Multiple myeloma (also known as myeloma or plasma cell myeloma) is a type of bone marrow cancer. Plasma cells found in the bone marrow divide uncontrollably and form tumours that can destroy bones (leading to bone pain) and damage the kidneys. In addition, there is an increased risk of infection as the cancerous plasma cells overcrowd healthy plasma cells preventing the normal production of blood cells, and therefore antibodies, required for immunity.
Multiple myeloma is a disease of the elderly, with the median age at diagnosis of 69 years, and it is more common in men than women. While it is a relatively rare cancer, it is one of the more common haematological malignancies and the economic costs associated with multiple myeloma are among the highest.
Treatment is complex and therapy choices depend on patient age, severity of symptoms and whether or not he will undergo stem cell transplantation. Treatment modalities include chemotherapy and immunosuppression, transplantation, radiation therapy, and adjunct therapies (eg bisphosphonates for bone complications or surgery to treat or prevent bone fractures).
While significant developments have been made in the treatment of multiple myeloma during the past 10 years, the disease remains incurable. But with the approval within the past year of two new drugs (pomalidomide and carfilzomib) and several novel agents at phase III development, it appears that drug development for multiple myeloma continues to gain momentum.
Immunomodulatory agents
Immunomodulatory drugs inhibit key factors in the immune system responsible for immune reactions (eg tumour necrosis factor) and also have antiangiogenic effects.
Thalidomide (Thalomid; Celgene Corporation) was the first immunomodulatory agent used in multiple myeloma and is an effective first-line therapy when given in combination with dexamethasone (a corticosteroid).
Thalidomide is an old drug with a widely publicised dark past. But the first reports of the potential efficacy of thalidomide in patients with multiple myeloma were published in 1999. From then onwards, a revolution in the treatment armamentarium of multiple myeloma began as thalidomide and its analogues emerged as promising agents.
The thalidomide analogue lenalidomide (Revlimid; Celgene Corporation) is already marketed as a second-line therapy for multiple myeloma. Another thalidomide analogue, pomalidomide (Pomalyst; Celgene Corporation), was approved in early 2013 by the US Food and Drug Administration (FDA) as a second-line therapy, in combination with low-dose dexamethasone, in multiple myeloma patients who experienced disease progression despite at least two prior therapies (including lenalidomide and bortezomib).
Pomalidomide is available in the US only through the Pomalyst Risk Evaluation and Mitigation Strategy (REMS) programme because, like thalidomide and lenalidomide, it can cause severe life-threatening birth defects. It also carries a black-box warning because it can cause blood clots. Approval of pomalidomide was based on response rate. Further evidence of its efficacy in this patient population has recently been reported, showing that pomalidomide significantly improved progression free survival (PFS; 15.7 vs 8 weeks) and overall survival (OS) when given in combination with low-dose dexamethasone versus in combination with high-dose dexamethasone. Celgene is awaiting approval from the European Medicines Agency (EMA), which is expected during the second half of 2013.
Development over the past decade of novel therapeutic strategies (eg immunomodulatory agents) may have helped improve response rates, but they have also added to the cost of treatment given that they are used additively with standard therapies and do not entirely replace older treatment modalities.
Lenalidomide was originally approved in 2005 as a second-line therapy for multiple myeloma; a subsequent application in 2010 to the EMA’s Committee for Medicinal Products (CHMP) for extension of the label to first-line therapy and maintenance therapy was withdrawn in June 2012 at the request of the CHMP due to a lack of ‘mature data’. This is likely because the CHMP would be most interested in demonstration of a survival benefit before approval or reimbursement would be considered. However, it appears that using lenalidomide earlier in the disease course remains a priority as it is already used off-label as a first-line therapy, and Celgene plans to apply in 2013 for regulatory approval in the US for use on patients with newly-diagnosed multiple myeloma.
Chemotherapy: Proteasome inhibitors
There are currently two approved proteasome inhibitors – bortezomib (Velcade, Millennium Pharmaceuticals) and carfilzomib (Kyprolis, Ono Pharmaceutical) – both of which are administered intravenously. Proteasome inhibitors are chemotherapeutic agents that induce cancer cell death by inhibiting the proteasome enzyme complex involved in cell cycle control and growth.
