Individualized Therapy For Newly Diagnosed Multiple Myeloma (ASCO 2012)

Upfront therapy for newly diagnosed multiple myeloma patients should be risk-adapted and individualized, according to Dr. Vincent Rajkumar from the Mayo Clinic.
Dr. Rajkumar presented his opinions about upfront therapy for myeloma during an education session at the recent annual meeting of the American Society of Clinical Oncology (ASCO). During his presentation, he reviewed the induction treatment options for newly diagnosed multiple myeloma patients and discussed his opinions of the various options.
Induction therapy refers to the initial treatment given to newly diagnosed multiple myeloma patients to combat their cancer.
According to Dr. Rajkumar, there are currently many induction treatment options available. He has found at least 20 different induction regimens discussed in the scientific literature.
The challenge for physicians and patients is determining which treatment regimen best fits with a patient’s particular characteristics.
He pointed out that significant progress in the treatment of multiple myeloma has been made since the introduction of the novel agents thalidomide (Thalomid), Velcade (bortezomib), and Revlimid (lenalidomide). Several frontline regimens involving these agents have led to improved survival rates, response rates, and safety.
However, there are currently only a limited number of Phase 3 trials available that demonstrate the superiority of one regimen over another in terms of overall survival and quality of life (see related Beacon news).
“We are forced to make a choice, not based on data but based on opinion, and opinions vary,” said Dr. Rajkumar.
Dr. Rajkumar pointed out that the cost, convenience, and safety of available treatment regimens vary greatly. He noted that these factors should be taken into consideration, along with a patient's prognosis and expectations of treatment outcomes, when weighing the risks and benefits of a particular course of treatment.
Individualized Approach To Initial Treatment
According to Dr. Rajkumar, myeloma specialists usually use three factors to predict patient outcomes: patient characteristics, stage of disease, and the aggressiveness of disease.
In Dr. Rajkumar's experience, however, the stage of a patient's disease is not typically helpful in determining the optimal course of treatment.
Instead, he has found it best to individualize therapy based on patient characteristics and disease aggressiveness.
Patient characteristics, including age, organ function, and presence of unrelated diseases, are currently used to determine one's eligibility for an autologous stem cell transplant.
Genetic abnormalities that put myeloma patients at risk of shorter duration of response to therapy and shorter survival are also taken into consideration when determining the initial course of therapy.
Dr. Rajkumar divides patients into three risk-groups based on the absence or presence of specific genetic abnormalities in the patient's myeloma cells.
The groups are: standard-risk patients, which constitute approximately 75 percent of all myeloma patients; high-risk patients, which include those with the 17p deletion, t(14;16) translocation, or t(14;20) translocation; and intermediate-risk patients, which include those with the t(4;14) translocation.
The individually tailored approach to treatment allows patients to pursue treatments depending on their risk factors and expectations of outcomes.
While Dr. Rajkumar recommends that standard-risk patients be treated with regimens that have proven effective and well-tolerated in Phase 3 studies, he suggests that high-risk patients may be more willing to take on the additional risks of newer therapies in clinical trials.
“A patient who only has two years to live may have a different tolerance to risk than a patient who has 10 years to live,” he said. “Their attitude about how much risk they are willing to take changes.”
Dr. Rajkumar clarified that risk-adapted therapy involves choosing the right therapy for each patient. It does not mean that the standard-risk patients receive the weakest therapy. Instead, he explained that “Standard-risk patients should receive therapies that have good data behind them.”
Initial Treatment Options For Transplant-Eligible Patients
Patients who are eligible for high-dose chemotherapy followed by an autologous stem cell transplant are generally treated with two to four cycles of initial (induction) therapy prior to stem cell collection. The main induction options available in the U.S. are a combination of Revlimid and dexamethasone (Decadron) (abbreviated as RD) or Velcade-based regimens.
(Velcade is approved in the U.S. and many other countries for the treatment of newly diagnosed myeloma patients. Revlimid, on the other hand, is not. Thus, due to restrictions on so-called "off-label" use of medications in countries other than the U.S., Revlimid is not typically an option for newly diagnosed patients outside the U.S.)
For standard-risk, newly diagnosed patients who are eligible for a transplant, RD is highly active but may impair stem cell collection. Velcade-based therapies, on the other hand, do not affect stem cell harvest, but may result in higher rates of peripheral neuropathy (pain and tingling in the extremities due to nerve damage).
While there are no randomized trials to date that have compared Velcade-based regimens with RD, there are data available comparing different Velcade-based therapies.
Velcade, cyclophosphamide (Cytoxan), and dexamethasone (abbreviated VCD or CyBorD); Velcade, thalidomide, and dexamethasone (abbreviated VTD); and Velcade, Revlimid, and dexamethasone (abbreviated VRD or RVD) are combinations that are in various stages of development.
VCD has demonstrated effectiveness and tolerability in newly diagnosed patients, and is less expensive than both VTD and VRD, “making it an attractive option for initial treatment,” said Dr. Rajkumar.
