Velcade-Treanda-Prednisone Combo Demonstrates Efficacy And Improves Kidney Function In Relapsed And Refractory Myeloma Patients

Results from a recent retrospective analysis conducted in Germany indicate that the com­bi­na­tion of Velcade plus Treanda and pred­ni­sone is effective for re­lapsed and refractory multiple myeloma pa­tients with kidney im­pair­ment.

Specifically, 67 percent of pa­tients responded to the treatment, and kidney func­tion improved in 86 percent of pa­tients. The study investigators point out that the responses were rapid, with a median time to response of three weeks.  With a median progression-free survival of 10 months, some pa­tients experienced a long-term treatment-free interval.

Most of the severe side effects of the com­bi­na­tion were blood-related. Moderate to severe infections oc­curred in 35 percent of pa­tients, but many were due to the underlying disease.

There was, however, a noticeably higher likelihood of severe side effects among the pa­tients in the study who had the most severe kidney im­pair­ment.

In addition, comparison of the frequency of severe side effects seen in this study with those seen in a com­pa­ra­ble study involving pa­tients with normal kidney function suggests that kidney im­pair­ment increases the likelihood of severe side effects due to the Velcade+Treanda+pred­ni­sone com­bi­na­tion.

Thus, physicians may need to consider adjusting the dosing of the com­bi­na­tion regimen in pa­tients with kidney im­pair­ment.

Overall, the investigators report that the efficacy and safety of this three-drug com­bi­na­tion compare favorably to those of other three-drug com­bi­na­tions involving a novel agent, such as Velcade (bortezomib), Revlimid (lenalidomide), or thalidomide (Thalomid); a chemotherapeutic agent, such as Treanda (bendamustine), melphalan (Alkeran), doxorubicin (Adriamycin), cyclophosphamide (Cytoxan), or vincristine (Oncovin); and a steroid, such as pred­ni­sone or dexa­metha­sone (Decadron).

The investigators therefore recommend that the com­bi­na­tion therapy be investigated further in larger clinical trials.

Background

Impaired kidney function is a common and serious complication of multiple myeloma. It affects an estimated 10 percent to 40 percent of myeloma pa­tients at the time of diagnosis and 25 percent to 50 percent of pa­tients during the course of the disease.

Kidney im­pair­ment in myeloma pa­tients is often caused by excess free monoclonal light chain proteins in the blood. Light chains are part of the structure of monoclonal proteins, which are antibodies present in high concentrations in myeloma pa­tients. When light chains enter the blood stream unattached to the heavy chains, they are then referred to as free light chains and can impair kidney function.

In myeloma pa­tients, kidney im­pair­ment leads to a higher risk of complications following treatment.

Due to the limited regenerative ability of cells in the kidney, an immediate and fast-acting anti-myeloma ther­a­peutic regimen is needed to improve kidney function.

In previous studies, treatment with chemotherapy drugs and novel agents resulted in recovery of kidney function in up to 50 percent of pa­tients. Improvement of kidney function was most frequent and quickest in pa­tients treated with Velcade-based regimens.

In 2010, the International Myeloma Working Group (IMWG), a group of leading myeloma experts, published a recommendation that pa­tients with kidney im­pair­ment undergo treatment with Velcade plus dexa­metha­sone.  The IMWG also recommended the com­bi­na­tion regimen of Velcade, melphalan, and pred­ni­sone as treatment for elderly pa­tients with kidney im­pair­ment (see related Beacon news).

Treanda belongs to a class of drugs known as alkylating agents, which also includes melphalan and cyclophosphamide.  These agents work by damaging the DNA of cancer cells and causing the cells to die.

The United States Food and Drug Administration approved Treanda for the treatment of chronic lymphocytic leukemia and certain lymphomas. Although Treanda is not yet approved in the United States as a treatment for myeloma, it is approved for that use in Germany, where it is marketed under the trade name Ribomustin.

The com­bi­na­tion of Velcade plus Treanda and pred­ni­sone is currently being investigated as a potential treatment for both newly diagnosed and relapsed myeloma pa­tients.  Several studies also have investigated the efficacy and safety of Treanda, alone or in com­bi­na­tion with thalidomide and dexa­metha­sone, in pa­tients with kidney im­pair­ment.

In the current study, the investigators wanted to analyze the efficacy and safety of Velcade, Treanda, and pred­ni­sone in relapsed myeloma pa­tients with kidney im­pair­ment.

Study Design

Investigators from University Clinical Center at the University of Leipzig in Germany retrospectively analyzed data from 36 pa­tients treated at their institution from March 2005 to March 2013.

The median pa­tient age was 64 years.

The pa­tients had received a median of three prior therapies, with about half having undergone stem cell transplantation (53 percent of pa­tients).  The median time from diagnosis to the current treatment was 38 months, and the median duration of the last remission prior to the current treatment was three months; 69 percent of pa­tients were refractory to their last treatment.

