Day 3 of the 14th International Myeloma Workshop in Kyoto, Japan included a discussion on the management and treatment options available in patients with myeloma related renal impairment. In the afternoon, the discussion switched to consolidation and maintenance therapy and closed with a review of myeloma in Asia.

Treatment of myeloma related renal impairment

Renal impairment has been associated with poor prognosis and shorter survival in patients with multiple myeloma (MM), not only because of the advanced state of disease that causes renal impairment but also because of the limited treatment options and dose reductions commonly implemented in these patients that lead to diminished efficacy.

While it is true that renal insufficiency may increase the toxicity of various  therapies in MM, recent data suggest that novel agents such as thalidomide and bortezomib are safe and effective in patients with MM and renal failure. Bortezomib plus dexamethasone is the recommended treatment for MM patients with renal impairment of any grade. Bortezomib should be started at the standard dose of 1.3 mg/m2 on days 1,4, 8 and 11 of a 3-week cycle, and dexamethasone at a dose of 20 mg on the day of and the day after bortezomib administration. In fit patients, the addition of a third agent, such as thalidomide, cyclophosphamide or doxorubicin should be considered. For patients who are not eligible for bortezomib-based regimens, lenalidomide is a feasible and effective option for mild and moderate renal impairment. There may be a role for plasma exchange and high cut-off haemodialysis filters in MM patients who present with acute renal failure.

Carfilzomib is a selective proteasome inhibitor that, like bortezomib, primarily inhibits the chymotrypsin-like activity of the proteasome. The pharmacokinetics and safety of carfilzomib have been shown not to be influenced by the degree of baseline renal impairment, and carfilzomib is well tolerated and has demonstrated promising efficacy in this group of patients. Carfilzomib is licensed for use in the treatment of MM in the USA.

Consolidation and maintenance

Consolidation therapy is short-term and intended to further enhance the frequency and quality of response obtained with previous treatment phases. Traditionally, the most important consolidation therapy for transplant-eligible patients has been considered to be autologous stem cell transplant (ASCT), based upon the demonstrated ability of high-dose melphalan to overcome resistance to conventional chemotherapy. Induction therapy before ASCT now incorporates immunomodulatory derivatives thalidomide or lenalidomide, and the proteasome inhibitor bortezomib.

This has resulted in significant improvements in complete response (CR) rates. Recent studies have demonstrated that ASCT is complimentary to novel agents and further enhances the degree of tumour reduction. The high activity of thalidomide, lenalidomide and bortezomib has led to their investigational use as part of consolidation therapy after ASCT. In these Phase II and III studies, these novel agents have been given either alone or in combination with one another for 2-5 months. Results have shown consistent increases in CR rates, even to a molecular or immunophenotypic level, in comparison with that seen after single or double ASCT. In some studies, this response was associated with prolonged progression-free survival (PFS) and overall survival (OS) from the start of consolidation therapy.

Maintenance therapy has been extensively investigated in MM. Until recently, data were conflicting and the benefits did not seem to outweigh the risks and costs associated with maintenance. Three recent randomised trials have shown that lenalidomide maintenance was associated with prolonged PFS in MM; one showed a survival benefit. Two additional randomised trials have shown benefit of maintenance with bortezomib in terms of PFS and OS. However, in these trials it was difficult to separate the value of maintenance from the variations in induction therapy between the two arms being tested. Many questions remain in terms of whether maintenance therapy should be offered, which therapy should be given and how long it should be given for. The answers will partly depend on the patient profile, include risk. In terms of duration, recent data suggest that a minimum of 8-12 months of post-ASCT immunomodulatory therapy should be considered. In Europe, maintenance therapy is currently only available in the context of a clinical trial.

Myeloma in Asia

Myeloma incidence is lower in the Asian population compared to the Caucasian population. However, there is evidence that the rates of MM are increasing in Asia, as evidenced by recent analysis of figures for Japan, Taiwan and South Korea. Clinical studies have so far failed to identify any unique clinical or cytogenic characteristics associated with MM in the Asian population. However, high rates of del17p have been reported in China and need to be further explored.

The advent of novel therapies in the treatment of MM have significantly improved outcomes in this patient population. A recent analysis of the efficacy of novel therapies as induction regimens in Taiwan have shown significant improvements in CR versus previously used therapies. As a result melphalan-prednisone-bortezomib (MPV) or melphalan-prednisone-thalidomide (MPT) are now recommended as first-line therapies in MM patients in Taiwan.
Novel therapies have associated toxicities that could vary according to the race of the patient.

In a recent analysis of thalidomide, lenalidomide and bortezomib use in Japan, toxicity profiles were reviewed and compared to that seen in Western populations. Overall, the toxicity profiles of the three drugs were found to be similar to that reported in Western countries except for a lower incidence of venous thromboembolism with immunomodulatory therapy.

A number of Working Parties have been established in Asia, including Japan, China and South Korea. As a result, a number of clinical trials are now underway in these countries and promise to deliver valuable data on MM in Asia and lead to the improvement of treatment outcomes in this patient population.