(Plasma cell myeloma, plasmacytoma)
Multiple myeloma is a malignant tumor of plasma cells that produce monoclonal immunoglobulins invade adjacent bone tissue and destroy it. Common manifestations include bone pain, renal failure, hypercalcemia, anemia and recurrent infections. The diagnosis usually requires proof of a paraprotein (sometimes in the urine and not detectable in the serum; in rare cases, it is entirely absent) and either osteolytic bone lesions, light chain proteinuria or increased plasma cells in the bone marrow. For the diagnosis usually a bone marrow biopsy is necessary. Specific treatment usually involves a combination of conventional chemotherapy, corticosteroids and one or more of the newer agents such as bortezomib, carfilzomib, lenalidomide, thalidomide, pomalidomide, Daratumumab or elotuzumab. High dose melphalan followed by autologous peripheral blood stem cell transplantation may also be used.
The incidence of multiple myeloma is 2-4 / 100,000. Men and women are in the ratio of 1.6: 1 affected, and the average age is about 65 years. The prevalence is among black twice in fair-skinned people. The etiology is unknown, although chromosomal and genetic factors, radiation and chemicals are suspected.
Multiple myeloma is a malignant tumor of plasma cells that produce monoclonal immunoglobulins invade adjacent bone tissue and destroy it. Common manifestations include bone pain, renal failure, hypercalcemia, anemia and recurrent infections. The diagnosis usually requires proof of a paraprotein (sometimes in the urine and not detectable in the serum; in rare cases, it is entirely absent) and either osteolytic bone lesions, light chain proteinuria or increased plasma cells in the bone marrow. For the diagnosis usually a bone marrow biopsy is necessary. Specific treatment usually involves a combination of conventional chemotherapy, corticosteroids and one or more of the newer agents such as bortezomib, carfilzomib, lenalidomide, thalidomide, pomalidomide, Daratumumab or elotuzumab. High dose melphalan followed by autologous peripheral blood stem cell transplantation may also be used. The incidence of multiple myeloma is 2-4 / 100,000. Men and women are in the ratio of 1.6: 1 affected, and the average age is about 65 years. The prevalence is among black twice in fair-skinned people. The etiology is unknown, although chromosomal and genetic factors, radiation and chemicals are suspected. Pathophysiology Para protein produced by malignant plasma cells is about 55% of the patients Mylom IgG, about 20% IgA; by the patients, which produce either IgG or IgA, 40% have also a Bence Jones proteinuria by free monoclonal kappa (?) – is labeled or lambda (?) light chains in the urine. In 15-20% of patients, plasma cells only Bence Jones proteins secrete. IgD myeloma accounts for about 1% of all cases. In rare cases, patients have no M protein in the blood and urine, although a new assay of free light chains in serum now shows monoclonal light chains in many of these patients. Diffuse osteoporotic or circumscribed osteolytic lesions usually occur in pelvis, spine, ribs, and skull. The lesions caused by bone displacement as a result of expanding plasmacytomas or by cytokines that are secreted by malignant plasma cells activate osteoclasts and suppress osteoblasts. The osteolysis are usually multiple; occasionally solitary intramedullary masses find. An increased bone loss can also lead to hypercalcemia. Extraosseous solitary plasmacytomas are not typical, but can in any tissue, especially in the upper respiratory tract may occur. In many patients, renal failure (myeloma kidney) is present at diagnosis or develops in the course of the disease. Renal failure has many causes; mostly it results from a deposition of light chains in the distal tubules or hypercalcemia. The patients often develop anemia, which is usually caused by kidney disease, or by suppression of erythropoiesis by tumor cells, but sometimes also by a lack of iron. In some patients, there is an increased susceptibility to bacterial infections. As a result of new treatments, especially the use of proteasome inhibitors Bortezomib and Carfilzomib, there is increasing viral infections, in particular herpes zoster infections. Amyloidosis occurs in 10% of myeloma patients, most commonly in those with M proteins of 2? type. There can be several forms of multiple myeloma differ (s. Various forms of multiple myeloma). Various forms of multiple myeloma shape characteristics Extramedullary plasmacytoma plasmacytomas that occur outside of the bone marrow Solitary plasmacytoma of bone Singular Knochenplasmozytom, which is usually no paraprotein produced osteosclerotic myeloma (POEMS syndrome), polyneuropathy (chronic inflammatory polyneuropathy) organomegaly (hepatomegaly, splenomegaly and lymphadenopathy) endocrinopathy (z. B. gynecomastia , Testicular atrophy) M protein lesions (eg. As hyperpigmentation, increased hair growth) Nichtsezernierendes myeloma lack of paraprotein in serum and urine presence of paraprotein in plasma cells symptoms and complaints Persistent bone pain (especially in the back or chest), kidney failure and recurrent bacterial infections are