Many of the pa­tients (42 percent) had previously been treated with Velcade, and about a third and a fifth of the pa­tients had been previously treated with thalidomide and Revlimid, respectively.

The pa­tients in the study were divided into two groups based on their kidney function. The first group in­cluded 20 pa­tients with moderate or severe kidney im­pair­ment; the second group included 16 pa­tients with kidney failure, 56 percent of whom were on dialysis.

All pa­tients received 60 mg/m² of Treanda during a 30-minute infusion on days 1 and 2; 100 mg of pred­ni­sone orally on days 1, 2, 4, 8, and 11; and 1.3 mg/m² of Velcade intravenously on days 1, 4, 8, and 11 of a 21-day treatment cycle.

Patients on dialysis received Treanda and Velcade 30 minutes after the end of dialysis on the designated days.

For the eight pa­tients in the study with peripheral neuropathy, the dose of Velcade was reduced to 1.0 mg/m².

The 21-day cycle was repeated up to seven times, until either a maximum response, side effects requiring a dose change, or disease progression occurred.

The median follow-up time was 22 months.

Results

Overall, 67 percent of pa­tients responded to the treatment after a median of two cycles, with 8 percent achieving a complete response, 8 percent a near-complete response, 17 percent a very good partial response, and 33 percent a partial response.

There was no significant difference in overall response rates for pa­tients with moderate to severe kidney im­pair­ment and pa­tients with kidney failure.

According to the investigators, the treatment worked quickly. The median time to response was 21 days, and the median time to maximum response was 42 days. Overall, 25 percent of pa­tients reached their maximum response after the first cycle of treatment and another 36 percent after the second cycle.

The investigators point out that response time did not seem to be dependent on kidney function, since response times and maximum response times were similar for pa­tients with kidney im­pair­ment and those with kidney failure.

Patients with moderate or severe kidney im­pair­ment had better progression-free survival and overall survival than pa­tients with kidney failure. The median progression-free survival time of the pa­tients with kidney im­pair­ment was 10 months, compared to 3 months for the pa­tients with kidney failure.  The median overall survival for pa­tients with kidney im­pair­ment was 25 months, compared to 7 months for pa­tients with kidney failure.

Altogether, 86 percent of pa­tients improved their kidney function after treatment with Velcade, Treanda, and pred­ni­sone; 31 percent of pa­tients achieved a complete kidney function response, 14 percent a partial kidney function response, and 42 percent a minor kidney function response.

The median time to first improvement in kidney function was 21 days, and the median time to maximum kidney improvement was 42 days, which corresponded to how long it took for the myeloma to respond to treatment. Forty-four percent of the nine dialysis-dependent pa­tients became dialysis-independent, and an additional 33 percent achieved minor responses with occasional dialysis independence.

Treatment continued until maximum response in 44 percent of pa­tients.

Fourteen percent of pa­tients discontinued treatment after the second cycle to receive autologous stem cell transplants. All of these transplants were completed successfully.

Forty-two percent of pa­tients ended treatment prematurely, including 11 percent due to primary disease progression, 17 percent due to secondary progression after a short response, and 8 percent due to preexisting low blood cell counts or low platelet counts during treatment. Another 6 percent of pa­tients died during treatment after infections associated with severe preexisting neutropenia.

According to the investigators, the com­bi­na­tion of Velcade, Treanda, and pred­ni­sone was well-tolerated.  However, 89 percent of pa­tients experienced severe to life-threatening side effects. The most common of these severe side effects were low platelet counts (81 percent), low leukocyte counts (61 percent), anemia (56 percent), and low neutrophil counts (50 percent). Additionally, moderate to severe infections occurred in 35 percent of all pa­tients.

Side effects were noticeably more common in the pa­tients with kidney failure, suggesting that physicians may need to consider adjusting the dosing of the com­bi­na­tion regimen in pa­tients with kidney failure.

The investigators note that the frequency of severe side effects in this study was similar to what has been previously reported for pa­tients with normal kidney function treated with Velcade-Treanda com­bi­na­tion regimens.

However, it is not entirely clear that this is the case.  Instead, it appears that the pa­tients in this study were more likely to experience severe blood count-related side effects than those in a comparable study involving the same treatment regimen, but in pa­tients with normal kidney function (abstract).

For example, there was a higher frequency of severe low platelet counts (81 percent versus 62 percent), low leukocyte counts (61 percent versus 50 percent), and anemia (56 percent versus 23 percent) in the current study compared to the study testing Velcade+Treanda+pred­ni­sone in pa­tients with normal kidney function.

Thus, although the Velcade, Treanda, and pred­ni­sone com­bi­na­tion appears to be effective in relapsed myeloma pa­tients with kidney im­pair­ment, it also appears that physicians will need to consider carefully the dosing of the regimen in such pa­tients.

For more information, please refer to the study in the Journal of Cancer Research and Clinical Oncology (abstract).