Multiple myeloma / plasmacytoma

Multiple myeloma or plasmacytoma is a malignant disease of the bone marrow. It belongs to the group of malignant lymphomas

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Under the microscope, the bone marrow sample shows an abnormally large number of plasma cells (dark purple) - an indication of multiple myeloma

© Okapia / NAS / Biophoto

Multiple myeloma (plasmacytoma) - in short

Multiple myeloma (plasmacytoma, Kahler's disease) is caused by a single, degenerate plasma cell (differentiated B-cell lymphocyte) that spreads through cloning (reproduction of identical cell types) in the bone marrow. If a single, circumscribed tumor is called a plasmacytoma, multiple myeloma affects several areas. In rare cases, an infestation outside the bone marrow can also occur. The causes of the disease are not exactly known. The most common complaints in multiple myeloma are bone pain, and even minor injuries can lead to fractures. Anemia or an increased susceptibility to infections can also be noticed. However, many of those affected do not have any complaints when the diagnosis is made. The disease is then discovered by chance during a blood or urine test. The past few years have made great strides in therapy. New treatment concepts have been and are currently being developed and tested in clinical studies. In addition to conventional chemotherapy and intensified chemotherapy with subsequent stem cell transplantation, various new drugs are used. The aim of treatment is to reduce symptoms and achieve a long-lasting remission (decrease in symptoms). Even if a myeloma is often not permanently curable, in most cases a significant increase in life and an improvement in quality of life can be achieved.

What is Multiple Myeloma?

In this disease, a clone (genetically identical cells) of degenerate plasma cells (myeloma cells) spreads in the bone marrow. Plasma cells in general belong to the group of B lymphocytes, which are able to produce antibodies (immunoglobulins). In multiple myeloma, a plasma cell reproduces which produces non-functional antibodies. The degenerate plasma cells often attack different parts of the skeleton at the same time. This diffuse infiltration is called multiple myeloma. If the myeloma cells form a single, circumscribed tumor, which can also occur outside the bone marrow (extramedullary), one speaks of a plasmacytoma. The plasmacytoma is therefore a special form of myeloma.

Multiple myeloma belongs to the group of non-Hodgkin lymphomas.

The disease is rare, but it is the second most common malignant disease of the hematopoietic system. The frequency is given as three to four new cases of the disease per 100,000 inhabitants per year in Germany (incidence). The average age of onset is 72 years for men and 74 years for women.

Background information - lymphomas

Malignant diseases of the lymphatic system are known as malignant lymphomas and include a number of different cancers. The lymphatic system is formed by the lymphatics, lymph nodes, spleen, thymus and the lymphatic tissue in the gastrointestinal tract and throat.

The cells of the lymphatic system are the lymphocytes. They are divided into B- and T-cell lymphocytes and play an important role in the immune system. The lymphocytes belong to the white blood cells (leukocytes).

Classification of lymphomas

Malignant (malignant) lymphomas are divided into Hodgkin lymphomas and non-Hodgkin lymphomas (non-Hodgin lymphomas). The non-Hodgkin lymphoma group includes around 30 different lymphoma diseases that affect the lymphatic system. Multiple myeloma is also counted among the non-Hodgkin lymphomas.

Among other things, red and white blood cells are found in the blood. In multiple myeloma, a certain type of white blood cell - called plasma cells - becomes ill

© Okapia / NAS / Stem Jems

Causes: what are myeloma triggers?

Degenerate plasma cells lead to multiple myeloma. However, it is still unclear why the plasma cells degenerate. Ionizing radiation, pesticides and benzene are discussed as promoting factors, as well as obesity (adiposity) and chronic infections. The disease can rarely occur in families. A genetic change (trisomies and gene translocations of certain chromosomes) is found in around 40 percent of the sick. This indicates a possible hereditary component. However, multiple meyloma is not yet considered a typical hereditary disease.

Clinical precursors of multiple myeloma are monoclonal gammopathy of unclear significance (MGUS) and smouldering myeloma.

Background information - B lymphocytes and plasma cells

Both T and B lymphocytes play an important role in the immune system. Differentiated B lymphocytes are able to form antibodies. This is an important part of the so-called humoral immune defense. After contact with an antigen (e.g. components of bacteria or viruses), the B lymphocytes differentiate into a plasma cell (antibody-producing cell) or a memory cell. As a result of renewed contact with the antigen (e.g. renewed virus infection), this can remember the pathogen and produce antibodies much faster.