the most common initial symptoms; but many patients are discovered in routine laboratory tests by the increased total protein value in serum or proteinuria. Pathological fractures are typical, and vertebral subsidence can cause Spinalkanalkompression and paraplegia. Signs of anemia may dominate or in some patients be the only reason for further study, some patients show signs of hyperviscosity syndrome on (symptoms and complaints). Peripheral neuropathy, carpal tunnel syndrome, bleeding tendency and character of hypercalcemia (z. B. polydipsia,) are typical. Patients can also imagine a kidney failure. Lymphadenopathy and hepatosplenomegaly are unusual. Diagnostic blood count with platelet, peripheral blood smear, BSG, and clinical chemistry (serum urea, creatinine, calcium, uric acid, LDH) serum and urine protein electrophoresis followed by immunofixation; quantitative immunoglobulins; free light chains in serum radiography (skeletal status) bone marrow examination Suspicion of multiple myeloma, patients> 40 years with persistent, unexplained bone pain, which occur mainly at night or at rest, and other typical symptoms or unexplained laboratory abnormalities such as elevated blood or urine protein, hypercalcemia, renal failure or anemia. The laboratory tests include blood routine determinations, protein electrophoresis, X-rays and bone marrow examination (1,2). Routine blood tests include blood count, erythrocyte sedimentation rate and clinical chemistry. Anemia is found in 80% of patients, typically normocytic and normochromic with rouleaux formation, wherein it is accumulations of 3-12 erythrocytes stacked strung together. Leukocyte and platelet counts are usually in the normal range. The erythrocyte sedimentation rate is usually> 100 mm / h, and serum urea, serum creatinine, LDH and serum uric acid may be increased. The anion gap is sometimes lowered. Hypercalcemia can be found at diagnosis in about 10% of patients. Clinical calculator: The anion protein electrophoresis is carried out with a serum sample and with the concentrated 24-hour urine to determine paraprotein quantitatively in urine. The serum electrophoresis facing paraproteins at 80-90% of patients. The remaining 10-20% are usually patients with only free monoclonal light chains (Bence Jones protein), or IgD. These Paraproteins are almost always detectable by urine protein electrophoresis. The immunofixation can prove the immunoglobulin class of M proteins (IgG, IgA, or less frequently IgD, IgM or IgE) and detect light chain proteins if the Serumimmunelektrophorese brings a false-negative result. The immuno-fixation is carried out with negative serum electrophoresis if multiple myeloma is suspected. An analysis of free light chains in serum showing the kappa and lambda ratio can confirm the diagnosis and are also used to monitor the effectiveness of therapy and for statements about the prognosis. The beta-2 microglobulin serum levels is determined when the diagnosis is confirmed or is highly likely; together with the albumin in serum, it is used to classify patients according to the international stage system (see Table: International Staging System for Multiple Myeloma). International Staging System for Multiple Myeloma Stage Criteria Median survival (months) 1 beta 2Mikroglobulin <3.5 mcg / ml and serum albumin ? 3.5 g / dL 62 II Non stage I or III 44 III beta 2Mikroglobulin ? 5.5 mcg / ml 29 Radiographs include an assessment of the skeleton (d. H. plain X-ray of the skull, bones, spine, pelvis and ribs). Punched lytic bone lesions or diffuse osteoporosis are found in 80% of cases. Skelettszintigraphien are usually not helpful. MRI can reveal more details and be done if pain or neurological symptoms occur in certain places. PET-CT can provide prognostic information and help determine whether patients have a single plasmacytoma or multiple myeloma. A bone marrow aspiration and a bone marrow biopsy be performed. You can uncover loose arrangements or clusters of plasma cells. Myeloma is diagnosed when> 0% of the cells are plasma cells. However, the type of bone marrow involvement is variable, which is why some samples from myeloma patients may have <10% plasma cells. Nevertheless, the amount of plasma cells in the bone marrow is rarely normal. The plasma cell morphology does not correlate with the class of synthesized immunoglobulins. Chromosomal studies on bone marrow (eg. As the use zytogener investigation methods such as fluorescence in situ hybridization [FISH] and immunohistochemistry can show in plasma cells, which are associated with different survival rates specific karyotypic abnormalities. The diagnosis and differentiation from other malignancies ( z. B. metastatic carcinoma, lymphoma, leukemia), and monoclonal gammopathy of undetermined Signifikanzerfordert usually several criteria clonal bone marrow plasma cells or myeloma M protein in the plasma and / or (urinary organ damage hypercalcemia, renal insufficiency, anemia or skeletal lesions) in patients with paraprotein in serum myeloma is regarded as detected when a Bence-Jones proteinuria> 300 mg / 24 h or abnormal free light chains in the serum, osteolytic lesions (no evidence of tumor