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 ^[1] (Thalomid), Velcade ^[2] (bortezomib), and Revlimid ^[3] (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 ^[4] 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 ^[5] (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 ^[6] (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 ^[7] (Alkeran)-based combinations are treatment options for this patient population.

Three-drug combinations including melphalan ^[7] (Alkeran) and prednisone ^[8] 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 ^[9] (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 ^[10] (pdf) Dr. Rajkumar wrote to accompany his presentation, as well as the slides ^[11] (pdf) from Dr. Rajkumar’s presentation, which he has made available for download and viewing as a courtesy to The Beacon’s readers.