Advances in Multiple Myeloma

 In Cancer

Five decades ago, multiple myeloma (MM) was an enigmatic disease characterised by plasma cell infiltration in the bone marrow and presence of monoclonal proteins in the serum. The most unique features of MM are the destruction of bones of the skeleton and the resultant pain it causes. No effective systemic therapy existed, and it was felt back then that MM was a terminal disease and the aim of treatment was essentially palliative. Steroids had remained the mainstay of treatment.

Despite the progressive introduction of various chemotherapeutic agents since the 1970s, MM has remained largely incurable unlike other haematological malignancies like lymphoma or leukaemia, and the median survival of patients had remained stagnant at about three years from diagnosis for almost three decades, as depicted in a study from the Mayo clinic [Figure 1]. 

Figure 1. Overall survival from diagnosis of MM at the mayo clinic

Figure 1. Overall survival from diagnosis of MM at the mayo clinic

Even with more complex chemotherapy regimens, a complete remission in MM was rare and the treatment goal was the attainment of a ‘plateau phase’ in the disease. When it was later found that patients could tolerate higher doses of conventional chemotherapy with the support of stem cell transplantation, this modality became the standard of care for younger patients.

This technique however, could only accord, on the average, one to two more years of survival at the price of significant toxic side effects. Needless to say, this excluded a large proportion of elderly patients who actually forms the majority of patients suffering from MM.

Advances in Diagnostics

At the turn of the century, rapid progress in our understanding of the pathobiology of the disease has led to both improvement in diagnostic techniques, as well as options and outcomes. The advances in diagnostic methods have included immunofixation to identify low level presence and type of clonal paraprotein, to measurement of serum free light chains to evaluate the disease activity, especially in patients with oligo or non-secretory disease, and to define stringent complete remission.

Although skeletal survey by plain X-rays remains a standard investigative procedure, since the 1990s MRI has been a sensitive method to evaluate both bone lesions and marrow involvement. The advent of positron-emission tomography (PET) scan now allows detection of residual and occult extramedullary involvement by MM.

The traditional quantitation of MM cell in bone marrow was also supplemented with cytogenetics in the 1980s, fluoroscence in-situ hybridisation examination in the 1990s, and multicolour immunoflourescence analysis in the 2000s.

With additional genetic tests, we begin to see MM as a mixed bag of diseases, rather than a homogenous disorder, and beginto understand why survival range of MM patients can span anywhere from two years to more than 10 years. This allows the first insight into formulating individualised therapy for MM patients.

The Role of the Marrow Microenvironment

The most recent advance has been our understanding that the bone marrow microenvironment supports MM cell growth, survival and development of drug resistance.

This has led to a change in the treatment paradigm to target not only the tumour cells, but also the marrow microenvironment. Instead of giving toxic treatment to broadly destroy cancer cells as well as many normal innocent by-stander cells, novel agents are being developed to deliver more focused treatments that target specific biological processes in the cancer cell, as well as disrupting interactions between the cancer cell and its supportive microenvironment.

Three new drugs with novel mechanisms of action – thalidomide, bortezomib, and lenalidomide – have been approved for MM in the last five years and they completely changed the therapeutic scenario. The introduction of these agents to clinical use has resulted in an improved median survival of MM patients from two to three years to about five years [Figure 1]. 

Bortezomib, for example, acts by increasing the level of toxic substances in the MM cell by inhibiting the waste disposal system of the cell. As a result, toxic substances accumulate in the MM cell resulting in its death. In contrast, however, normal cells are less susceptible to bortezomib’s effect and hence collateral damages seen with conventional chemotherapy is never a significant issue with the use of targeted therapies like bortezomib.

Based on evidence from randomised phase III clinical trials, agents like bortezomib were initially approved for treatment of relapsed MM. Prior to availability of data on the use of these novel agents in the frontline setting, the impressive impact of these drugs seen in the relapse setting has led physicians wondering if patients would benefit even further with earlier exposure of these drugs.

Moving a novel drug to upfront use for all patients will inevitably escalate healthcare costs. From 2006, MM physicians from Singapore General Hospital and National University Hospital began adopting a risk-adapted approach to MM. Backed by the improved capability of cytogenetic laboratories, MM patients found to have bad genes in the MM cells were offered upfront therapy with bortezomib before the Health Sciences Authority (HSA) has granted approval for this indication.

The impact of such a strategy of anticipating and moving ahead of evidence-based practice became apparent in 2011, when the survival rates of MM patients in Singapore was evaluated.

The upfront risk adapted strategy has significantly resulted in improved survival rates of MM patients, from a median of 4. 3 years to an approximated seven to eight years [Figure 2].

Figure 2. Overall survival from diagnosis of MM in Singapore

Figure 2. Overall survival from diagnosis of MM in Singapore

This is largely attributed to salvaging patients with bad-risk disease and averting their early mortality with early exposure to bortezomib. These findings were recently presented at the American Society of Clinical Oncology Meeting at Chicago, USA.

Not surprisingly, the latest randomised phase III studies now have demonstrated that upfront exposure to novel agents like bortezomib is the preferred standard of care for newly-diagnosed patients with MM.

The effectiveness of novel upfront combinations now raises question about the need and place of transplants in MM. Recent advances in high-density, high throughput array technology have enabled the interrogation of genomic changes both at DNA and transcriptional levels, allowed for molecular classification of MM, and provided the scientific rationale for novel targeted therapies.

Currently, more than 20 new agents are undergoing clinical evaluation in MM. Myeloma rides on the forefront of rapid progress in the field of oncology [Figure 3]. 

Figure 3. Progress in therapeutic options for MM

Figure 3. Progress in therapeutic options for MM

Such dramatic improvement in survival over a short span of time is unprecedented.

Indeed, we are on the threshold of a curative outcome. The concept of tailoring treatment to suit individual needs based on our understanding of the biology of MM as well and the availability of an expanded therapeutic armamentarium against MM is now becoming a reality.

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