Based on cost and safety, RD and VCD regimens appear to be the preferred treatment options for standard-risk, transplant eligible patients, according to Dr. Rajkumar.
Intermediate-risk patients who are transplant-eligible typically respond well to Velcade-based regimens. Data from previous trials have shown optimal responses resulting from double stem cell transplants and subsequent Velcade-based maintenance therapy.
“These patients absolutely need Velcade, so I would go with VCD,” said Dr. Rajkumar.
Unfortunately, treatment regimens recommended for transplant-eligible standard-risk and intermediate-risk patients have not significantly improved outcomes in high-risk patients.
Thus, “For high-risk patients, I’m willing to spend whatever it costs to use the regimen that gets the highest complete response rate, and that’s where VRD comes in,” said Dr. Rajkumar.
Initial Treatment Options For Patients Not Eligible For Transplant
Dr. Rajkumar pointed out that for transplant-ineligble patients, the regimens that are available for transplant-eligible patients, such as RD, VCD, and VRD, can be used. In addition, melphalan (Alkeran)-based combinations are treatment options for this patient population.
Three-drug combinations including melphalan (Alkeran) and prednisone are been tested in a number of clinical trials. The combination of melphalan, prednisone, and thalidomide (abbreviated MPT) has demonstrated improved overall survival and response rates compared to melphalan and prednisone alone.
A Phase 2 trial of Velcade, melphalan, and prednisone (abbreviated VMP) also led to improved overall survival compared to melphalan-prednisone, but VMP was associated with a higher risk of neuropathy. The VCD regimen can be used as an alternative to VMP, while minimizing side effects.
Overall, MPT and VMP regimens yield the strongest responses in this patient population, but both have inferior safety profiles compared to RD and VCD.
This is one of the reasons, Dr. Rajkumar pointed out, that melphalan-based regimens are rarely used in the United States.
“We basically use the same three regimens as for transplant-eligible patients,” he concluded. “We really don’t have to make a difference.”
Based on cost and safety factors, Dr. Rajkumar believes RD and VCD are the better treatment options for standard-risk patients who are ineligible for transplantation.
For intermediate-risk patients, Dr. Rajkumar recommended treatment with VCD, and for high-risk patients he recommended treatment with VRD. However, he pointed out that the VRD regimen should not be used for all patients, in part because there are no Phase 3 trial data available yet justifying such use.
Initial Treatment Options For Patients With Special Forms Of Multiple Myeloma
Dr. Rajkumar also made recommendations for patients with special forms of multiple myeloma:
For patients with plasma cell leukemia (a disease similar to myeloma, with more than 20 percent of plasma cells in the peripheral blood) or extensive extramedullary disease (development of malignant plasma cells in organs or soft tissues outside the bone marrow), Dr. Rajkumar recommends the VDT-PACE regimen (VDT plus cisplatin, doxorubicin (Adriamycin), cyclophosphamide, and etoposide) plus double stem cell transplantation, followed by Velcade-based maintenance therapy.
For patients with acute kidney failure, safety is the most important factor determining treatment choices. “For patients with acute kidney failure, you want to use drugs that are absolutely safe in patients with kidney failure,” said Dr. Rajkumar. He recommended the VCD or VTD regimens for this patient population.
General Dosing Recommendations
For all patient populations, Dr. Rajkumar recommended using Velcade only once weekly for all Velcade-based regimens, since once-weekly Velcade has been shown to be as effective but better tolerated than twice-weekly Velcade.
“When you use Velcade twice weekly, you will cause complications for the patients,” he explained.
He also recommended using only low-dose dexamethasone in all combination treatments.
For more information, please see the article (pdf) Dr. Rajkumar wrote to accompany his presentation, as well as the slides (pdf) from Dr. Rajkumar’s presentation, which he has made available for download and viewing as a courtesy to The Beacon’s readers.
Related Articles:
- 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
- Eyelid-Related Complications Of Velcade Therapy: New Insights And Recommendations
- Importance Of Factors Affecting Multiple Myeloma Survival Changes With Patient Age
- Nelfinavir Shows Only Limited Success In Overcoming Revlimid Resistance In Multiple Myeloma Patients
Hi Virginia: A great review of Dr. Rajkumar's s current opinion of individualized induction treatment for MM. I would suspect that this treatment has been individualized for years with different oncologists practicing what they think is correct and modifying it to the patient distinctive characteristics outlined in your review.
What is incredibly disappointing to me is that a brilliant researcher like Dr. Rajkumar recommends a one-size-fits all dosing regimen for all patients. As an example, he points out that melphalan based regimens are rarely used in the United States because of their safety profiles. However, it is known that the pharmacokinetic profile (absorption, distribution, metabolism and clearance) of melphalan varies widely between patients and yet the same dosing regimen is used for all. Perhaps by getting the dose right we could dramatically reduce toxicities. This but an example. For each grouping of patients we should not only decide which agents to use but how much of each to use and how often. This can be done and is not expensive.