There are different types of antibodies that play different roles in the defense against bacteria or viruses. The various antibodies are divided into the so-called immunoglobulins (Ig) M, G, A, D and E according to their basic structure.

In multiple myeloma, a plasma cell (B-cell lymphocyte) degenerates

© Shutterstock / Fancy Tapis

What happens now with multiple myeloma?

In contrast to healthy plasma cells, degenerate plasma cells (myeloma cells) experience uncontrolled cell division and thus cell proliferation. The increased cells form growths in the bone marrow. At the same time, the myeloma cells, also uncontrolled, form large amounts of protein substances that are similar to antibodies (immunoglobulins) but have no function. One speaks of so-called paraproteins. All daughter cells are genetically identical, they all belong to one clone (monoclonal) and all form the same (monoclonal) immunoglobulin. Often, small so-called light chain proteins (Bence Jones proteins) are also formed. Certain types of multiple myeloma only make light chain protein. There are seldom forms that do not form any paraprotein at all. One then speaks of an asecretory myeloma.

Due to the uncontrolled reproduction of the degenerate plasma cells, the normal cells in the bone marrow are increasingly displaced and the bone substance is attacked. This also explains the diverse consequences of multiple myeloma.

Back pain can have many causes - sometimes multiple myeloma is behind it

© Fotolia / Robert Kneschke

Symptoms: what symptoms does multiple myeloma cause?

  • Bone pain: The most common complaints in multiple myeloma are bone pain and, in particular, back pain caused by the involvement of the spine. The pain often increases with movement. The cause is often initially unnoticed broken bones. These so-called pathological fractures are caused by a thinning of the bone by the tumor cells. Since multiple myeloma spreads into the bones from the beginning, the symptoms of bone involvement are among the early symptoms.

If no further examinations are carried out, the symptoms can initially be misinterpreted as rheumatism or osteoporosis.

  • Anemia: Even anemia, at least in a mild form, often occurs in the early stages. It can be noticed by paleness (especially of the mucous membranes), tiredness, exhaustion, headaches and restricted physical performance, but it can also go unnoticed, especially if it develops slowly.
  • Increased susceptibility to infection: Due to the increasing displacement of healthy bone marrow by tumor cells, blood formation in the bone marrow is disrupted with a reduction in red and white blood cells. A deficiency in special white blood cells (leukopenia), the so-called granulocytes, and normal B cells (plasma cells), which form functional antibodies, lead to a weak immune system. The patients are more prone to infections, especially of a bacterial nature.
  • Kidney dysfunction: In later stages of the disease, symptoms can occur due to increasing kidney dysfunction. Consequences of a kidney dysfunction include water retention (edema). In the case of advanced kidney damage, urine production can initially be reduced (oliguria) and finally dry up completely (anuria). For more information on the symptoms, please refer to the Kidney Failure Guide.
  • Foamy urine: Some patients report excessively foamy urine. This occurs in patients in whom the plasma cells mainly produce light chain proteins (Bence Jones proteins), which are increasingly excreted in the urine. Bence Jones proteinuria is also found in other lymphoma diseases.
  • Confusion and muscle cramps: Due to the increased bone breakdown, triggered by the osteoclast activation by myeloma cells (see info box "What are the consequences of multiple myeloma?"), The calcium level in the blood increases (hypercalcemia), which can be reflected in confusion and muscle cramps.
  • Weight loss: In the context of the tumor disease, unwanted weight loss can occur.

The following symptoms can also appear:

The immunoglobulins formed by the tumor can thicken the blood (hyperviscosity syndrome).Under certain circumstances, circulatory disorders of different degrees arise - from the painful insufficient blood flow in individual fingers to circulatory disorders in vital organs (heart attack, stroke, infarcts in the internal organs).

Comparatively rarely, there is also a disturbance in the formation of blood platelets with a tendency to bleed. A prolonged bleeding time after an injury and / or punctiform bleeding on the skin (so-called petechiae) are typical here.

