Results of a small Phase 2 study may lead to improved outcomes for newly diagnosed patients who are unable to achieve a deep response with a Revlimid- or thalidomide-based initial therapy.

The study indicates that follow-on treatment with a Velcade-based regimen can noticeably deepen responses in these patients.

“We were certainly pleased to see that we were able to confirm our hypothesis that offering Velcade-containing, non-cross-resistant combinations to patients whose response had stalled after [Revlimid- or thalidomide-] based therapy can improve the depth of response,” said the study’s lead investigator, Dr. Ruben Niesvizky from the Weill Cornell Medical College in New York City.

The researchers also found that the addition of Velcade (bortezomib) to high-dose cyclophosphamide (Cytoxan) and Neupogen (filgrastim) for stem cell mobilization significantly increased the stem cell yield.

"We were very much surprised to find that this novel combination can significantly enhance the amount of stem cells obtained at the time of stem cell harvest," Dr. Niesvizky told The Beacon.

Based on their findings, Dr. Niesvizky and his colleagues conclude that it may be useful to identify patients early who have a limited response to initial therapy so that they can be switched to a different regimen with the goal of improving their responses prior to stem cell transplantation.

Furthermore, they believe these findings warrant further evaluation of the effect of Velcade on stem cell mobilization.

The new study raises an important question that will need to be addressed in subsequent research, namely: For newly diagnosed myeloma patients, does a sequential approach to treatment, like the one explored in the current study, lead to better outcomes compared to a single initial treatment regimen involving three or four drugs, such as Revlimid (lenalidomide) combined with Velcade and dexamethasone (Decadron).

Background

For most newly diagnosed myeloma patients, initial treatment consists of a combination regimen involving several anti-myeloma therapies.  The combination regimen usually includes one or more novel myeloma therapies, together with either dexamethasone or prednisone

The introduction of novel myeloma therapies – such as Velcade, Revlimid, and thalidomide – over the course of the past decade has significantly improved treatment outcomes for newly diagnosed patients.

However, not all patients reach the desired very good partial response or better after receiving initial therapy.

This is important because research has shown that reaching at least a very good partial response after initial therapy is associated with improved outcomes, including longer progression-free survival and overall survival.

Prior research also has shown that treating myeloma patients with a sequence of different initial therapies may increase the proportion of patients who reach a very good partial response.

Since Velcade and the immunomodulatory agents Revlimid and thalidomide work differently, the authors of the current study felt that sequential use of these two drug categories might increase the share of patients who achieve a deep response.

Study Design

In the current study, researchers from Weill Cornell Medical College in New York evaluated the efficacy and tolerability of a Velcade-based regimen for myeloma patients who had relapsed after, or who had only achieved a partial response to, previous Revlimid- or thalidomide-based therapies.

The treatment regimen included initial therapy with a Velcade-based regimen followed, in most cases, by stem cell mobilization with a regimen that also included Velcade.  Most of the patients in the study then went on to receive high-dose chemotherapy followed by a stem cell transplant.

Velcade was added to the stem cell mobilization therapy to further lower the tumor burden before stem cell transplantation.

Between July 2005 and April 2011, 38 myeloma patients with a median age of 61 years were enrolled in the study.

Eighteen percent of the patients had high-risk chromosomal abnormalities.

About 70 percent of the patients had achieved a partial response to their initial therapy before entering the trial.  The remaining patients had stable disease.

All patients received up to six 21-day treatment cycles consisting of 1.3 mg/m² of Velcade on days 1, 4, 8, and 11 and 40 mg of dexamethasone on days 1 to 4, 8 to 11, and 15 to 18.

Patients who did not reach a partial response or better by the second cycle, or a very good partial response or better by the fourth cycle, received 30 mg/m² of Doxil (doxorubicin liposomal) on day 4 for all remaining cycles.

For stem cell mobilization, a majority of patients received, immediately following initial therapy, one cycle of 1.3 mg/m² of Velcade on days 1, 4, 8, and 11 plus 3 g/m² of high-dose cyclophoshamide on day 8 as well as 10 µg/kg of Neupogen per day for 10 consecutive days, starting on day 9.

The target number of stem cells for collection was 10 million cells per kilogram of body weight, a recommendation set by the International Myeloma Working Group for myeloma patients who plan to undergo two stem cell transplants.

Overall, 74 percent of patients received Doxil during initial therapy, including 42 percent who started during cycle three, and 32 percent who started during cycle five.

Study Results

The researchers found that 61 percent of patients responded to the follow-on Velcade-based therapy, including 18 percent who achieved a complete response, 21 percent who reached a very good partial response, and 21 percent who achieved a partial response.

All response classifications are based on comparisons of a patient's protein levels during and after the follow-on therapy to the patient's protein level just prior to starting the follow-on therapy.

All but one of the patients in the study went on to have stem cells harvested after the follow-on therapy.

Of the patients who had their stem cells harvested, 71 percent underwent stem cell mobilization with a combination of Velcade, cyclophosphamide, and Neupogen.  The remaining patients received either cyclophosphamide plus Neupogen, or Neupogen alone, as their mobilization regimen.

Of the patients who underwent stem cell mobilization with Velcade, 37 percent achieved a deeper response after mobilization. The overall response rate achieved in these patients was 96 percent, including 15 percent who achieved a stringent complete response, 11 percent a complete response, 22 percent a very good partial response, and 48 percent a partial response.

In comparison, the overall response rate in patients who did not have Velcade in their stem cell mobilization regimen was only 40 percent.

Again, these response rates are based on comparisons of a patient's protein levels after stem cell mobilization with those that were measured before the start of the Velcade-based follow-on therapy at the beginning of the study.

The addition of Velcade to the stem cell mobilization regimen had a positive effect on stem cell yields. Patients who underwent Velcade-based mobilization collected a median of 23 million cells per kilogram of body weight within a median of one day, substantially exceeding the study goal.

In comparison, patients who underwent mobilization without the addition of Velcade collected a median of 10 million cells per kilogram of body weight in a median of one day.

After stem cell mobilization, 89 percent of the patients went on to have a stem cell transplant.

After a median follow-up of 47 months, the median progression-free survival time for all of the patients included in the study was 47 months, and the five-year overall survival rate was 76 percent.

According to the researchers, the Velcade-based follow-on therapy was well tolerated and the side effects were consistent with those previously reported for this regimen.

The most common severe side effects during the follow-on therapy included low platelet counts (13 percent), hand-foot syndrome (redness, swelling, and pain on the palms of the hands and soles of the feet ) (11 percent), peripheral neuropathy (pain and tingling in the extremities due to nerve damage) (8 percent), and low white blood cell counts (5 percent).

For more information, please see the study in Clinical Cancer Research (abstract).