I would beg the docs to give us patients a break and minimize our toxicities.
Gary, don't physicians basically individualize the dosing of myeloma drugs already? It's called "down dosing if side effects show up."
As long as the side effects aren't permanent or very serious, what's wrong with that approach?
I know you feel that dosing should be "individualized" so that the amount of drug maintained in each patient's blood is essentially the same. But how do you know that approach will result in the same efficacy or, for that matter, the same side effects?
Some people are allergic to dogs and some aren't. The same amount of a drug in one person's blood stream will cause nausea while, in another patient, it won't.
People are different, as you have said many times in the comments here, but you forget that argument when you argue that dosing should be "individualized" so that everyone gets THE SAME amount of the drug in their blood stream.
Interesting points from both of you.
In support of Gary....As a 215 pound patient, I wondered why I was induced with the standard 40mg Rev while my friend got the same 40 mg and he's only 160 pounds. I would assume I have significantly more bone marrow than he has, so my MM cells were exposed to a much lower concentration. I asked Celgene and their reply was "well, that's how the studies were done". Since I wasn't getting a great response and had no side effects, I wanted to go with a higher rate but they wouldn't do it.
In support of Cheryl...I assume they would have tried a lower dose on me if I was having bad side effects and that would have accomplished what you were suggesting. Although, I'd like to have had the option of going higher.
Dear Cheryl and Stan: Let me assure you that physicians do not individualize dosing. Instead they give everyone the same dosing and then they "titrate" patients based on what they observe. They do try to normalize dosing based on weight or body surface area but many studies have show that such correlations are frivolous.
Consider two patients taking an orally administered drug. In one case only 5% of the drug is absorbed into the blood while in the other 75% of the drug is absorbed. An example is gabapentin. It shouldn't be rocket science to figure out that the patients should be given different dose regimensd because their toxicities and efficacies will be different. Yet no attempt is made to determine this bioavailability before the drug is administered. It is only after things go wrong or nothing happens that corrective action is taken. How hard is it to get this bioavailability and predict effiacy? Only a few blood draws on a patient at a very low dose of a medicine are needed.
When I suggest this to various physicians the response is either 1)Who is going to pay for the blood draws or 2) if it was so simple we would be doing it already. How sad. We are the ones that suffer.
Thanks, Gary and Stan, for the follow-up comments.
Gary, I think we're talking passed each other. What you said doctors do is, I believe, exactly what I said doctors do. What you call "titration" is just individualizing dosing by starting patients at some standard dose, and then watching to see whether the dose needs to be adjusted based on whether or not side effects appear.
There are compelling reasons why doctors do this, particularly when it comes to anti-cancer drugs. They want to use the highest dose possible to get the highest anti-cancer effect possible. (Yes, I know that the superiority of low-dose dex calls that assumption into question, but that's a whole different debate.)
Also, you haven't answered the key question I raised earlier about the approach you are recommending, which is: Why should we believe that the best dose of a drug for everyone is the dose that achieves the SAME blood level of a drug in everyone? I may tolerate gabapentin at higher levels in my blood than you. Also, I may need more gabapentin in my blood to get the same effect that the drug has on you at a lower blood level.
To me, it seems that you're being misleading when you're saying that your approach individualizes dosing. In reality, it just standardizes dosing in a different way.
Cheryl,
Your arguments make sense at a certain level, but I also think there is something to what Gary is saying.
There have been studies looking at the kind of dose individualization that Gary describes, and the results have been very positive. Moreover, the studies have involved drugs used in the treatment of cancer.
For example, this study,
http://www.sciencedirect.com/science/article/pii/S1533002812000692
reported on a trial that compared individualized ("PK-adjusted") dosing of the cancer drug fluorouracil (5-FU) to the standard approach to choosing the drug dose, which uses a patient's body surface area (BSA). The trial was conducted with colon cancer patients.
The results are pretty impressive. Here is the summary from the article abstract:
"The objective response rate was 69.7% in the PK-adjusted arm, and median overall survival and median progression-free survival were 28 and 16 months, respectively. In the traditional patients who received BSA dosage, objective response rate was 46%, and overall survival and progression-free survival were 22 and 10 months, respectively. Grade 3/4 toxicity was 1.7% for diarrhea, 0.8% for mucositis, and 18% for neutropenia in the dose-monitored group; they were 12%, 15%, and 25%, respectively, in the BSA group."
In other words, individualizing the dose generated better efficacy with lower side effects.
Hi,
is del 13q considered a high risk chromosomal abnormality?
I am getting confused about the subject. I may be wrong but sometimes it is listed as such, some other time it is not.
(In an english study I found it listed as a favourable abnormality respect to other abnorm.)
Thanks.
Progress toward fundraising goal
for all of 2020:
15%
For more information, see the Beacon's
"2020 Fundraising: Goals And Updates" page