In some cases the light chains formed by the myeloma cells (see info box "What happens now with multiple myeloma") are deposited in organs such as the heart, kidneys, gastrointestinal tract, liver or spleen (amyloidosis) and can impair the function of the organs . It can even lead to a complete loss of function (kidney or liver failure).

What are the consequences of multiple myeloma?

The malignant cells spread in the bone marrow. The myeloma cells form substances that inhibit bone-building cells (osteoblasts) and promote bone-breaking cells (osteoclasts). This leads to an imbalance with the predominance of bone-degrading cells. This has various consequences:

  • The bone is dissolved in various places (so-called osteolysis). Therefore, there is an increased risk of bone fractures (pathological fracture).
  • At the same time, calcium is released when the bone structure breaks down. The pathological increase in the amount of calcium in the blood can lead to kidney damage, among other things.
  • The tumor cells displace the normal bone marrow cells in the bone marrow, which are responsible for the formation of red and white blood cells. A deficiency in red blood cells leads to anemia (anemia), a deficiency in white blood cells (leukopenia) weakens the immune system. This leads to a tendency for bacterial infections in particular.
  • A reduction in the number of blood platelets (thrombocytopenia) can lead to an increased tendency to bleed.
  • In most cases, the degenerated plasma cells form large quantities of identical, sometimes incomplete, but in any case non-functional antibodies (monoclonal immunoglobulin or paraprotein) that can be detected in the blood. A certain type of these antibodies, the so-called free light chain proteins (Bence Jones proteins), are excreted in the urine and can clog the excretory system of the kidney, the so-called tubules, and thereby also damage the kidney.

Many myeloma foci (black spots) can be seen in the X-ray

© Shutterstock / Santibhavank P.

Diagnosis: how does the doctor diagnose multiple myeloma?

The disease can be discovered in different ways. In many patients, abnormal blood or urine findings incidentally lead to the diagnosis. An extremely high rate of sedimentation or an increase in protein in the blood or urine are often indications of the disease. In other patients, the condition is discovered because of bone pain. If multiple myeloma is suspected, various diagnostic measures follow.

In addition to the consultation with the doctor and the physical examination, the following further examinations are important for establishing the diagnosis: a bone marrow puncture with cytogenetic examinations, laboratory examinations (including the protein composition in blood and urine) and radiological examinations (x-rays, CT, MRI, PET) of the skeleton.

Bone marrow puncture: Here - under local anesthesia - the bone in the upper iliac crest, for example, is pierced up to the medullary canal using a thick hollow needle and, similar to a blood sample, a small amount of bone marrow is sucked in (aspirated) or punched out directly (punch biopsy). The material obtained is sent to a laboratory for further examination, and the aspirated cells are cytologically examined under a microscope. The punch biopsy is also examined histologically under the microscope using special cutting and staining techniques.

Laboratory tests (blood and urine tests):

  • Serum protein electrophoresis and detection of protein in the urine: In serum protein electrophoresis, different types of protein are separated from one another. In multiple myeloma, large amounts of the same type of protein are present. Two types can be distinguished, namely monoclonal immunoglobulin (paraprotein) and monoclonal light chain proteins. The monoclonal immunoglobulin can be seen in electrophoresis as a narrow-base peak (M gradient). The light chains (so-called Bence Jones proteins) can also be detected in the urine (24-hour urine collection). Urine test strips are not suitable for the detection of paraprotein.
    Beta-2 microglobulin is also a protein that is determined in the urine and blood serum and is a measure of kidney function.
  • Further blood serum tests: determination of the differential blood count (red and white blood cells and platelets), blood salts (sodium, potassium, calcium), kidney values, inflammation values ​​and parameters of blood clotting.

Imaging procedures: In order to further substantiate the suspicion of the disease and to be able to estimate the stage of the disease, a so-called X-ray skeletal status is recorded. In the past, this was done with the help of conventional x-rays according to a fixed scheme (Paris scheme, includes x-rays of the skull, spine, ribs, pelvis, thighbones and humerus). Nowadays, however, a so-called "low-dose" full-body computed tomography examination is usually carried out. This special form of computed tomography works with a low dose of radiation and is considered to be the method that can most accurately depict even minor disintegration phenomena on the bones (osteolyses). Magnetic resonance imaging (MRI) can be helpful, for example, when assessing tumors in the area of ​​the spine and assessing soft tissue parts.

