Experts Review Current And Future Research Into New Multiple Myeloma Treatments
Earlier this year, an international group of myeloma experts published a review of ongoing research into new myeloma treatments. This review not only described a wide range of potential new myeloma treatments, but also included the experts' thoughts on where research into new treatments should go in the future.
Given the recent new drug application for carfilzomib and the upcoming annual meeting of the American Society of Hematology -- which undoubtedly will host discussions of many potential new myeloma treatments -- it seems an appropriate time to go back to the experts' review from earlier this year and highlight some of its key points.
The experts begin their review by noting that, despite significant advances in the treatment of multiple myeloma during the last decade, it continues to be challenging to find effective therapies for patients at high risk for early relapse and for patients resistant to multiple drugs or drug combinations. This makes the search for new treatments particularly important.
The Next Generation of Novel Agents
Regimens containing the novel agents Velcade (bortezomib), thalidomide (Thalomid), and Revlimid (lenalidomide) have played a key role in improving progression-free and overall survival in multiple myeloma patients. According to the authors of the review article, new drugs that work similarly as these novel agents, but have improved efficacy or safety, have been showing particular promise in clinical trials over the past several years.
Carfilzomib: The Next Generation Velcade
Velcade works by inhibiting proteasome, which is responsible for the break down of proteins in both healthy and cancerous cells. Treatment with Velcade results in the accumulation of proteins within the cell, and it is believed that this excess protein leads to cell death, suppressing tumor growth.
Carfilzomib, which belongs to the same class of drugs as Velcade, has shown high efficacy in clinical trials and may have fewer side effects than Velcade (see related Beacon news). Particularly notable are its lower rates of peripheral neuropathy (nerve damage in the extremities).
There also are other proteasome inhibitors under development for the treatment of myeloma, including salinosporamide A (marizomib,NPI-0052), and MLN9708/MLN2238, a chemical cousin of Velcade that can be taken orally.
Pomalidomide: The Next Generation Revlimid
Pomalidomide is closely related to thalidomide and Revlimid. Although the exact ways in which this class of drugs works remain unclear, all three are immunomodulatory agents (drugs that affect the immune system), and they apparently encourage a patient’s immune system to attack and destroy myeloma cells. Clinical trials have shown that pomalidomide is effective in patients who are resistant to treatment with thalidomide, Velcade, and Revlimid (see related Beacon news).
Dr. Vincent Rajkumar, a professor of medicine at the Mayo Clinic, noted in a recent column for The Myeloma Beacon that, of the many drugs currently in development for multiple myeloma, only pomalidomide and carfilzomib have shown significant single-agent activity in multiple clinical trials (see related Beacon news).
In addition to the improvements being made in the currently available multiple myeloma drug classes, ongoing research is being done to identify new classes of drugs.
The authors of the review article believe that several drugs, while not showing potential as single agents themselves, may prove to be effective if given in combination with other currently approved drugs, such as Velcade (see related Beacon news). These include the histone deacetylase inhibitors, Zolinza (vorinostat), panobinostat (Farydak) and Istodax (romidepsin), which have shown activity when combined with Velcade.
The anti CS-1 antibody, elotuzumab has also been included in this list. This drug targets proteins that are displayed on the surface of myeloma cells but not on healthy cells. Clinical trials are currently underway to examine the activity of elotuzumab in patients with refractory or relapsed myeloma. It is anticipated that the drug will work best when combined with Revlimid and dexamethasone (Decadron), rather than as a single agent.
Other potential drugs that may work best in combination with existing therapies include heat shock protein inhibitors (see related Beacon news), phosphoinositide 3-kinase pathway inhibitors (for example perifosine), and mTOR inhibitors, such as Torisel (temsirolimus). At this time, however, none of the drugs in these classes have been approved by the U.S. Food and Drug Administration (FDA) specifically to treat multiple myeloma.
The authors conclude their review of current research on new myeloma treatments by touching on an alphabet soup of drugs in early-stage clinical trials -- drugs such as ACE-011, BHQ880, BI-505, defibrotide, GDC-0449, imetelstat (GRN163L), MLN4924, MLN8237, NVP-BEZ235, and siltuximab (CNT 328). In addition, the authors describe several potential early stage treatments that may stimulate the body's immune system to attack myeloma cells.
Improving Clinical Trial Results
According to the authors of the review, a large number of drugs that are being developed for multiple myeloma have shown promise in preclinical trials. These preclinical trials are not carried out in humans, but instead in other models of the disease, such as cells grown in the laboratory setting or small animals (for example mice). The review authors point out, however, that despite initial promise, fewer than 10 percent of cancer drugs that begin testing in humans ever receive approval from the FDA for patient use.
