Management of multiple myeloma in Hong Kong
Multiple myeloma (MM) accounts for about 10% of all hematologic malignancies.1 In Hong Kong, the majority of MM patients are older than 65-years-old. Management of these patients needs special consideration due to age-related comorbidities. During an interview, Dr. Herman Liu, Specialist in Hematology and Hematological Oncology explained the overview of management of MM in Hong Kong.
The diagnosis of MM
The diagnosis of MM requires the presence of one or more myeloma‐defining events (MDEs) in addition to 10% or more clonal plasma cells on bone marrow examination or a biopsy‐proven plasmacytoma.1 MDEs consist of established features of hypercalcemia, renal failure, anemia, or lytic bone lesions (CRAB). Furthermore, MDEs have 3 specific biomarkers - clonal bone marrow plasma cells of 60% or higher, serum free light chain ratio of 100mg/L or higher, and more than one focal lesion on magnetic resonance imaging.1 These biomarkers are associated with an approximately 80% risk of progression to symptomatic end‐organ damage.1
Understanding mortality in MM
A multidisciplinary approach has improved the management of MM over the past few decades. A European population-based study reported an increase in 5-year survival in patients with MM from 29.8% in 1997–1999 to 39.6% in 2006–2008.2 Additionally, data from the Swedish Myeloma Registry found improvement in prognosis between 2008 and 2015.3
Despite the current positive trend in survival, response to anti-MM therapy remains variable.4 Although some treated patients survive progression-free for more than 10 years, approximately 10% die within a year of diagnosis.4 Furthermore, in most patients, MM will relapse and they subsequently die due to the refractory disease.4
Study populations of clinical trials often include a mixture of surviving patients and many lose their lives to the disease. A clear understanding of why patients with MM die is still lacking as the data focusing on deceased patients are minimal. Mortality is usually attributed to combined effects of active MM and comorbid factors, but it is also linked to cytogenetic abnormalities that drive disease aggressiveness.4 The comorbidities and cytogenic abnormalities are linked to the advanced age of the MM patients.
Is MM a disease of the elderly?
MM is generally considered a disease of the elderly, with a median presentation at the age of 69 to 72.5 In addition, the global proportion of elderly people is rapidly increasing, and MM patients appear to be increasing in parallel.6 In Hong Kong, 68% of newly diagnosed MM patients in 2016 were older than 65-years-old.7 It should thus be mandatory to consider factors associated with aging, such as comorbidities and functional status when implementing treatment among these patients. The heterogenicity of aging, such as patients ranging from extremely fit to severely frail, results in complexities in treatment. Nevertheless, a myriad of comorbidities associated with aging may further impair organ function, consequently influencing the pharmacological therapies used.8 Eventually, patients older than 75 years with reduced performance status will have a shorter MM-specific survival. Figure 1 depicts the factors to be considered when treating elderly patients with MM.
Therapeutic advancement in MM
The introduction of novel anti-myeloma drugs along with consolidation with high dose melphalan followed by autologous stem cell transplantation (ASCT) has marked an era of significant therapeutic advancement in MM.9 Survival of MM patients has thus improved significantly in the last 15 years.10 ASCT is an option for patients younger than 65 years in Hong Kong. In patients older than 65 years, pharmacological therapies are considered. There are many active drugs to treat MM in addition to alkylators and corticosteroids. Thalidomide, lenalidomide and pomalidomide are termed immunomodulatory agents. Bortezomib, carfilzomib and ixazomib are proteasome inhibitors. Elotuzumab and daratumumab are monoclonal antibodies targeting plasma cell receptors. Numerous regimens have been developed with these new drugs, and each year, additional new regimens are being developed.
Challenges in managing the elderly myeloma patients
As mentioned, aging is associated with progressive decline in physiological systems, including but not limited to cardiovascular, renal and hepatic function, but also an overall decrease in physiological function.9 As the elderly MM patients often have associated disabilities and comorbidities, the therapeutic approach is different compared to younger patients, making treatment decisions complex. However, the recent novel therapeutics have increased the overall survival despite degree of frailty.11 The degree of frailty and the treatment indication according to the risk is presented in Figure 2.11
Initial treatment in patients eligible for transplantation
Typically, patients are treated with approximately 3 to 4 cycles of induction therapy with bortezomib, lenalidomide and dexamethasone (VRD) prior to stem cell harvest.12 If lenalidomide is not available for use as initial therapy or in the presence of acute renal failure, other bortezomib‐containing regimens, such as bortezomib-thalidomide‐dexamethasone (VTD) or bortezomib‐cyclophosphamide‐dexamethasone (VCD), can be used instead of VRD. After harvest, patients can either undergo frontline ASCT or resume induction therapy delaying ASCT until first relapse.12 In general, the low‐dose dexamethasone regimen (40mg, once a week) is preferred to minimize toxicity. In a randomized trial, the low‐dose dexamethasone approach was associated with superior survival and significantly lower toxicity. Similarly, the neurotoxicity of bortezomib can be greatly diminished by administering bortezomib once a week instead of twice weekly.12
Initial treatment in patients NOT eligible for transplantation
In patients with newly diagnosed MM, who are not candidates for ASCT because of age or other comorbidities, initial therapy with VRD can be administered for approximately 8 to 12 cycles, followed by maintenance therapy with lenalidomide. Alternatives to VRD include VCD and VTD as discussed earlier.12
Stem cell transplantation
In Hong Kong, ASCT is considered after VRD followed by lenalidomide. However, a recent trial compared early versus delayed ASCT in patients treated with VRD followed by lenalidomide maintenance. Patients were randomized to receive either VRD (3 cycles) followed by ASCT and then VRD consolidation (2 cycles) versus VRD × 8 cycles with ASCT reserved for relapse.12 Both arms received lenalidomide maintenance for 1 year. A significant improvement in progression‐free survival was expected with early ASCT, but this has so far not been translated into a difference in overall survival. Allogeneic transplantation is still investigational but can be considered for young patients with high‐risk disease in first relapse.12
Maintenance with lenalidomide is the standard of care for most patients after initial therapy.12 A significant improvement in overall survival was seen with lenalidomide maintenance compared with placebo or no therapy. For high‐risk patients, bortezomib‐based maintenance should be considered.
Most MM patients are referred from other specialties when the patients seek treatment for CRAB features. However, general physicians should pay caution when elderly patients present with unexplained bone pain or fractures, anemia, and recurrent infections. As age has a significant impact on the treatment plan, early diagnosis is imperative for ensuring a better care for the MM patients.
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