Velcade-Doxil-Dexamethasone-Thalidomide Combination May Be Effective In Relapsed/Refractory Myeloma
Results of a recent Italian study show that a four-drug combination regimen of Velcade, Doxil, dexamethasone, and thalidomide may be more effective than two- or three-drug combinations for multiple myeloma patients who have relapsed or are resistant to prior treatment.
“This study clearly reinforced the idea that aggressive therapy, even in the second-line relapse setting, is of great value,” said Dr. Mario Curti, a hematologist at Los Alamitos Medical Center in Los Alamitos, California, who was not involved in the study. “It allows another treatment option to be considered in the relapse setting, especially for those [patients] who are not transplant candidates.”
The study authors indicated, however, that because patients achieved a complete response with the four-drug combination therapy only when their disease was not too far advanced, this combination may be effective only when used in the initial stages of relapsed or resistant disease.
“We reported that patients treated in third or subsequent relapse [did not] obtain a complete response,” explained the study’s lead author Dr. Massimo Offidani from the Ospedali Riuniti in Ancona, Italy. “These are the data which other [researchers] have also found.”
Because of the side effects associated with the four-drug combination therapy, the study authors suggested that less intensive therapies may benefit patients in the later stages of disease, when quality of life and disease control are more important than quality of remission.
Recent research has shown that four-drug combination treatments may be more effective in newly diagnosed multiple myeloma patients than two- or three drug combinations (see related Beacon news). According to Dr. Offidani and his colleagues, there is currently no data available about the use of four-drug combinations in relapsed or refractory myeloma patients.
“There has been a historical bias against three- and four-drug regimens for patients with multiple myeloma, as it was felt to be too toxic in a population that already was substantially compromised due to their illness,” Dr. Curti told the Myeloma Beacon.
Preclinical studies have shown that thalidomide (Thalomid) enhances the activity of Velcade (bortezomib) and dexamethasone (Decadron). Additionally, they have shown that Doxil (doxorubicin liposomal) enhances the activity of thalidomide and Velcade-dexamethasone against myeloma cells.
Based on these findings, Dr. Offidani and his colleagues sought to determine whether or not a four-drug combination of Velcade, Doxil, dexamethasone, and thalidomide would be an effective treatment for relapsed or refractory myeloma patients.
They also assessed whether outcome could be improved by further treating the patients with alternating cycles of Velcade-dexamethasone and thalidomide-dexamethasone followed by thalidomide treatment during remission.
The study included 46 relapsed and refractory patients with a median age of 64 years. Participants had received a median of one prior therapy.
Patients received six 28-day cycles of 1.3 mg/m2 Velcade on days 1, 4, 8, and 11; 30 mg/m2 Doxil on day 4; 20 mg oral dexamethasone on days 1 to 2, 4 to 5, 8 to 9, and 11 to 12; and 100 mg oral thalidomide daily.
Because nine of the first 20 patients receiving treatment experienced pain and tingling sensations from nerve damage to the extremities, the study authors amended the regimen in all therapeutic phases to 1.3 mg/m2 Velcade on days 1, 4, and 11, and 50 mg thalidomide daily.
Among the participants, 76 percent responded to the four-drug combination. Specifically, 35 percent achieved a complete response, 33 percent achieved a very good partial response, and 9 percent achieved a partial response.
The study authors found that the rate of complete responses was higher in patients who had received two or fewer prior therapies than in patients with more prior therapies (41 percent versus 0 percent). Other factors including age, prior autologous stem cell transplant, and refractory disease did not affect the quality of response.
The most common side effect associated with the four-drug combination treatment was pain and tingling sensations from nerve damage to the extremities (30 percent). Additionally, 15 percent developed infections, 28 percent experienced low blood cell counts, and 4 percent developed blood clots in the veins.
Of the patients who completed the four-drug regimen, 57 percent went on to receive six alternating 28-day cycles of 1.3 mg/m2 Velcade on days 1, 4, and 11 plus 20 mg oral dexamethasone on days 1 to 4, and 50 mg thalidomide daily plus 20 mg oral dexamethasone on days 1 to 4.
