Multiple myeloma is a malignant disease of plasma cells with a worldwide incidence of 6—7 cases per persons per year.
Multiple Myeloma Diagnosis and Treatment
It is among the 20 most common types of cancer in Germany. The diagnostic evaluation of multiple myeloma comprises thorough history-taking and physical examination, various laboratory tests including analysis of a hour urine sample, a bone-marrow biopsy, and skeletal radiography. Systemic treatment should be administered only when organ damage has been diagnosed.
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High-dose therapy with autologous stem-cell transplantation remains the treatment of choice for patients under age 70 who are otherwise in good health. For patients who are not candidates for high-dose therapy or who have had a recurrence of multiple myeloma after prior high-dose therapy, there are a number of further conventional treatment options.
Patients need not only systemic antineoplastic treatment, but also supportive treatment for the prevention of treatment-induced toxicity and myeloma-associated organ damage. Recent therapeutic advances have made the treatment of multiple myeloma both more complex and more costly.
In particular, the median survival of patients with multiple myeloma has been markedly prolonged through the use of targeted drugs such as proteasome inhibitors and immune modulators.
Multiple myeloma is a systemic malignant disease of the blood, in most cases incurable. Multiple myeloma is characterized by the uncontrolled proliferation of monoclonal plasma cells in the bone marrow, leading to production of nonfunctional intact immunoglobulins or immunoglobulin chains. In the WHO classification, multiple myeloma is differentiated from the following plasma cell diseases 1 :. POEMS syndrome polyneuropathy, organomegaly, endocrinopathy, monoclonal plasma cell disease, and skin changes.
In Germany there are around new cases of multiple myeloma each year and it is the third most commonly occurring disease of the blood after leukemia and non-Hodgkin lymphoma. The median age at onset is 71 years for men and 74 years for women 2.
The etiology of the disease remains poorly understood. Together with ionizing radiation, pesticides and benzol, obesity and chronic infection have been postulated as factors favoring the occurrence of multiple myeloma e1 , e2. Another transitional phase on the way to symptomatic multiple myeloma is smoldering asymptomatic myeloma, which, in common with monoclonal gammopathy of uncertain significance, is characterized by the absence of organ damage CRAB criteria Table 1.
Smoldering myeloma differs from monoclonal gammopathy of uncertain significance, however, in its higher risk of progression to multiple myeloma. Smoldering myeloma does not require treatment, but therapeutic measures should nevertheless be considered in the presence of certain risk factors e3.
The Diagnosis and Treatment of Multiple Myeloma
The indication for initiation of treatment for multiple myeloma is essentially determined according to the CRAB criteria. In a recommendation published in , the International Myeloma Working Group IMWG revised the criteria and extended them to symptomatic multiple myeloma. The existing criteria were supplemented by newly defined biomarkers that identify asymptomatic patients with an elevated risk of progression.
These patients might be treated with the aim to avoid early end-organ damage Box 1 6. CRAB criteria: threshold values in multiple myeloma for assessment of disease consequences:.
It is unclear at present whether initiation of treatment solely on the grounds of these as yet insufficiently validated biomarkers improves the overall prognosis of patients with multiple myeloma.
Further evaluation of the biomarkers in prospective randomized studies is therefore necessary because of the risk of overtreatment.
The most widely used classification of multiple myeloma was developed by Durie and Salmon and introduced 40 years ago. The stage correlates with estimated tumor mass along with clinical symptoms. The prognostic significance of the findings for the individual patient is limited, however 7. The year saw the introduction of an international staging system ISS that is easy to apply in clinical practice, economical, and predicts the course of disease 8.
The genetic changes associated with a poor prognosis on FISH analysis include the immunoglobulin heavy-chain translocations t 4;14 , t 14;16 , and t 14;20 , the 17p deletion, the 1p deletion, and amplifications of 1q.