A third proteasome inhibitor that recently entered phase III development is Millennium Pharmaceuticals’ ixazomib (MLN9708), which is the first proteasome inhibitor to be administered orally for multiple myeloma. Ixazomib is being investigated in a phase III trial in combination with dexamethasone and lenalidomide versus placebo plus dexamethasone and lenalidomide in patients with relapsed and/or refractory multiple myeloma.
The primary endpoint is PFS, and trial completion is expected in 2019. Ixazomib is also under investigation in a phase I/II trial as a first-line therapy (in combination with lenalidomide and low-dose dexamethasone) in patients with newly-diagnosed multiple myeloma.
HDAC inhibitors
Histone deacetylase (HDAC) inhibitors act by disrupting a key mechanism in the transformation of normal cells to cancerous cells: epigenetic modulation of tumour suppressor genes. Their use leads to cell death. Two HDAC inhibitors have reached phase III development: vorinostat (Zolinza, Merck) and panobinostat (Novartis).
A global phase III trial, called Vantage 088, was initiated in November 2008, which assessed vorinostat in combination with bortezomib in 637 patients with relapsed/refractory multiple myeloma who had experienced disease progression after receiving between 1-3 prior therapies. Final results from this trial demonstrated that vorinostat plus bortezomib significantly improved the duration of PFS (primary endpoint; relative risk reduction of 23 per cent), compared with standard bortezomib therapy.
Panobinostat appears to be closer than vorinostat to approval for multiple myeloma as Novartis has formally announced plans to file this year. A phase II trial of panobinostat plus bortezomib and dexamethasone in bortezomib-refractory patients with relapsed and refractory MM (PANORAMA II), and a placebo-controlled phase III trial of the same combination in patients with relapsed MM (PANORAMA I), are both expected to be completed by mid-2013. The use of panobinostat in other combinations will also be tested in phase I/II trials including: panobinostat plus bortezomib, lenalidomide and dexamethasone in transplanteligible patients with newly-diagnosed MM; panobinostat plus carfilzomib in patients with relapsed/refractory multiple myeloma; and panobinostat plus bortezomib, cyclophosphamide and dexamethasone in treatment-naïve patients with MM.
Other anti-cancer agents
Plitidepsin (Aplidin; PharmaMar) induces cell death through various cellular pathways. A two-stage, pivotal phase III trial (ADMYRE) of plitidepsin in combination with dexamethasone versus dexamethasone alone in patients with relapsed/refractory MM is underway in the US, Europe and Australia. PharmaMar received approval from the Independent Data Monitoring Committee (IDMC) in December 2012 to progress the trial to stage II, after analysis of stage I data in 60 patients indicated the study comfortably met the established efficacy threshold. Completion of the ADMYRE trial is expected in June 2014.
Perifosine is a small-molecule, signal transduction pathway inhibitor being developed as an oral anticancer agent by AEterna Zentaris. A phase III trial investigating the efficacy and safety of perifosine in combination with bortezomib and dexamethasone in patients with relapsed/refractory multiple myeloma is underway in several countries including the US, Canada and some eastern European countries. A pre-planned interim analysis is expected to be carried out during the first quarter of 2013, and study completion is planned in the third quarter of 2014.
Targeted therapy
Elotuzumab (Bristol-Myers Squibb [BMS], AbbVie [formerly Abbott Laboratories]) is a humanised monoclonal antibody that binds to the cell surface glycoprotein CS1.
This cell surface protein is found mainly on myeloma cells and not on normal bone marrow cells, which means it enhances immune cell mediated killing specifically of cancerous myeloma cells while sparing healthy cells.
Two pivotal, global phase III trials of elotuzumab are currently underway, which are designed to assess the antibody in combination with lenalidomide and low-dose dexamethasone in different multiple myeloma patient populations. The first of these (ELOQUENT-1) is assessing the combination regimen in patients with previously untreated disease, and the second trial (ELOQUENT-2) involves patients with relapsed/ refractory disease who have received 1-3 prior therapies.
Changing the treatment paradigm
The introduction of thalidomide, bortezomib and lenalidomide changed the treatment paradigm of multiple myeloma, and considerable progress has been made since then to discover new therapies, resulting in several promising agents in the late-stage pipeline. If a clear clinical advantage can be demonstrated (survival benefit), the additional costs of using such agents may be considered worthwhile.
In addition, the earlier clinical development landscape is active, with at least ten novel agents at phase II. And while multiple myelomaremains an incurable disease, it is particularly important to offer hope to patients to prolong their survival and quality of life through the development of novel treatments and treatment combinations.