Pathophysiology of multiple myeloma:

1- Origin of myeloma clone and its future medullary:

– There seems to be born of memory B cells after activation in germinal centers of the spleen (or peripheral nodes).

– The “critical” event could occur upon reactivation by the antigen, the consequences of translocation at the time of the Switch in the region encoding the heavy chain genes of immunoglobulins (IgG or A or E …) in chromosome 14 – even in myeloma “light chain”.

– The initial clonal cell is “prémédullaire”. It circulates in the blood and will stay “random” in the marrow (homing) where, under the effect of cytokines and growth factors, it will proliferate.

– The role of the microenvironment of the marrow is important for the development of spinal cord disease (dendritic cells, KSHV or HHV-8 virus infecting dendritic cells, various growth factors HGF, fibroblast growth factor (FGF) and especially the IL-6 stromal cells).

– One of the major stimulants of the proliferation of myeloma cells as osteoclastic activity is interleukin 6 (IL-6) produced mainly by the spinal périplasmocytaire atmosphere, but also by producing plasma cell autocrine and whose rates is proportional to that of C-reactive protein (CRP) that follows. The transforming growth factors (TGF) b1, secreted by the plasma cells, stimulates the production of IL-6 and depresses normal B cells and T. IL-6 inhibits apoptosis induced by dexamethasone (and, conversely, dexamethasone decreases the activation due to the IL-6), but not that induced by irradiation. The IL-1-b is expressed by the myeloma cells [and not by normal plasma cells or – or rarely – in monoclonal gammopathy of undetermined significance (MGUS)] and appears to contribute to malignant scalability.

– New events “oncogenic” can occur, further exacerbating the “malignancy” proliferation: mutation of the ras oncogene (in 1/3 of patients) (originally independent cells IL-6 ); mutation (inactivation) of the p53 gene (especially in plasma cell leukemia); suppressor Rb gene mutation (which facilitates the entry into S phase); . various deletions of CDK inhibitors (antagonists of the inactivating effect of pRb); overexpression of cyclin D (which inactivates pRb with CDKs and promotes entry into the cycle); overexpression (rather than rearrangement) of c-myc or Bcl-2.

2- prémyélomateux States: monoclonal gammopathy of undetermined significance

It has long been called “benign monoclonal gammopathy” situations (3 times more common than myeloma “symptomatic”) where a stable monoclonal immunoglobulin was observed without any tumor scalability event (bone disease; cytopenia or hypercalcemia) and without either inhibition of lymphocyte clones normal B: So without lower rate of other immunoglobulins. A guidance element is the low peak rates (less than 30 g / L) and – typically – the low plasma medullary (<5 or 10%), although the latter sign is more debatable. These states, indeed often of long evolution and spontaneously “benign”, today called monoclonal gammopathy of undetermined significance. The work of Kyle are well appear that this is actually myeloma clones stabilized at a low level of malignancy, but with the characters of malignancy (eg proved by the existence of quantitative abnormalities of DNA content cells), which confirms the risk of subsequent progression towards an authentic haematological malignancies (myeloma, lymphoma, or macroglobulinemia) estimated at 20% at 13 years. This malignant scalability is dependent cytokine action (Fig. 1) and induced by the occurrence of secondary events listed above. All inherently “malignant” it is, this monoclonal gammopathy “stable” does not justify treatment in the present state of our knowledge. At this stage chemotherapy trials are often ineffective, so harmful (for the risk of infection or leukemia); it is not impossible that chemotherapy can even help generate an activation of quiescent clone or select resistant cells.

3- Etiology:

As in many malignant diseases, “carcinogenesis” myeloma is multifactorial. The hypothesis of a viral factor progresses today and it seems that the virus associated with Kaposi’s sarcoma (HHV-8), very often objectified in dendritic cells myeloma (but not plasma cells), plays an important role. Environmental factors are possible and explain notably more frequent among farmers. Finally, the existence of some familial cases is genetic discuss participation of individualizing “lands at risk.”

4- pathophysiological explanation of symptoms:

– Several cytokines secreted by myeloma cells or induced effects on the bone marrow stroma (IL-6, TNF b) have a stimulating activity on osteoclasts (osteoclast activating factor, OFA): this results in osteolysis by decoupling construction and process of bone destruction. This stimulation of osteoclasts is in contact with the malignant plasma cells. These are grouped into small clusters nodular (the cells normally having adhesion molecules on their surface), so osteolytic lesions are usually disseminated micronodular appearance. At osteolysis joins a trend of hypercalcemia (usually without hypophosphatemia), which is not strictly proportional to the abundance of bone lesions, and can make its own symptomatology and risk of renal tubulopathy. These multiple bone lesions weaken the bones affected (those that contain the most marrow, that is to say, the bones of the axial skeleton and ribs), and promote microfractures (painful), or spontaneous fractures of certain diaphyses ( femur, humerus), ribs or vertebrae (settlement).

– In some forms, plasma cells do not express adhesion molecules (CD56 particular), resulting in a loss of homing and propensity to group into clusters spinal cord: the case of rare “plasma cell leukemia “where the bone lesions, initially less frequent, are more often diffuse type of decalcification. However, rare forms are osteoblastic. They are not associated with hypercalcemia and especially see themselves in a very special form, the POEMS syndrome.

– From bone lesions, the plasma cell tumor can spread to neighboring structures: pleural invasion from a coast, above all, from a vertebra, extending to the spinal canal (risk of epidural involvement and compression spinal cord) or the conjugation holes (intercostal neuralgia, sciatica).

