Treatment of multiple myeloma

Multiple myeloma is a malignant disease of plasma cells that is characterised by secretion of paraprotein, humoral immunodeficiency, anaemia, lytic bone lesions, and kidney dysfunction. Although the median survival of patients with multiple myeloma has improved from seven months to five years with treatment, the disease remains largely incurable.¹

Conventional treatment includes melphalan and prednisone, now used sparingly because of its propensity to compromise collection of haematopoietic stem cells, other combinations, and regimens containing high dose corticosteroids. The latter—including dexamethasone; vincristine, doxorubicin, and dexamethasone; and cyclophosphamide, vincristine, doxorubicin, and methylprednisolone—are preferred for induction because of their excellent anti-myeloma activity and lack of marrow toxicity.

High dose chemotherapy, particularly melphalan, with autologous haematopoietic stem cell transplantation improves response rates and their duration and survival compared with conventional chemotherapy. It is now commonly used as consolidation treatment.¹ The superiority of consolidation with haematopoietic stem cell transplantation over continued conventional treatment has been confirmed in two randomised studies with a 12 month increase in median overall survival.²,³ Another study has shown that the overall survival of patients who received haematopoietic stem cell transplants after relapse was comparable to those who received transplants immediately after induction; this implies that high dose therapy is beneficial even when used later in the course of the disease.⁴

The benefit of haematopoietic stem cell transplantation extends to individuals in their 70s and patients with renal failure—patients usually excluded from high dose chemotherapy regimens.¹ Interestingly, unlike other haematological malignancies where an autograft is usually performed in remission, most patients with multiple myeloma achieving complete remission do so after transplantation, and refractoriness to induction treatment does not necessarily indicate a poor prognosis after transplantation.⁵

Unfortunately, even after haematopoietic stem cell transplantation, relapse is only a matter of time, although a minority of patients seems to survive over a decade in remission (“operational cure”). Maintenance treatment after transplantation with corticosteroids or α interferon is often prescribed to delay relapse. Although this probably does prolong the duration of remission, it is unclear if it confers a survival benefit. Augmentation of immune responses to the disease with dendritic cells and idiotype vaccination is also being evaluated.

Two sequential autologous transplants (tandem transplantation) have been used in an attempt to improve response rates and survival.⁶ Evidence to support this practice is, however, insufficient because the only study showing benefit for two transplants over one⁷ is handicapped by the use of a conditioning regimen known to be associated with inferior outcome.⁸ With around 5000 patients being autografted for multiple myeloma in the United States each year, routine tandem transplantation could increase healthcare costs by $300-600m (£190-380; €270-540). Perhaps ongoing European trials will settle this contentious issue. A second transplant is a possible option for disease relapsing after one transplant and may yield a result that is comparable to tandem transplantation.

Allogeneic haematopoietic stem cell transplantation cures a proportion of patients through immunologically mediated graft versus myeloma effect.⁹ High mortality related to treatment has been a problem historically, but the use of safer preparative regimens of reduced intensity could improve long term results.

Bisphosphonates are given routinely to all patients with multiple myeloma to improve bone density and reduce skeletal complications. These drugs are also thought to possess some anti-myeloma activity through effects on the immune system and the marrow microenvironment. Other important measures for supportive care include treatment of anaemia with erythropoietin, adequate control of pain, and prophylaxis of opportunistic infections, particularly varicella zoster.

New options for salvage treatment may narrow the gap, if one exists, between single and tandem autotransplantation. The discovery of the activity of thalidomide in multiple myeloma¹⁰ has led to studies of other agents that target both the tumour cells and the marrow microenvironment.¹¹ Thalidomide is effective in about a third of patients with advanced disease and is synergistic with other agents active in multiple myeloma. Its exact mechanism of action is unclear, but inhibition of angiogenesis, modulation of cytokines, and immunological effects are probably involved. Thalidomide, singly and in combination, is now standard treatment for relapsed or refractory myeloma and is also being used as frontline and maintenance treatment.¹¹ Newer derivatives of thalidomide, such as CC5013, have greater biological activity and fewer adverse effects, including teratogenicity. Preliminary studies show a response in 30-50% of patients with refractory disease.¹¹

Bortezomib inhibits the proteasome, an intracellular organelle responsible for protein disposal. The response rate to bortezomib in extensively treated myeloma is around 50%.¹² The drug has recently been approved by the US Food and Drug Administration in record time on the basis of these encouraging phase II results.

The ongoing work sets the stage for interesting and welcome developments in the treatment of myeloma over the next few years. Many new agents will undoubtedly be used alone and in combination, and for salvage treatment as well as for induction—challenging current standards of care. Better understanding of the genetic makeup of myeloma cells and its correlation with treatment outcome will enable customisation of treatment for individual patients. The result, one hopes, will be a cure for some, if not most, patients with multiple myeloma within the foreseeable future.