What types of myeloma are there and how is the diagnosis made?

Symptomatic myeloma is when more than 10 percent abnormal plasma cells are found in the microscopic examination of the bone marrow, abnormal protein (paraprotein) is detectable in the blood or urine, or symptoms or organ damage are present (so-called CRAB criteria: hypercalcemia, kidney damage , Anemia, bone destruction). Symptomatic myeloma also exists if an abnormal light chain quotient or more than one myeloma focus is detectable on the MRI or if at least 60 percent of abnormal plasma cells are found in the bone marrow (SLIM criteria).

A so-called asymptomatic myeloma (smoldering myeloma) is present if at least 10 percent monoclonal plasma cells are present in the bone marrow and / or a certain amount of pathological protein is exceeded in the serum and / or urine, but otherwise there are no symptoms or organ damage.

The detection of a single bone focus in MRI or CT and the detection of clonal cells in laboratory tests speak in favor of the diagnosis of plasmacytoma, even if less than 10 percent of monoclonal plasma cells are present in the bone marrow. The pathological protein in the blood and urine may be missing. There is no further organ damage.

In so-called monoclonal gammopathy of unclear significance (MGUS), there are also less than 10 percent clonal plasma cells in the bone marrow and abnormal protein in the blood, albeit in a smaller amount. Otherwise, however, there are no findings that are relevant to the disease.

Plasma cell leukemia is when there are more myeloma cells in the blood.

The therapy for multiple myeloma depends on the individual case. For example, it can include chemotherapy

© iStock / Annedde

Therapy: How is Multiple Myeloma Treated?

The goals of treating myeloma are to control the symptoms, which means that those affected should not have any symptoms as much as possible, and to prolong life through persistent remission. In medicine, remission means that the disease can no longer be detected. But this is not to be equated with a cure. In most cases, it is recommended that those affected seek treatment in specialized centers as part of studies. In many cases such a successful therapy is possible. Since the disease varies greatly in each patient, individual therapy planning is necessary.

Who needs to be treated?

Whether or not myeloma needs treatment depends on whether the person is suffering from symptoms and whether the disease has already damaged the body. The criteria that determine the need for therapy include the so-called CRAB criteria (hypercalcemia - increased calcium level in the blood, renal insufficiency - renal insufficiency, anemia - anemia, bone lesions - involvement of the bones). The CRAB criteria are supplemented by imaging procedures and serological examination parameters. Just one criterion is sufficient for a need for therapy.

Other reasons for treatment include hyperviscosity syndrome or general symptoms such as fever over 38 ° C for no apparent cause, night sweats or unwanted weight loss over 10 percent in the last six months (so-called B symptoms) and myeloma-related pain.

Patients with asymptomatic myeloma usually do not need immediate treatment. You should be closely monitored so that treatment can be initiated immediately if any symptoms arise. Clinical studies are investigating whether earlier treatment can have a beneficial effect on the course of the disease. In general, this has not yet been proven.

If therapy is appropriate, the procedure differs mainly according to the age and state of health of the person affected. The treatment takes place according to an individual treatment plan.

What treatment options are there?

As a so-called first-line therapy, patients who are eligible for the initial diagnosis receive an autologous stem cell transplant. These intensified therapy concepts are mainly used for younger patients (biological age ≤70) in good general condition and without concomitant diseases.

The first-line therapy with high-dose therapy then divides them as follows:

  • induction
  • High-dose therapy with autologous transplantation
  • Consolidation (if necessary)
  • Conservation (if applicable)

Induction therapy for high-dose therapy: In addition to chemotherapeutic agents, so-called new substances such as bortezomib, lenalidomide and thalidomide also play an important role in therapy. They improve the effectiveness and the response rates of classic chemotherapy. These positive effects must be weighed against their side effects and possible late side effects. Usually the active ingredients are administered in combination in three to four cycles. The aim of induction therapy is to control the disease well or even to achieve remission in order to have good starting conditions for stem cell transplantation.

