomide (Thalomid) and Revlimid (lenalidomide). It was first studied by Schey and colleagues from the United Kingdom who treated 24 relapsed or refractory patients and found a response rate of 54 percent. Next, Lacy and colleagues at the Mayo Clinic tested the combination of pomalidomide with low dose dexamethasone (Decadron) and showed efficacy in relapsed disease, in patients who had failed Revlimid and in patients who had failed both Revlimid and Velcade (bortezomib). These results have since been confirmed by the Multiple Myeloma Research Consortium (MMRC) and by investigators from the Intergroupe Francophone du Myeloma (IFM). Side effects seem reasonable and similar to Revlimid. Clinical trials are ongoing around the world. I hope that pomalidomide is approved soon.
Carfilzomib: Carfilzomib is a new proteasome inhibitor. It has a different chemical structure than Velcade, the prototype proteasome inhibitor. In a series of clinical trials conducted by the MMRC, carfilzomib produced responses in approximately 50 percent of patients with relapsed myeloma, including 15 percent who were refractory to Velcade. Carfilzomib is given intravenously. It appears to be well tolerated and has a lower risk of neuropathy (pain or tingling in the extremities) compared with Velcade. As with pomalidomide, confirmatory studies are ongoing around the world, and I am hopeful that the drug will be approved soon.
In the second category are agents that have not shown clear single-agent activity in myeloma, but are promising nevertheless based on responses seen when they were combined with other drugs.
The histone deacetylase inhibitors, Zolinza (vorinostat) and panobinostat (Farydak), have both shown activity when combined with Velcade. With these drugs, we have reports of patients with myeloma that was progressing while receiving Velcade therapy that responded promptly upon the addition or either Zolinza or panobinostat. Clinical trials with these agents also suggest that the response rate when used in combination with Velcade is more than what we would ordinarily expect to see with Velcade alone. Large trials are ongoing with these treatments, and we eagerly await the results of these trials to determine the role and fate of these two drugs.
Another treatment in this category is the anti CS-1 antibody, elotuzumab. The response rate with elotuzumab plus Revlimid and dexamethasone (Rd) appears to be much higher than what would be expected with Rd alone.
Other potential drugs that could join this category are heat shock protein inhibitors (e.g., KW-2478) and phosphoinositide 3-kinase pathway inhibitors (e.g., perifosine).
There is one other drug that does not fit well into either category listed above, but nevertheless is just as promising: MLN9708, an oral proteasome inhibitor. My enthusiasm for this agent stems from the fact that it is available on clinical trials and that it belongs to a drug class that has already produced two active agents, namely Velcade and carfilzomib.
I raised some questions in the beginning. I think I answered the first three. The fourth (also stated in the title) was not meant to be rhetorical. I know for a fact that the many myeloma investigators working on these trials understand the urgency of the situation. The companies that make these compounds recognize the need for speed and have been incredibly supportive. The myeloma field has shown the oncology world a path to drug development with 4 new drug approvals in the last 10 years. I am quite hopeful that for most myeloma patients, the future will indeed happen soon enough.
Dr. S. Vincent Rajkumar is a professor of medicine at the Mayo Clinic in Rochester, Minnesota. His research focuses on clinical, epidemiological, and laboratory research for myeloma and related disorders.
Dr. Rajkumar,
Good article on the current drugs in the pipeline and a sincere "Thank you" for your work in combating this disease. As a patient, I am disappointed that researchers spend so much time on drugs that at best give us temporary remissions. Why is more time not spent on improving Allo transplants, or something that could lead to longer remissions or even cure without long term use of these toxic drugs? More young patients are getting this disease. I am worried that the current trend in Myeloma seems to be increaded use of drugs that we do not know what the longer term side effects are.
Sincerely,
Mark
^^^^
Here I am: 31, from Italy, diagnosed in June 2010 and now in remission.
Dr. Rajkumar, thank you again, that you write a column at the beacon. That's a great deal for us patients to get informed by a myeloma thought leader. Please allow me to share my thoughts: Unfortunately - at date - there are statistically about 20.000 patients dying from myeloma in the U.S. every year. For this patients new discoveries come too late. Even 2011 we have no real control and significant progress. We're not there at all.*
Anyway, in your article from December 2010 you talked about combinations, that could be the way to a better control. You described that new class agents, that accompanies the older ones, are desperately needed. What are your opinions of the promising new class agents (Arry 520; MOR202; STA-9090; INK128; El101; MAGE-A3 vaccine etc.)? Best regards, Peter Parker
*(Myeloma killed one of my dearest friends with 42 recently. A passed away from host-versus-gradt disease will going through an allo transplant. He had only 3 years with myeloma. Specialists said: We could do nothing for you.)
Dr. Rajkumar-, will the discovery of the genetic myeloma markup (Broad-Institut) help the myeloma research significantly? The experts from my research center talk about important progress in the discovery of the mechanism, that changes smoldering to active myeloma. Do you think, there could be a real breakthrough, that we will see in the nearest future? I must admit, that the news from the last events (ASH, ASCO, ASCR) and most of the studies has been disappointing for me, because the steps seem to be small and with refractory disease the new agents are lab heroes without relatively poor outcome in the relapse setting. When will the revolution start? Thank you, Thomas L.