The authors therefore stress that more preclinical testing is needed and that the models used during this testing should more closely mimic the disease as it is observed in humans. They emphasize, for example, that the environment surrounding the tumor is of equal importance to the tumor itself, and suggest that more models take this so-called “microenvirnoment” into more careful consideration.
They also recommend that patients be carefully selected when clinical trials of a drug begin. Because some drugs may perform better in specific patient populations, these populations should be established before the start of clinical trials, and patients should be screened to ensure they are in this population before they are enrolled.
Personalized Treatment For Multiple Myeloma
The experts conclude their review by noting that, through work carried out over several decades, cancer biologists have discovered that cancer treatment cannot be a “one-size-fits-all” solution. At the same time, determining the best method for treating an individual patient for their cancer at the correct time during their disease has proven to be the most challenging aspect of research. Many researchers believe, however, that this kind of “personalized therapy” offers the most hope for cancer patients.
In this regard, the authors note that the International Staging System, the availability of genetic testing, and the development of risk classification systems by institutions such as the Mayo Clinic and the University of Arkansa have all contributed to greater individualization of multiple myeloma treatment.
The ultimate goal, according to the review authors, will be to identify subsets of patients that will respond most effectively to certain drugs or drug combinations and, thereby, improve the progression-free and overall survival of myeloma patients. Further investigation is therefore needed into the classification of patients and the development of clinically relevant tests to identify patient classes.
While such studies may not be easy to implement, the authors believe that such issues are likely the next major frontier of myeloma research in the coming years.
For more information, please see the review in the Journal of Clinical Oncology (abstract).
Related Articles:
- Getting To Know: Tiragolumab
- Eyelid-Related Complications Of Velcade Therapy: New Insights And Recommendations
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
- Lather, Rinse, Repeat: Will It Work With BCMA-Targeted Therapies For Multiple Myeloma?
- bb2121 Continues To Impress As Potential New Multiple Myeloma Therapy (ASCO 2018)
Did anyone think of trying Ipilimumab in Multiple Myeloma Patients? Since immunomodulary drugs work so well in Multiple Myeloma there could be a strong rationale in trying this off label. At the moment I can not find any open trials in this context. Any toughts?
Melissa and Maike: Nice summary of situation. A little disappointing that we are not finding novel drugs with different mechanisms for controlling MM. Consequently, we have to look at combos or cocktails of existing or look alike agents and some how magically personalize them to patients. An incredibly task especially since we don't have any clinical trails and have no idea what the dosage regimen should be. As a colleague said we simple will throw all the "stuff" we have on the wall and see what sticks. I have a better idea. Why don't we individualize the doses to the patients ability to adsorb,distribute,metabolize and eliminate the agents (ADME)? If we don't it is entirely possible that we may "throw" the best stuff at the wall see no effect (underdose) or extreme toxicities (overdose). Since it appears we have limited options lets get it right.
Manfred,
I am the farthest thing from an expert on this topic, but I will make an attempt to answer your question. If any Doctors or Staff see my response and it is not correct, please feel free to correct me. I was diagnosed with MM about 13 months ago and did not have any idea what it was before diagnosis. My educational background is not in Science.
The reason we have MM in the first place is that our Immune systems do not recognize the Myeloma (abnormal Plasma Cells) as destructive. If our Immune systems were working properly, they would destroy the Myeloma cells. There are even times that our Immune Systems will try and help the Myeloma cells survive and grow.
http://www.sciencedaily.com/releases/2009/10/091005123043.htm
That is what makes the IMID's such an innovative drug in Myeloma therapy - they are the one class of drugs that seems to make our Immune sytems work against the Myeloma, but the effect is only temporary and the patient will likely relapse after using them. The authors mention that the reason the IMID's can do that is not fully understood.
Ipilimumab has been studied on Blood Cancer patients that have relapsed after Allogeneic transplants. According to the American Cancer Societies website Ipilimumab works in this way: "Ipilimumab is designed to seek out and lock onto CTLA-4, a protein that normally helps keep immune system cells called T cells in check." Stimulating a MM patients T cells may not work against the Myeloma because the Immune system does not recognize the Myeloma as the threat that it is. A patient that did an Allo may get a positive response because they have a new Immune system that will hopefully recognize the Myeloma as foreign and the threat it is and kill it.
http://clinicaltrials.gov/ct2/show/NCT00060372
http://www.redorbit.com/news/health/763298/ipilimumab_mdx010_safety_and_clinical_response_data_in_lymphomas_and/index.html
I hope that answers your question.