After receiving this second therapy, 37 percent achieved a complete response, 35 percent achieved a very good partial response, and 4 percent achieved a partial response. According to Dr. Offidani and his colleagues, these response rates are much better than the 20 percent complete response rates that have been reported with two-drug combinations recently.
Of the patients who completed this second therapy, 44 percent went on to receive 50 mg thalidomide daily during remission until they relapsed or experienced intolerable side effects. Dr. Offidani and his colleagues found that thalidomide did not improve patient response during remission.
After a median follow-up of 31 months, 61 percent of participants relapsed, and 44 percent died.
The median overall survival was 40 months, and the median time to disease progression was 18.5 months.
The study authors found that patients who completed the treatment protocol had a significantly longer time to disease progression than patients who did not complete the protocol (not reached versus seven months).
“I don’t know what will be the impact [of this four-drug regimen] in the near future of myeloma therapy,” Dr. Offidani told The Myeloma Beacon, “but we can state that [it] represents a new, effective rescue possibility for patients with relapsed-refractory multiple myeloma.”
The study authors recommended further investigation of the four-drug combination therapy in larger Phase 2 and Phase 3 trials.
“I suspect a larger Phase 3 study would prove beneficial in solidifying this combination as a new standard of care in relapsed myeloma,” said Dr. Curti.
For more information, please see the article in the Annals of Hematology (abstract).
Related Articles:
- Nelfinavir-Velcade Combination Very Active In Advanced, Velcade-Resistant Multiple Myeloma
- Eyelid-Related Complications Of Velcade Therapy: New Insights And Recommendations
- Revlimid, Velcade, and Dexamethasone, Followed By Stem Cell Transplantation, Yields Deep Responses And Considerable Overall Survival In Newly Diagnosed Multiple Myeloma
- Adding Clarithromycin To Velcade-Based Myeloma Treatment Regimen Fails To Increase Efficacy While Markedly Increasing Side Effects
- Sustained Complete Response To Initial Treatment Associated With Substantial Survival Benefit In Multiple Myeloma
The Chinese are using NFkB down regulators such as CURCUMIN and TRIPTOLIDE combined with
XIONG HUANG=REALGAR = ARSENIC DISULPHIDE.
TRISENOX=ARSENIC TRIOXIDE, has worked in Israel and the USA-Australia is trialling PHENASAN,THIS IS ALSO ARSENIC TRIOXIDE.
The side effects of the arsenic are mils compared to these more mainstream treatments-I think that Arsenic should be the first treatment-not the last-XIONG HUANG, IN CHINA,ZARNIKH, IN IRAN AND SHAMEEL, in India are all being used to treat cancer-at much lower cost -There is no big money involoved ?
Thanks for your comment, Alex.
Trisenox (arsenic trioxide) is approved in the United States as a treatment for acute promyelocytic leukemia. Doctors in the U.S. are relatively free to prescribe drugs outside of their officially approved use, and they often do so, especially if there are sound data supporting such prescribing. This was the case, for example, with thalidomide, which was widely used as a treatment for myeloma before it was formally approved for that use.
In the case of Trisenox, there were a number of clinical trials in the first decade of this century designed to test its efficacy and side effects as a treatment for myeloma. You can see a list of many of these trials at clinicaltrials.gov, specifically this page:
http://clinicaltrials.gov/ct2/results?term=arsenic+myeloma
As you'll see, some of the trials were completed, but most were either suspended, withdrawn, or terminated. None of them ever provided Cephalon, the company that markets Trisenox, with sufficient evidence for it to decide to pursue full FDA approval for the medication as a treatment for myeloma.
Likewise, based on the information in this document, http://bit.ly/kZ9BYg , it appears that Cephalon has given up on plans to seek any European approval for Trisenox as a myeloma treatment.