metastatasierenden disease or granulomatous Kr ankheit present) and a flat or grouped accumulation of plasma cells in the bone marrow. Diagnosis Note Rajkumar SV, Kumar S. Multiple myeloma: diagnosis and treatment. Mayo Clinic Proc91 (1): 101-119, 2016.doi: 10.1016 / j.mayocp.2015.11.007. Rajkumar V. Myeloma today: disease definitions and treatment advances. Am J Hematol91 (1): 90-100, 2016. doi: 10.1002 / ajh.24392. Prognosis The disease is progressive and has no cure, but the median survival by recent advances in treatment was improved to> 5 years. Poor prognostic factors at diagnosis are decreased serum albumin and increased beta-2 microglobulin levels. Patients with kidney failure who initially also an unfavorable prognosis, unless renal function has been improved by the treatment (the current treatment options usually applies). Certain cytogenetic abnormalities increase the risk of poor prognosis. Because multiple myeloma ultimately leads to death, the patient talks about the care in the terminal phase are likely to benefit, where the doctors and affected family members and friends to participate. It can be discussed issues such as living wills, use of feeding tubes and pain relief. Treatment chemotherapy in symptomatic patients thalidomide, lenalidomide or pomalidomide and / or bortezomib or carfilzomib plus corticosteroids and / or conventional chemotherapy Monoclonal antibodies, including elotuzumab and Daratumumab Possibly maintenance therapy with corticosteroids, thalidomide and / or lenalidomide (Editor’s note: and Ibrutinib, Idelalisib) maybe autologous stem cell transplantation may be radiation therapy in specific symptomatic areas that are not on systemic therapy to address the treatment of complications (anemia, hypercalcemia, renal failure, infections, skeletal lesions) the treatment of myeloma has improved in the last ten years, and the long-term survival a realistic goal of therapy (1-3). The therapy involves the direct treatment of malignant cells in symptomatic patients or those with organ dysfunction associated with myeloma (anemia, renal failure, hypercalcemia, or bone disease). Asymptomatic patients do not benefit from treatment, so it is usually begun with the first appearance of symptoms or complications usually. Patients should be treated with evidence of lytic lesions or bone loss (osteopenia or osteoporosis) with monthly zoledronic acid or pamidronate infusions to reduce the risk of skeletal complications. Treatment Information Rajkumar SV, Kumar S. Multiple myeloma: diagnosis and treatment. Mayo Clinic Proc91 (1): 101-119, 2016.doi: 10.1016 / j.mayocp.2015.11.007. Rajkumar V. Myeloma today: disease definitions and treatment advances. doi 90-100, 2016: Am J Hematol91 (1) 10.1002 /ajh.24392. Berenson J, Spektor T, Wang J. Advances in the management of multiple myeloma. 2016. Treatment of malignant cells Heretofore, traditional chemotherapy po only Melphalan and prednisone in cycles of 4 to 6 weeks with monthly review of the therapeutic success. Recent studies show an improved result by the addition of either bortezomib, lenalidomide, or thalidomide. Other chemotherapeutic agents, including cyclophosphamide, bendamustine, doxorubicin, and the newer analog pegylated liposomal doxorubicin, are also effective when used with an immunomodulatory drug (thalidomide, lenalidomide, or its more recent analogue pomalidomide) or a proteasome inhibitor (bortezomib or a newer substance Carfilzomib) be combined. Many other patients with bortezomib, corticosteroids and either thalidomide (or lenalidomide), chemotherapy or both treated effectively. Speaks chemotherapy (see Table: Defined therapy responses in oncology), this is reflected by a reduction in bone pain and fatigue, a reduction of paraprotein in serum and urine, lowering the level of the involved serum free light chain by an increase in red blood cells and by an improved kidney function in patients with renal failure. An autologous peripheral blood stem cell transplantation may be considered for patients into consideration which have an adequate cardiac, hepatic, pulmonary and renal function, particularly if the disease is stable or has responded to some cycles of the initial therapy. However, recent studies suggest that the newer treatments are very effective and could make transplants necessary in rare cases. An allogeneic stem cell transplantation after non-myeloablative therapy (eg. As low-dose cyclophosphamide and fludarabine or radiation) can lead to a myeloma-free survival of 5-10 years in some patients. However, there is allogeneic stem cell transplantation with myeloablative or non-myeloablative chemotherapy because of the high morbidity and mortality resulting from graft-versus-host disease, still in the experimental stage. In relapsed or refractory myeloma combinations of bortezomib or carfilzomib, and thalidomide, lenalidomide or pomalidomide can be used with chemotherapy or corticosteroids. These drugs are usually combined with other active drugs, which the patient has not been treated, even though patients may respond with prolonged remission on retreatment with the same regimen with a remission. Patients who do not respond to