Results of a recent Spanish study suggest that elderly multiple myeloma patients who receive Velcade plus thalidomide or Velcade plus pred­nisone as maintenance therapy achieve deeper responses following initial therapy with Velcade-based treatment regimens.

In addition, elderly myeloma patients who receive Velcade plus thalido­mide as maintenance therapy may achieve better treatment outcomes and longer survival rates than patients who receive Velcade plus pred­nisone as maintenance therapy.

“In our trial, VT [Velcade plus thalidomide] was slightly superior to VP [Velcade plus prednisone] in response rate and outcome, but the dif­ferences didn't reach statistical significance,” said Dr. María-Victoria Mateos from the Hospital Universitario in Salamanca, Spain, and lead investigator of the study. “By contrast, VT was more toxic than VP, especially in terms of peripheral neuropathy, leading to more discontinuations.”

“One attractive approach is to try to optimize this scheme, replacing thalidomide with lenalidomide [Revlimid], an immunomodulatory agent more potent and less toxic than thalidomide,” added Dr. Mateos.

“Indeed, there is a certain advantage for Velcade plus thalidomide, and in the case of maintenance [therapy], that option appears somewhat better than Velcade plus prednisone,” said Dr. Ruben Niesvizky of Weill Cornell Medical College in New York, who was not involved in the study.

However, Dr. Niesvizky added that the differences between the two types of maintenance therapy in the study were not statistically significant.

“The important question is how Velcade plus thalidomide or Velcade plus prednisone would compare to placebo or no maintenance [therapy] at all,” he commented.

Dr. Mateos further clarified, “Although this approach is attractive, this strategy should be restricted at the present time to patients enrolled into clinical trials. There are numerous planned and ongoing trials addressing different questions about the optimal regimen and dose.”

The combination regimen of melphalan ^[1] (Alkeran) and prednisone ^[2] – abbreviated as MP – had been a standard initial treatment for elderly patients with multiple myeloma for many years.

In recent years, however, researchers have sought to investigate new combinations for the treatment of elderly myeloma patients that may be more effective than the MP regimen.

Researchers have found that adding one or more of the novel agents – Velcade ^[3] (bortezomib), Revlimid ^[4] (lenalidomide), or thalidomide ^[5] (Thalomid) – to the combination increases response rates and improves survival.

Additionally, research has shown that maintenance therapies following initial treatment enhance treatment outcomes compared to MP alone.

Results of a previous study, for instance, showed that the combination regimen of Velcade, melphalan, prednisone, and thalidomide – abbreviated as VMPT – followed by a maintenance regimen of Velcade plus thalidomide produced superior response rates compared to VMP treatment without maintenance therapy (see related Beacon ^[6] news).

Results of another study indicated that the combination regimen of Velcade, thalidomide, and prednisone – abbreviated as VTP – is as effective as VMP, and that maintenance therapy with Velcade plus thalidomide or prednisone further enhanced response rates in elderly myeloma patients (see related Beacon ^[7] news).

Velcade has also been shown to increase response rates when used alone as maintenance therapy following initial treatment with three different Velcade-based regimens in elderly myeloma patients (see related Beacon ^[8] news).

“In elderly patients, we piloted a weekly Velcade schedule and it was successful after any initial therapy (Velcade-dexamethasone ^[9] (Decadron), Velcade-thalidomide-dexamethasone, or VMP),” said Dr. Niesvizky, the lead investigator of the study on single-agent Velcade as maintenance therapy.

In the current study, researchers sought to determine whether a maintenance regimen consisting of Velcade plus thalidomide (VT) or Velcade plus prednisone (VP) would improve treatment outcomes in elderly myeloma patients following initial therapy with VMP or VTP.

The study included 260 elderly, newly diagnosed myeloma patients, who were enrolled beginning in 2005.

All patients received six cycles of initial therapy with either the VMP or VTP combination regimen. The combined overall response rate after initial therapy was 24 percent.

Among these patients, 178 were then randomly assigned to receive maintenance therapy with either VT or VP.  All patients were at least 65 years of age, and the median ages of the two groups were 71 years and 72 years, respectively.

After a median follow-up of 38 months, the researchers found that maintenance therapy improved the complete response rate to 42 percent.  Patients experienced the improved response within a median of three months.

However, patients who received maintenance therapy with VT achieved a higher complete response rate than patients who received VP (46 percent versus 39 percent).

Patients who received VT also had a longer median progression-free survival than patients who received VP (39 months versus 32 months).

Moreover, the five-year overall survival rate was also higher for patients who received VT than patients who received VP (69 percent versus 50 percent).

The differences between the response rates, progression-free survival, and overall survival for the VT and VP maintenance groups were not statistically different.  Likewise, improvement in response, progression-free survival, and overall survival were not affected by the type of initial therapy the patients received prior to maintenance therapy.

However, the researchers found that the achievement of a complete response or improvement in depth of response during the maintenance phase was associated with significantly improved progression-free survival and overall survival.

According to the study investigators, though, the maintenance regimens were unable to overcome the adverse effects of chromosomal abnormalities in the patient population.

Patients with high-risk chromosomal abnormalities had significantly shorter progression-free survival (28 months for VT and 27 months for VP) compared to standard-risk patients (47 months for VT and 36 months for VP).

The four-year overall survival was also shorter for high-risk patients (55 percent for VT and 53 percent for VP) compared to standard-risk patients (79 percent for VT and 69 percent for VP).

“Although it is well known that the introduction of novel agents in the treatment of elderly myeloma patients improves the outcome of patients with high-risk cytogenetic [chromosomal] abnormalities as compared with the old therapies, these novel strategies are not able to overcome the poor prognosis,” said Dr. Mateos.

Severe side effects were more common among patients receiving VT maintenance (17 percent of patients) compared to VP maintenance (5 percent).

In particular, 9 percent of patients who received VT and 3 percent of patients who received VP developed severe cases of peripheral neuropathy, a condition characterized by pain, tingling, or loss of sensation in the hands and feet and a common side effect of both Velcade and thalidomide.  In addition, 2 percent of patients receiving VT maintenance experienced serious heart-related side effects.

“The field is moving to use maintenance therapy in [elderly myeloma] patients, but we need more controlled data to confirm the use of Velcade maintenance,” Dr. Niesvizky told The Beacon.

For more information, please see the article in the journal Blood ^[10] (abstract).