Now for the sake of full disclosure, I was treated first at Mayo and then at UAMS, and I am like most patients who become vested in the program that they chose to follow. It is for this reason, Priya Menon of Cure Talk was kind enough to co-author and edit this article and promised to keep it grounded and fact based. Her take on the data and my analysis follows this segment. I will not get into a debate about the UAMS claim of a 60% cure rate for the 85% of their patients that are considered low risk, however I will share the most recent data from the TT3 program with the multiple myeloma patient community. I do happen to be one of the hopeful that pray it is true, and that my myeloma will never come back,
What is TT3 anyway? It happens to be midway in the progression of clinical trial at UAMS that started with TT1, and then went on all the way to TT6. The TT stands for Total Therapy and became well know as an approach that uses all available drugs in up front treatment for childhood leukemia(ALL) at St. Judes Children's Hospital. The thought being that the best chance of eliminating all disease is at the beginning of treatment when the cancer has not been exposed to any drugs, and has not developed any resistant. This approach has saved the lives of many children and has moved the cure rate from less than 10% to 95% in childhood leukemia. UAMS uses this same approach for multiple myeloma. For TT3 it represents induction, two stem cell transplants, consolidation, and 3 years of maintenance, with the use of the drug combinations VDT-PACE, Melphalan, and VTD. A more in depth description of the protocol can found in a two part series by Nick Van Dyk and Pat Killingsworth called "Total Therapy Demystified" if you just click on PART1 and then PART2.
I often talk about a treatment continuum that goes from Dr. Berenson's "Less is Best" to Dr. Barlogie's "More is Cure", and therefore UAMS represents one extreme on this continuum. What I have found is that the top 50 to 75 skilled multiple myeloma professionals in the world may have very different approaches to treatment, but all far outperform the published life expectancy and survival rate statistics. And as you see on the home page of www.myelomasurvival.com Dr. Barlogie and Dr. Berenson have some of the very best results, and they have vastly different treatment philosophies.
So why isn't everyone using a TT3 type of protocol? There are a number of reasons, some of which include the following.
1) Some people just don't believe the results are real! This even when the results are being audited as required for all clinical trial studies. UAMS as a member of SWOG (Southwest Oncology Group) use the firm Cancer Research and Biostatistics
2) Many patients think that this can only be done at UAMS, where I would bet most of the 500 CIBMTR(Center for International Blood and Marrow Transplant Research)Transplant Hospitals are qualified to accomplish this protocol.
3) There are a number of programs that have excellent results and the patient may chose to select one that is championed by another skilled multiple myeloma professional. Like the "Less is Best" program of the IMBCR or mSmart protocol of Mayo.
4) The TT3 protocol requires two stem cell transplants and not all patients are eligible for this procedure because of poor health or comorbidities.
5) Older patients may chose to not have a stem cell transplant and go the novel therapy route.
6) Many multiple myeloma specialists believe that the treatment is just too aggressive.
7) Insurance issues, like the fact Medicare will pay for only one Stem Cell Transplant, or a qualified center is not in your PPO network, or it is not an approved procedure.
I would argue that as long as you have a skilled multiple myeloma professional on your team, and have access to a well established transplant program, that a TT protocol could be duplicated at many locations around the world. However, I would add that the UAMS program is the location that initiated this protocol for MM, and has the most experience (over 10,000 transplants) with its application.
One thing that you will find is that there are a number of programs around the United States that most likely utilize a similar protocol or one that is more aggressive than the average program. The reason is because the doctors at these locations obtained much of their multiple myeloma experience at UAMS, and under the tutelage of Dr. Barlogie. These programs include the following:
Sundar Jagannath, MD - The Mount Sinai Medical Center, NY, NY
Jayesh Mehta, MD - Northwestern University Feinberg School of Medicine, Chicago, IL
David Siegel, MD - John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ
Seema Singhal, MD - Northwestern Memorial Hospital, Chicago, IL
Guido Tricot, MD - University of Iowa Hospitals and Clinics,Iowa City, Iowa
David Vesole, MD - John Theurer Cancer Center at Hackensack University Medical Center, Hackensack, NJ
Medical College of Wisconsin, Milwaukee, Wisconsin
Maurizio Zangari, MD - Huntsman Cancer Institute, Salt Lake City, Utah
The data that Dr. Barlogie provided represents a conservative estimate of life expectancy in excess of 15 years, which is 3.8 times the published SEER life expectancy of 4 years. The TT3 program had introduced the new novel agents of Velcade and Revlimid into the Total Therapy protocol and is a leap forward over the prior TT1 and TT2 treatment regimens.
Priya Menon provided the following take on this most recent TT3 data:
Total Therapy has been evolving for the past 20 years and has gone through several different protocols. TT3 protocol is significant since apart from its miraculous results, the protocol used two novel agents – Revlimid and Velcade at a time when these new drugs were saved to be used in the event of a relapse in other cancer centers.