On conventional chromosome analysis the 13q deletion is also associated with an unfavorable prognosis. The symptoms reported by patients with multiple myeloma on presentation are often non-specific and may already have been present for an extended period.
In addition to history taking and physical examination, the diagnostic work-up for multiple myeloma comprises clinical chemistry, cytogenetic analysis of bone marrow, and radiological investigation to detect bone changes.
For reasons of sensitivity, the conventional whole-body radiographic bone survey the so-called Paris scheme has largely been abandoned in favor of low-dose whole-body computed tomography. Magnetic resonance imaging and FDG positron emission tomography can be used for clarification if required.
Box 2 summarizes the investigations that are necessary for initial diagnosis of multiple myeloma Determination of free light chains including FLC ratio , immunofixation electrophoresis.
Patients with a clonal plasma cell disease and signs of manifest or threatened organ damage must receive adequate systemic therapy.
The upper age limit of 65 or 70 years is determined not so much by age per se as by medical fitness and regulations. The treatment begins with induction chemotherapy. The principal active substances are the proteasome inhibitors Velcade bortezomib and dexamethasone the VD protocol. In most cases, however, Velcade bortezomib and dexamethasone are combined with cyclophosphamide or adriamycin, or alternatively with thalidomide VTD , for the sake of improved efficacy.
In August the European Medicines Agency extended the indication for bortezomib to cover non-pretreated patients before planned high-dose treatment and stem cell transplantation. The induction therapy used for this indication in the USA, combining the immunomodulatory substance lenalidomide with dexamethasone, has not received European approval for use in patients suited for transplantation. The time that elapsed before the next occurrence of disease activity or death progression-free survival was a median 20 months longer in the high-dose group.
Whether, in view of more effective induction regimens, single or tandem high-dose treatment is preferable remains to be established by prospective randomized controlled trials. The guidelines are inconsistent in this respect. The value of a second course of high-dose treatment in the event of insufficient response i.
Blood ; abstract Concepts for improvement or maintenance of remission are being investigated in the attempt to delay recurrence of multiple myeloma. Cytostatic drugs, steroids, interferon, and also thalidomide have been tested but largely abandoned owing to significant adverse effects and, in some cases, lack of sufficient efficacy.
In several studies administration of lenalidomide up to the time of first progression has been shown to prolong progression-free survival 17 — Because of an increased incidence of secondary malignancies, inconsistent results with regard to prolongation of overall survival, and the lack of approval by licensing authorities in Germany, maintenance treatment with lenalidomide has not yet become standard.
Given its short duration and its potential to achieve extended progression-free interval, high-dose treatment should also be considered as a first-line treatment for patients aged 65 to 75 years whose cognitive and physical status is good. The adverse effects seem to increase sharply from the age of 65 upward, and only small numbers of patients have been treated with the standard dose 20 , e9 , e So-called conventional therapy is the treatment of choice for patients over 75 years of age.
A randomized controlled trial published in showed that melphalan and prednisolone MP plus thalidomide MPT was superior to MP alone or greatly attenuated high-dose treatment with regard to progression-free survival and overall survival As a result, the MPT protocol was licensed for this indication.
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A year later, the results of another randomized controlled trial appeared: the combination of prednisolone and bortezomib showed clear superiority of the VMP protocol bortezomib, melphalan, prednisone over the standard treatment in all time-related endpoints In this first generation of studies, however, the high degree of efficacy was associated with high rates of discontinuation due to toxicity.
For this reason, alternative ways of administering bortezomib were developed e. Lenalidomide is more effective than thalidomide, but causes more hematological adverse effects. In a protocol no longer including melphalan, it was shown that lenalidomide could be successful in treating older patients: the French study group compared continuous administration of lenalidomide and dexamethasone up to the time of first progression with 18 cycles of lenalidomide and dexamethasone and with the standard of 12 cycles of melphalan, prednisone, and thalidomide Both progression-free survival and overall survival were better in the experimental arm of the study than with the hitherto standard treatment.