any specific combination of drugs could show improvements when another drug in the same class (eg. As proteasome inhibitors, immunomodulators, chemotherapeutic agents) is used as a substitute. With progression of the disease, monoclonal antibodies may be effective, including Daratumumab and elotuzumab, the latter when it is combined with lenalidomide and dexamethasone and the new oral proteasome inhibitor Ixazomib. Maintenance treatment with non-cytotoxic active substances such as interferon alpha have been attempted, which increases the reflectance but the survival time has not improved and side effects. Also corticosteroids alone are effective in maintenance therapy. Thalidomide can be effective as a maintenance therapy and recent studies showed that lenalidomide is alone or with corticosteroids also an effective maintenance therapy. However, there was in the recent past some concerns about secondary malignancies in patients receiving long-term therapy with lenalidomide, especially after an autologous Stammzellentransplantation.Behandlung of complications In addition to direct treatment of malignant cells, the complications must be dealt with, including anemia, hypercalcemia include renal failure, infections and skeletal lesions. Recombinant erythropoietin (40,000 units s.c. once a week) can be used for the treatment of anemia in patients whose anemia is not adequately remedied by the chemotherapy. If the anemia caused serious cardiovascular or systemic symptoms, erythrocyte concentrates are transfused. A plasma exchange is indicated for the development of a hyperviscosity (symptoms and complaints). Patients often suffer from iron deficiency and require intravenous iron. Patients with anemia should be the serum iron, transferrin and ferritin levels are measured periodically to monitor the iron stores. Hyperkalzämiewird with strong saluresis, i.v. Bisphosphonate after rehydration and occasionally treated calcitonin or prednisone. Hyperurikämiekann occur in some patients with a high tumor burden and underlying metabolic problems. However, most patients do not require allopurinol. Allopurinol is indicated in patients with high uric acid levels in serum or high tumor burden and a high risk of an induced by treatment of tumor lysis syndrome. Renal impairment may be improved by adequate hydration. Even patients with prolonged massive Bence Jones proteinuria (? 10-30 g / day) may have an intact kidney function, if a urine excretion is ensured> 2000 ml / day. Dehydration in combination with iv hochosmolarem Contrast agents can trigger an acute oligurisches renal failure in patients with Bence Jones proteinuria. Plasma exchange can be effective in some cases. Infection risk rather during a chemotherapy-induced neutropenia. Additionally, you experience infections with the herpes zoster virus common in patients treated with newer drugs for myeloma, especially bortezomib or carfilzomib. Proven bacterial infections should be treated with antibiotics; However, the prophylactic use of antibiotics is not routinely recommended. Prophylactic administration of antiviral drugs (eg. Acyclovir, valganciclovir, famciclovir) is indicated in patients who receive either bortezomib or carfilzomib. Prophylactic administration of i.v. Immunoglobulins can reduce the risk of infection, however, is usually provided for patients with recurrent infections. To prevent infections, pneumococcal and influenza vaccinations should be carried out. However, the use of live vaccines in these immunocompromised patients is not recommended. Skeletal lesions require numerous supportive measures. Maintaining the ability to walk, and the substitution of calcium and vitamin D help to maintain bone density. The vitamin D levels should be measured in the diagnosis and in regular intervals and the vitamin D-dosage adjusted accordingly. Analgesics and palliative radiotherapy doses (18-24 Gy) can relieve bone pain. However, radiation therapy can produce significant toxicity and because it suppresses bone marrow function, affect the tolerance of the patient for haematotoxic cytostatics. Most patients, especially those with lytic lesions and generalized osteoporosis or osteopenia should monthly iv Bisphosphonate obtained (either pamidronate or zoledronic acid). Bisphosphonates reduce skeletal complications and bone pain and may have an antitumor effect. Important points malignant plasma cells produce monoclonal immunoglobulin and penetrate the bone and destroy them. The extension of plasmacytomas and cytokine secretion cause multiple, discrete osteolytic lesions (usually in the pelvis, the spine, the ribs and the skull) and diffuse osteoporosis; Pain, fractures and hypercalcemia are common. Anemia and renal failure are common. Amyloidosis develops in about 10%, typically in patients that produce excess lambda light chains. Electrophoresis of proteins in serum and urine followed by immunofixation, quantitative immunoglobulins and the measurement of the free light chain in the serum is performed. Symptomatic patients and patients with organ dysfunction should be treated with medication; certain patients should receive autologous stem cell transplantation as a treatment.