High-dose therapy with autologous stem cell transplantation: The time of stem cell collection is determined depending on the response to induction therapy. To mobilize the stem cells, a growth factor (G-CSF; granulocyte colony stimulating factor) is first given alone or in combination with chemotherapy. The growth factor causes progenitor cells to be released from the bone marrow. These are released into the bloodstream and can be removed in this way (apharesis). This is followed by high-dose chemotherapy, usually with melphalan, to kill as many myeloma cells as possible. However, this treatment also leads to massive suppression of normal bone marrow. Therefore, the blood stem cells were removed from the patient prior to treatment. These are returned to the patient after the chemotherapy is over (transfused, autologous = self-obtained stem cells).

Additional consolidation therapy: After a stem cell transplant, a further consolidation therapy can be useful, especially for patients who have not achieved remission after the transplant (possibly two transplants). This consists, for example, of the drugs used in induction therapy.

Maintenance therapy: Even after successful treatment, there is a high risk of relapse. The new drugs bortezomib, lenalidomide and thalidomide can help delay a relapse. Maintenance therapy with these active ingredients can be considered both after intensified therapy concepts and after conventional chemotherapy. The benefits for all patient groups have not yet been conclusively clarified. Only lenalidomide is currently approved as maintenance therapy in Europe for patients with multiple myeloma after autologous stem cell transplantation (ABSZT). Maintenance therapy is still the subject of clinical research.

If a transplant is not possible:

Conventional dosed induction therapy is usually recommended for those affected who are older than 70 years or who are frail or who suffer from other diseases in addition to multiple myeloma. In addition to chemotherapeutic agents, new substances such as bortezomib, lenalidomide and thalidomide can be used in combination with a cortisone preparation. There are currently two standard therapies, namely VMP (Velcade + Melphalan + Prednisolone) or Rd (Revlimid / Lenalidomid + Dexamethasone).

How do you treat a plasmacytoma?

A plasmacytoma can be irradiated with good success. Sometimes an operation is also necessary. Quite a few patients can be cured in this way. In some of the patients treated in this way, however, a relapse in the form of multiple myeloma can develop over the next 10 years.

Complementary therapeutic measures

Supportive measures are very important in the treatment of multiple myeloma. Bisphosphonates can counteract the loss of bone substance and relieve pain. Irradiation of bone foci can also have a pain-relieving effect and can be used to prevent bone fractures. Existing fractures usually need to be treated with surgery. Broken vertebral bodies can be stabilized by orthopedic surgeons using bone cement (kyphoplasty, vertebroplasty). If these measures are not sufficient, adequate pain therapy must also be given.

In many cases it is advisable to replace blood components in the course of the disease, and more rarely also immunoglobulins. Vaccinations can offer some protection against certain infections (e.g. flu, pneumococcal infection). If necessary, a hyperviscosity syndrome can be treated with plasmapheresis, which can "filter out" excess protein bodies from the blood.

Prognosis: What is life expectancy with multiple myeloma?

The existing organ damage, such as permanent damage to the kidney despite therapy, play an important role in the prognosis. In addition, there are other prognostic factors that allow a statement to be made about the probable course of the disease to a certain extent. These include, for example, the level of albumin in the blood, the amount of so-called β2-microglobulin and the type of chromosome changes in the tumor cells.

The disease cannot currently be cured. In many cases, however, a significant improvement in survival time and quality of life is possible thanks to newer therapeutic approaches. Further therapies and substances are in clinical trials and give hope for further improvement.

This text was created with the kind support of the Cancer Information Service at the German Cancer Research Center in Heidelberg.


Further sources:

  • Onkopedia, Multiple Myeloma. Online: https://www.onkopedia.com/de/onkopedia/guidelines/multiples-myelom/@@view/html/index.html (accessed December 18, 2018)
  • Deutsches Ärzteblatt, Gericke C. et al., Dtsch Arztebl Int 2016; 113 (27-28), Diagnosis and Therapy of Multiple Myeloma. Online: https://www.aerzteblatt.de/archiv/180615/Diagnostik-und-Therapie-des-Multiplen-Myeloms (accessed December 18, 2018)
  • German Cancer Society, Multiple Myeloma, Kahler's Disease. Online: https://www.krebsgesellschaft.de/onko-internetportal/basis-informationen-krebs/krebsarten/multiples-myelom-plasmozytom-morbus-kahler.html (accessed on December 17, 2018)