Findings from a prospective Phase 2 clinical trial indicate that the com­bi­na­tion of Revlimid, Velcade, and dexamethasone is effective in relapsed and refractory multiple myeloma patients.

The trial enrolled 64 patients, who had been treated with a median of two prior therapies, at six different U.S. cancer centers from 2006 to 2008.

Nearly two-thirds of the patients in the trial achieved at least a partial re­sponse, despite the fact that more than half of the patients had previous­ly been treated with Velcade ^[1] (bortezomib), and nearly three quarters had previously been treated with thalidomide ^[2] (Thal­o­mid), a drug chem­i­cal­ly similar to Revlimid.

The median progression-free survival was 10 months after the start of treatment. The median overall sur­vival was 30 months from the start of treatment, and, at a median follow-up time of almost four years, 34 percent of patients were still alive.

The investigators note that the efficacy of the Revlimid ^[3] (lenalidomide)-Velcade-dexamethasone ^[4] (Decadron) combination appears to be lower than that of the three-drug combination of Kyprolis ^[5] (carfilzomib), a newly approved drug in the same class of drugs as Velcade, combined with Revlimid and dexamethasone.

In a trial of the Kyprolis-Revlimid-dexamethasone combination involving patients similar to those in the current study, 77 percent of patients responded to treatment, and the median progression-free survival was 15 months (see related Beacon ^[6] news).

However, the investigators point out that, in the current trial, the doses for Velcade and Revlimid were lower than the standard doses for both drugs, and that higher activity might be achieved if the Velcade and Revli­mid in the combination therapy were used at standard doses.

Patients in the trial were treated for a median of eight months, suggesting that the combination therapy was well tolerated. According to the researchers, the majority of side effects were mild to moderate in nature, and only 3 percent of patients experienced severe peripheral neuropathy (pain, tingling, or numbness in the extremities). The investigators note that Velcade was administered intravenously during the trial, and the use of subcutaneous (under-the-skin) Velcade might further lower the rate of peripheral neuropathy associated with the regimen.

One issue that could bear on the clinical relevance of the current study's results is that many patients in the U.S. already are treated with a combination of Revlimid, Velcade, and dexamethasone as frontline therapy -- a fact which could impact the combination's attractiveness as a treatment for relapsed/refractory patients.

In this regard, the researchers note that the results of their study support the use of the three-drug combination even in patients previously exposed to one or more of the drugs included in the combination.

Based on their findings, the investigators believe there is further potential for the development of the Rev­li­mid, Velcade, and dexamethasone combination.

Background

Although multiple myeloma remains a typically incurable disease, significant advances have been made in its treat­ment since the introduction of the novel agents thalidomide, Revlimid, and Velcade, and more recently Kyprolis and Pomalyst ^[7] (pomalidomide, Imnovid).

Previous research has shown that three-drug combinations involving the novel agents are generally more effective than two-drug combinations.

In addition, the three-drug combination of Revlimid, Velcade, and dexamethasone – commonly referred to as RVD or VRD – has been shown to be particularly effective in controlling mye­lo­ma.

For instance, a Phase 1/2 study of RVD as initial ther­a­py for newly diagnosed myeloma patients found that all patients responded to the treat­ment (see related Beacon ^[8] news).

In addition, results from a retrospective study showed that a majority of patients with advanced myeloma respond to RVD ther­a­py (see related Beacon ^[9] news).

Researchers therefore designed a prospective Phase 2 trial to assess the safety and efficacy of RVD in relapsed and refractory myeloma patients

Study Design

The Phase 2 trial included 64 relapsed and refractory myeloma patients who were recruited at six treatment centers across the United States between September 2006 and April 2008.

The median patient age was 65 years old.

The median time from diagnosis was 35 months. Patients had received a median of two prior therapies. Many of the patients had previously received thalidomide (75 percent), Velcade (53 percent), or Revlimid (6 percent); 8 percent of patients were resistant (refractory) to prior Velcade, and 3 percent were refractory to prior Revlimid.

In addition, a number of the patients had chromosomal abnormalities as determined by fluorescence in situ hybridization (FISH), including del(13/13q) (36 percent), del(17p) (13 percent), and t(4;14) (6 percent).

Patients received up to eight 21-day treatment cycles of 15 mg of Revlimid per day on days 1 to 14 of a 21-day treatment cycle, along with 1.0 mg/m² of Velcade on days 1, 4, 8 and 11.

Initially, the dexamethasone dosing was 40 mg (first four cycles) or 20 mg (cycles 5-8) on the days of, and after, Velcade dosing.  As the trial progressed, however, this dosing was reduced to 20 mg (first four cycles) and 10 mg (cycles 5-8).

Patients who achieved stable disease or better after eight treatment cycles could continue with maintenance therapy until disease progression or unacceptable toxicity. Maintenance therapy consisted of Velcade and Revlimid at doses tolerated at the end of cycle 8, plus 10 mg of dexamethasone on days 1, 2, 8, and 9. Rev­limid was administered on days 1 to 14 and Velcade on days 1 and 8.

The median follow-time was 44 months.

Study Results

The researchers reported that 66 percent of patients completed at least eight cycles of therapy with all three drugs, and 55 percent of patients continued into the maintenance phase of the trial.

Overall, 64 percent responded to treatment, with 11 percent achieving a complete response, 14 percent a near complete response, 3 percent a very good response, and 36 percent a partial response.

The researchers found there were no significant differences in overall response rates based on whether the patients were relapsed (62 percent), relapsed and refractory (67 percent), or had chromosomal ab­nor­mal­i­ties (66 percent). Prior Velcade exposure also did not seem to affect response.

The median time to best response was 2.3 months; the median duration of response was nine months; and patients received a median of 11 cycles of treatment.

The median progression-free survival was 10 months, and the median overall survival was 30 months, from the start of treatment with the combination regimen.

Given that participants in the trial had a median time since diagnosis of 35 months, these results indicate that participants had a median overall survival -- from time of diagnosis -- of 5.4 years (65 months).  In interpreting this outcome, however, it is important to bear in mind that enrollment in the study took place about seven years ago.

The only patient characteristic that was found to have an independent impact on response to treatment was having a low hemoglobin level (less than 12 g/dL) at the beginning of treatment.

Other variables, including having elevated lactate dehydrogenase (LDH) levels and the presence of chro­mo­somal abnormality del(13/13q) at the start of treatment, appeared at first glance to be associated with a lower likelihood of response.

But further analysis, taking into account the variety of factors that can affect response, found that these variables did not have an independent impact on response.

A low hemoglobin level also was the only patient characteristic to have a statistically independent impact on overall survival.

According to the investigators, RVD had an acceptable safety profile in this patient population, especially given that many of the patients had more than one prior line of therapy.

The most common side effects of any grade included sensory neuropathy (53 percent), fatigue (53 percent), low white blood cell counts (42 percent), and diarrhea (41 percent).

Overall, 66 percent of patients required dose modifications, and 8 percent of the patients discontinued RVD due to side effects.

For more information, please see the study by Richardson, P. et al., “A phase II trial of lenalidomide, bortezomib and dex­a­methasone in patients with relapsed and relapsed/refractory myeloma,”Blood, March 18, 2014 (preview online) (abstract ^[10]).