Mark
I find this quote to be more a problem than a solution:
"...cancer biologists have discovered that cancer treatment cannot be a “one-size-fits-all” solution.... The ultimate goal, according to the review authors, will be to identify subsets of patients that will respond most effectively to certain drugs or drug combinations and, thereby, improve the progression-free and overall survival of myeloma patients. "
The reason being that they set the ULTIMATE goal as " identifying subsets of patients"
Classifying patients is less of a problem at the moment than individualizing the DRUG dosing. If anything the ultimate goal should be to implement changes presently that can be impactful on the quality of life while the patient is being treated now.
For example, researchers put plasma cells in dishes and stem cells too and treat them with all kinds of experiemental drugs to discover if the plasma cell is resistant or undergoes apoptosis. Why doesn't anyone one do the same thing with newly diagnosed patients? Determine what drugs are effective on each individualized patient right now, as opposed to 'identifying subsets of patients' ...identify what drugs are working on the plasma cells clinically from the bone marrow aspirates.
Just like we do with antimicrobial therapy. We do a bacterial culture find out what the bugs are susceptible to and use the most effective drugs. And bacteria become resistant as well just like plasma cells..so my hope is that we do the most personalized drug treatment we can now.
Hi!
I have read so much news about many agents, that are in early-stage development: I'm foremost impressed by EL102 from Elara Pharma and Micromets myeloma bite, two interesting developments.
But the problem is that this early stage agents need (too much) time to be brought to the bedside - to us and our bones. Far too much time for us.
We need a real revolution and more Docs as Bart Barlogie, who is pulling und pushing for the impossible.
Dear fellow patients, let me know and post it, when you hear some good news. The time with myeloma is tough, but better times will come soon. I feel it - the cure is around the corner.
Best,
Peter
Hi Peter,
Have their been any updates on the BiTE antibody? Is it in Phase I clinical trials yet?
Most of the news announcement appear to be about the 2 pharma companies collaborating i.e. business deals..rather than science and/or clinical date on BiTE antibody.
Peter,
I think you are shortchanging a LOT of MM Doctors by making the comment that only a few are trying to look for a cure. For example, I did a myeloablative allogeneic transplant in my first remission - 8 months after diagnosis. I would say that is an attempt to cure a patient.
I do not go to the Fred Hutchinson Cancer Center in Seattle WA. They are the Center that does the most research in the US on the Mini Allo. They are trying to make the one potentially curative procedure available to more MM patients. I would say they are trying their best to move us toward a cure. Most of the research I did on Allos comes from Europe. There a lot of talented people looking for a cure.
Please understand, I have an immense amount of respect for Dr. Barlogie. He deserves a lot of credit for his contributions to MM research. I am most impressed with his record keeping, his research into the genetics of MM and how many of his patients convey a positive experience at his facility. But to say he is one of the few attempting to cure MM is unfair to a lot of other Doctors and Researchers.
Mark
Dear Mark,
I have to apologize! It was not my intention, to blame any myeloma doc nor underestimate their research. I admire them for doing research - there are so many outstandind personalites out there. But I do admire Professor Barlogie for his special approach and his Total Therapy-numbers. He (and he is hopefully one among others) gives people a hope for cure, although therapy his quite hard. I am even not one of his patients, because it's too expensive for me and my family to be treated in Arkansas. So sorry - it was just an emotional statement.
Dear Suzierose,
unfortunately Micromet is in early development, but the approach is a great one (love this bites eating myeloma cells) and another antibody brings stable disease in leukemia. EL102 from Elara Pharma will come in early 2012. But I've one more for you. The CD38-antibody MOR202 from Morphosys is in Phase 1/2 now. Hopefully we will hear some good news soon.
Peter
Manfred,
We checked with Bristol-Myers Squibb, the company that markets Yervoy (ipilimumab), whether it has any plans to develop the drug as a treatment for multiple myeloma. A spokeswoman informed us that "There are currently no plans for Yervoy in myeloma." There also are currently no trials listed in clinicaltrials.gov that explore Yervoy as a potential treatment for myeloma.
Yervoy was approved by the FDA earlier this year as a treatment for melanoma which has spread or cannot be removed by surgery.
@ Myeloma Beacon Staff: Thank you for your help. Even though it remains an exciting idea. Perhaps in combination with lenalidomide. BMS concentrates on more frequent and therefore more profit-promising diseases. It is a pity.
Peter,
No apology necessary. I must have done a very poor job of attempting to communicate a positive message. I was trying to point to a couple of examples of Doctors who are "pushing and pulling for the impossible" as you said. You have a great attitude about trying to BEAT this disease. Best of luck to you!
Mark