Dr. Rajkumar: thank you for the info and also for the time you give to this terrible disease. Could you please tell about any new trial after the sequence of the MM genome lest month?.
Any hope coming from the monoclonal antibodies on the way?.
Best.
Mary
Dr. R, great article and I thank you for it. Many patients who are lucky enough to get into CR, while worth celebrating, are all to aware that the hurdle of eventual relapse therapies may indeed be in their future. I have long maintained that while the path is not clear, it is exciting and filled with dedicated researching physicians in conjunction with organizations like MMRC, IMF and pharmas who are working hard to find a treatment that will bring us to a new paradigm in treating Myeloma. Thank you for helping us to understand and realize the dogged dedication of more than a few in this pursuit.
I'm also expecting news from the new discovery around myeloma genome. Thank you. Rose
Many investigators are continuing to pursue ways to improve allogeneic transplantation, through laboratory and clinical studies. Despite the recent disappointing results, the Bone Marrow Transplant - Clinical Trials Network (BMT-CTN) is continuing to work on a successor allogeneic stem cell transplant trial. Trying to improve allogeneic transplants and finding new drugs to target the disease are not mutually exclusive. I agree that we need to pursue both approaches.
I fully agree that what we need the most are new classes of agents. Drugs like pomalidomide, carfilzomib, MLN 9708 are derivatives of drug classes that we already know to be effective. Since there are no good laboratory assays that consistently predict clinical activity, it is hard to predict the likely winners. We just have to wait for the clinical trials. Thankfully, numerous trials are ongoing, and Im hopeful we will find new classes. Part of the problem in myeloma is that unlike, say, chronic myeloid leukemia and the bcr-abl translocation, we do not have an equivalent, specific, disease causing genetic abnormality that we can target. Another problem is that myeloma itself is probably a mix of different diseases on a molecular level, collectively called by one name based on clinical features. So it is hard to go after with a uniform approach. We do have specific drugs being developed targeting specific cytogenetic subtypes based on the genetic translocation, eg., t4;14. At present, I am also optimistic about cyclin dependent kinase inhibitors since pathogenetically most cytogenetic subtypes of myeloma have over expression of various cyclins. There are a couple of others that look promising based on early clinical results. Of the antibodies, antibodies to CS-1 (elotuzumab), CD38, IL-6 (a new fully humanized version), are high on the list.
The genetic roadmap that was published recently will be very helpful. But it will take time to sort through given the unbelievable amount of data contained in the sequencing. It is like the proverbial hunt for a needle in a haystack. It is a massive haystack, but thankfully lots of people are combing through it.
Dr. Rajkumar,
Thank you for this article and all you've done for myeloma patients. I especially value your commentary "Treatment of Myeloma: Cure vs Control." I'm curious why CEP-18770 was not one of the potential promising new drugs you mentioned. It has been raised as one of a number of possible drugs & clinical trials that may be useful to me in the future.
Thanks for pointing that out. CEP-18770 is an oral proteasome inhibitor, and should indeed be in the promising list, and there is an open trial recruting patients in the US.
Clarification- CEP-18770 is orally active in animal models, but the current clinical trial uses an intravenous formulation.
Hai, it was good to read a summary of newer drugs for Myeloma.I am a practising hematologist in Coimbatore in South India and am proud of you Dr.Rajkumar, for your poineering work in myeloma. As you may be aware myeloma occurs atleast a decade earlier in Indian paients and we have huge numbers of cases with limited access to latest treatments.
I have a question about Autologous SCT in myeloma, is it REALLY better than combination therapy in the bortezomib era? Keep up your good work, I heard you will be lecturing im Mumbai later his year. I hope to see you there.
I am an RN who worked in western medicine before, during and after Reagan turned our countries compassionate and available medical system into a for-profit, industrial, corporate affair totally at the mercy of big pharma. It used to be that doctors decided how to treat patients, now it seems that the insurance business people do. My beloved husband has advanced M.M. and everyone should watch the following video who has cancer.
At least watch the 1st 10-30 minutes . . .
http://vimeo.com/24821365 ["Burzynski: Cancer Is Serious Business"]
( 1 hour, 48 minutes )
Pamela
I have sen this video, are you suggesting this as a possibility for MM patients.?
Dr Raghu, I was surprised of your comments on patients in India, I am taking curcumin and had much faith in that, until I read your comments, as they would be taking curcumin daily, and yet have myeloma a decade earlier.
Hi Dr. Rajkumar,
Comparing Pomalidomide, Carfilzomib and Perifosine.
Which agent do you think can better extend the life of a colon cancer patient?
Thank you,
Henry
Hi Dr. Rajkumar,
Can you please share your views on drug under trial from vaxil of Isarael?
Many thanks,
R.D.Bhardwaj
Dear Dr. Rajkumar,
I am from Kochi, Kerala.My husband (age 52)is under treatment for multiple myeloma since 2006. He was responding for the treatments fairly well.Recently he is having pain in difeernt parts of the body and now his eye is also becoming smaller. Does it show any symptom that the disease is progressing. we have taken almost all the medicines like, bortinet, zondria, linaldidomide etc.is there any new treatment to control the disese. Hope you will send reply by e mail.
thanking you
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