Modified bortezomib, melphalan, prednisone nine cycles and continuous lenalidomide and dexamethasone until progression is detected are the first-line treatments of choice in patients for whom high-dose treatment ist not an option. Direct comparison of these two regimens would be desirable to determine whether one is superior to the other.
Figure 1 shows a treatment algorithm for patients with newly diagnosed multiple myeloma that requires treatment. Risk-adjusted treatment algorithm for newly diagnosed patients with multiple myeloma requiring treatment.
The best time to begin treatment is keenly debated. Patients with recurrent multiple myeloma whose general condition is good with no serious comorbidities can receive high-dose treatment with melphalan together with autologous stem cell transplantation e11 — e Proteasome inhibitors, immunomodulatory substances, and classical chemotherapy agents play a crucial role in the treatment of recurrent multiple myeloma. Bortezomib combined with corticosteroids or other substances e.
Clinical trials have shown that bortezomib can be efficacious even in patients previously treated successfully with this substance Novel proteasome inhibitors, e. Two large randomized controlled trials demonstrated that treatment with lenalidomide and dexamethasone is very effective, achieving significantly better overall survival than dexamethasone alone in patients with recurrent multiple myeloma The anti-CS1- SLAMF7 antibody elotuzumab and the histone-deacetylase inhibitor panobinostat are among the substances at the forefront of clinical development.
In a study that investigated lenalidomide plus dexamethasone with and without elotuzumab, patients treated with elotuzumab showed significantly longer progression-free survival Detailed analyses of overall survival have yet to be published.
On 3 September the European Medicines Agency approved the histone-deacetylase inhibitor panobinostat in combination with bortezomib and dexamethasone for treatment of previously treated multiple myeloma Elotuzumab has recently been licensed for treatment of recurrent multiple myeloma in Germany.
Supportive therapy comprises the management of the complications of myeloma and the adverse effects of the drugs used for treatment.
Pain is treated according to the well-known WHO pain relief ladder If non-steroidal anti-inflammatory drugs NSAIDs are given, the frequently impaired renal function should be closely monitored In addition, osteolyses—generally the lead symptom—are usually irradiated, as are soft-tissue plasmocytomas To delay further skeletal events, reduce pain, and correct hypercalcemia, regular administration of a bisphosphonate pamidronate, zoledronate, or clodronate is initiated in parallel with systemic treatment Before bisphosphonate treatment is started, careful assessment of the dental status is mandatory to avoid bisphosphonate-associated osteonecrosis of the jaw Treatment for 2 years is recommended, but can be ended after 1 year if full remission or very good partial remission has been achieved.
In the case of less favorable response bisphosphonate administration can be continued, but in view of the absence of clinical data the advisability of treatment beyond 2 years must be weighed up carefully 37 , Symptoms caused by peripheral neuropathy may occur as an adverse effect of treatment with bortezomib and thalidomide, necessitating dose reduction or treatment modification Preventive medication is not possible; supportive measures include physical therapy, tricyclic antidepressants, and anticonvulsives e.
Infections are the principal cause of death among patients with multiple myeloma. Despite the elevated risk of infection, routine administration of prophylactic antibiotics is not recommended; they can be given, however, on an individual basis in particular situations prolonged neutropenia, repeated infectious complications High numbers of infections have also been observed in the initial phase of treatment with immunomodulatory substances, and these patients might also benefit from being given prophylactic antimicrobials e In the case of prolonged neutropenia or recurring bacterial infections, granulocyte-colony stimulating factors G-CSF and intravenous immunoglobulins can be prescribed.
Administration of aciclovir to prevent shingles is a necessary accompaniment of bortezomib treatment and should be continued for 6 weeks after the last dose of bortezomib Patients with multiple myeloma are at increased risk of venous embolism.
The incidence lies between 8 and 22 per patients per year e