Regarding curcumin, please see this detailed article about the evidence regarding its potential as a myeloma treatment,
http://www.myelomabeacon.com/news/2010/02/17/curcumin-and-multiple-myeloma-preclinical-and-early-clinical-studies-are-promising-still-awaiting-more-clinical-evidence/
Regarding triptolide, there appears to be some preliminary data that the drug may have some activity against myeloma cells. See, for example, the publications listed at PubMed on the subject,
http://www.ncbi.nlm.nih.gov/pubmed?term=triptolide%20myeloma
However, as best we can tell, there have not been, nor are there currently ongoing, any clinical trials to test triptolide as a myeloma treatment.
Thanks-The Chinese are now using nano-REALGAR and the cleveland clinic have developed a Nickel /Arsenic Alloy-
Nano particle coated with Folic Acid that will penetrate cancer cells where the acidity releases the Arsenic ?
I visited a Kings Tomb in China, and he had a medical kit buried with him and it contained XIONG HUANG
= ARSENIC DISULPHIDE-They used it to treat cancer-In 1200-1300AD ?
XIONG HUANG is freely available in China and I spent a few hours at a traditional Medicine Clinic where I learned a lot about their treatment of cancers.
My father used FOWLERS SOLUTION =1% Potassium Arsenate was used to treat cancer in India prior to the 1790s-It also cured VD-Dr.Bramwell used in in 1878 aand SALVASAN in 1914 to treat pernicious anemia
that was always fatal-It is,NOW, thought to have been AML-prof.Bharat .Aggarwal said that MM amd AML may well be just different manifestations of the same disease. ? Dad used Fowlers to inject into facial tumours on cows and horses-The farmers used it and COOPERS SHEEP DIP to treat their own skin cancer-COOPERs was Arsenic Disulphide. I am told WHO still use Fowlers in Africa.
ZIOPHARM 101/202/303 show great promise as organo arsenicals-SALVASAN released in 1906 was the first.
KEEP AN OPEN MIND IT LETS IN MORE LIGHT-STAY WELL-ALEX.
If I'm not mistaken, Trisenox went through early-stage clinical trials as a potential myeloma agent, but did not show enough efficacy to justify its use, particularly given its side effects.
This article reports on a trial of Trisenox in combination with ascorbic acid and dexamethasone in relapsed or refractory myeloma patients:
http://haematologica-thj.org/content/91/12/1722.full.pdf
The article concludes "combination therapy with arsenic trioxide [ATO], ascorbic acid and dexamethasone is feasible, but has moderate efficacy and significant toxicity in heavily pretreated patients with advanced MM. So far, the results of ATO-based regimens are inferior to those of other new agents such as bortezomib and lenalidomide."
Another trial investigated whether adding Trisenox to melphalan and ascorbic acid prior to stem cell transplantation improved response rates. Here is the abstract:
http://www.bbmt.org/article/S1083-8791(08)00418-7/abstract
Patients in the study either received no Trisenox in addition to melphalan and ascorbic acid, or one of two doses of Trisenox.
The researchers who conducted the study found no difference in any of the response rates they looked at between the patients who received Trisenox and those who did not.
Has anyone got statistics on the survival rate and mortality figures for receiving a bone marrow transplant
My wife is off all chemotherapy as her myeloma is not progressing. If it does we will go to China as they are having good success at lower cost. I work in China and one Chinese drug company said they could not supply 300 mgm Xiong Huang tablets as they now have an exclusive contract to only supply a large swiss drug company. The price will very high. 300mgm Xiong Huang tablets are only $US 25-50 each and 20 tablets are needed for a course of treatment. They are getting 74% remission with one treatment. Jump ingto 92 % with a second treatment.
NOTE : PHENASAN ,made in Australia is = TRISENOX at much lower cost. Myeloma trials are under way In Fremantle, Western Australia.
I read that Magagascar Blue periwinkel( containing Indorubicin) was used in the 1400s ,combined with XIONG HUANG( natural Arsenic Di Sulphide) to treat a whole range of cancers. What an amazing race. How did they know. I have just read ," The Genius of China-3000 years of Science and Invention" This is a precis of the 13 volume " Science and Civilization in China"; by Prof.Joseph Needham-Needham Institute-University of Cambridge. They were treating endocrine disorders 150 years ago ?