Now, a little detailed look at TT3 protocol would put the current 9 years overall survival graph under scrutiny more in perspective and why we call it the Total Therapy. As Gary Petersen mentions,
Total Therapy 3 (TT3) combines an exhaustive multi-drug regimen with stem cell transplants. Patients are given two cycles of VTD-PACE; this is essentially Velcade (bortezomib), thalidomide, dexamethasone and continuous infusion of Cisplatin, doxorubicin, cyclophosphamide, and etoposide for 4 days. Two stem cell transplants with melphalan follow this. Consolidation therapy involves VTD-PACE and a total of 3 years of maintenance (first year with VTD, second and third year with TD).
We know that TT3 trial results were very encouraging and they had to be confirmed. For this, additional patients were enrolled in a TT3B trial in which the Velcade as maintenance therapy was administered for 3 years (instead of one) and Revlimid was used instead of thalidomide.
Myeloma patients were classified as low-risk or high-risk on the basis of their genes, and a difference in clinical outcomes were observed between low risk and high risk myeloma patients. 83% of participating patients were classified as low-risk myeloma patients and these patients demonstrated better OS, EFS, and CR in TT3 trials. Thus, without any doubt, TT3 is definitely a successful option for low-risk myeloma patients.
At 5 years, the overall survival reported in TT3 trials was 72%. The graph showing 64% overall survival at 9 years is truly phenomenal, pointing towards almost 15 years or more of life expectancy for the population under study. If the data includes both low risk and high-risk patients, this is definitely a significant treatment for myeloma patients. For the low risk population in the study, OS at nine years is 70%!
The high cure fractions observed in TT3 led to the design of TT4 protocol aimed at reducing dosage without compromising on achieved results TT5 for newly diagnosed high-risk patients, and TT6 for previously treated patients.
Now, only if UAMS were to be more open about sharing their data with outside evaluators, the scrutiny and suspicion that surrounds UAMS trial results would vanish and myeloma patients would have no qualms of considering UAMS TT protocols as a powerful therapy option.
All is not Roses however in the data, as was pointed out to me by Nick Van Dyk after this post was published. You can find Nick's extensive and exceptionally well written article at the link: http://nvdmyeloma.blogspot.com/2013/03/lies-damn-lies-and-statistics.html I may blog about this subject myself in more detail at a later date. One of the graphs below shows the CRD(Complete Response Duration) and previous graphs had shown them to have flattened out at 3 years which would indicate CURE. However, the new graph still shows a decline at 8 years, so the estimate for cure for this subset of low risk patients has yet to flatten out and confirm cure. BUMMER!!
Thank you Priya for helping me to provide a balanced analysis of the data. A bio for Dr. Barlogie is below.
As always, may God Bless your myeloma journey/ Gary Petersen and Priya Menon
Director of the
UAMS Myeloma Institute
Professor of Medicine and Pathology
Tommy May Chair in Oncology
Director, Myeloma Institute
M.D. Heidelberg University, University of Munich
Ph.D. Max Planck Institute for Medical Research
Residency (internal medicine, hematology and infectious diseases, rheumatology, nephrology, cardiology, gastroenterology), University of Muenster.
Clinical Fellowship (oncology), M.D. Anderson Hospital and Tumor Institute.
Numerous Professional Appointments at M.D. Anderson, including:
Professor of Medicine, Department of Hematology
Professor of Pathology, Department of Pathology
Chief, Section of Experimental Therapeutics, Department of Hematology
Chief, Cytometry Center, Department of Hematology
Honors and Awards:
Distinguished Alumnus Award – UT MD Anderson Cancer Center – 1998
Jan Waldenstrom Award for Myeloma Research – 1999
Celgene Career Achievement Award in Hematology Research – 2002
Robert A. Kyle Lifetime Achievement Award, International Myeloma Foundation – 2004
National Physician of the Year Award for Clinical Excellence, Castle Connolly Medical Ltd., 2006
American Society for Clinical Investigation
American Society of Clinical Oncology
American Society of Hematology
Association of American Physicians
International Society of Hematology
The American Society for Bone and Mineral Research
Additional Relevant Information:
Dr. Barlogie is an internationally recognized authority on the use of novel therapies to combat multiple myeloma for improved patient outcome. On the faculty at UAMS since 1989, Dr. Barlogie has built the largest center in the world devoted exclusively to clinical care for and research in multiple myeloma. More than 9,000 patients from every state in the U.S. and more than 50 countries have come to the Myeloma Institute.
With a keen insight into the biology of myeloma, Dr. Barlogie pioneered the use of tandem peripheral stem cell transplant for multiple myeloma. Other firsts under Dr. Barlogie’s leadership include performing transplants on an outpatient basis, safely transplanting patients age 70 and older, transplanting patients with renal disease, and introducing thalidomide as anti-angiogenesis therapy. Dr. Barlogie’s Total Therapy approach, by which multiple agents are provided upfront, has continually increased median survival, with a projected median survival of 15 years for patients enrolled in the third Total Therapy protocol.
A consummate clinician scientist, Dr. Barlogie has authored more than 544 papers in prestigious journals such as Blood, New England Journal of Medicine, Journal of Clinical Oncology, British Journal of Haematology, and Cancer. He has more than 595 abstracts and 75 book chapters to his credit, and serves on the editorial board of numerous journals.