Effects of cytokines and scalability of the myeloma cell
Effects of cytokines and scalability of the myeloma cell
Electrophoresis secreting myeloma: the "peak in the plain"
Electrophoresis secreting myeloma: the “peak in the plain”

– Like any malignant spinal pathology, myeloma proliferation tends to be accompanied by an inhibition of normal myelopoiesis. It is especially erythropoiesis is braked, but gradually as the tumor mass increases and increased scalability will occur neutropenia and thrombocytopenia. – In 75% of cases, myeloma is “secreting”, which results in the existence of a steep narrow base on protein electrophoresis (EPP): it corresponds to the secretion of the same immunoglobulin ( Ig) by the plasma cell clone. It usually moves in gamma globulin, sometimes b-globulins (especially in the case of IgA, IgD and IgM) and is responsible for a high elevation of the erythrocyte sedimentation rate (ESR), often reaching 100 mm in 1st time, even for low rates. Biologically, this explains the phenomenon of red cell rollers that can disrupt the study of blood smear and sometimes give false macrocytosis. When the rate is very high, this can lead to hyperviscosity may sound clinical, as to result in coma. Hemodilution can also be observed and artificially increase the degree of anemia. At first, the appearance of protein electrophoresis is that of a “peak in the hill.” But in highly scalable and myeloma tumor, inhibition of normal plasma cell clones leads to a collapse of the other immunoglobulins. The appearance is then that of a “peak in the plain” (Fig. 2). There is therefore a real functional hypogammaglobulinemia. It is therefore understandable type frequent complications in multiple myeloma: bacterial infections by encapsulated bacteria, as pneumococci, which need to be opsonized for phagocytosis.

– In other cases, the plasma cell does not excrete its immunoglobulin. For the reason above view, the appearance of protein electrophoresis is that of a major hypogammaglobulinaemia. Exceptionally, it is a true non-secretory myeloma, usually with very immature cells; sometimes (1-2%), it is a secreting myeloma but not excreting, where the study of spinal cord plasma cells by immunofluorescence may objectify immunoglobulin in their cytoplasm and thus prove their monoclonal nature. Most often, there is a myeloma excreting the light chain. Pathological plasma cell is then not able to combine the heavy and light chains: light chain is released, the heavy chain may be demonstrated in the cytoplasm. This type of myeloma “light chain” or “Bence Jones protein * (GGR)” exposed more than others to the risk of kidney failure. Indeed the light chain (which is always monoclonal kappa or lambda) has a molecular weight (17,000) much lower than that of albumin, the smallest protein physiologically retained by the glomeruli: it is entirely filtered. Proteinuria resulting (which should not be sought through the strip, which detects only albumin) subject to the risk of acute anuric tubulopathy if decreased urine output or in circumstances at risk, such as using iodinated contrast agents that promote reabsorption and precipitation in distal tubule cells of the protein Bence Jones. You should know that all myeloma secreting complete immunoglobulin can excrete surplus protein Bence-Jones. Finally, in rare cases of myeloma (5-10%), almost always lambda light chain, it can be installed an array of amyloidosis, we can distinguish the primary amyloidosis with amyloid deposits AL in glomeruli, the digestive tract and especially the heart, which achieve very poor prognosis explains the short survival of these patients.


Positive diagnosis:

1- It is based on the detection of a triple combination:

– Bone marrow infiltration by monoclonal plasma cells; – Secretion of a complete monoclonal immunoglobulin in serum and (or) a light chain monotypic in the urine;

– Osteolytic lesions. The typical form combines the three. There are however shapes secreting plasma cells only light chains (with low ESR, hypogammaglobulinaemia and proteinuria) secreting or not: the search for the plasma cell infiltration of bone marrow aspiration or better, bone marrow biopsy, with study monoclonality by immunofluorescence, is then essential. It is expected to find more than 10 or 15% dysmorphic sometimes plasma cells (some kernel sometimes “blast” and strongly nucleolus, in the vacuolated cytoplasm or flame). It is less necessary for diagnosis when the elements 2 and 3 are present. Sometimes it may be best to directly address a single or doubtful osteolytic lesion (vertebra, rib) rather than performing a systematic sternal puncture: in this case, a poor plasma cells in bone marrow aspiration would not rule out the diagnosis.

2- Multiple myeloma may give many complications:

They are not always observed simultaneously, some of which may never be seen in a given patient, each of which can be revealing.

SREs: they are the most frequent and most symptomatic: osteolytic areas in the bones containing the marrow; they are responsible for:

– Pain in the axial skeleton (spine, ribs, collarbone, pelvis, femurs) and humerus;

– Spontaneous fractures (femoral neck, pelvis, ribs, vertebrae, humerus); – Bone tumors visible inspection (sternum, ribs, skull);

– Nerve compression (sciatica, cervical radiculopathy) or spinal cord (paraplegia or quadriplegia, complete or not, by spinal or rocking, especially, casting epidural);

– Or asymptomatic and only detected on plain radiographs (micro-gaps to the punch without peripheral condensation – the skull or ribs, vertebral compression, thoracic opacity device; fewer and less specific: a diffuse appearance decalcification). These myeloma bone tumors are objectified by the scanner and magnetic resonance imaging (MRI), which can detect lesions not visible on conventional radiographs. However, the standard bone scan is not kidney utile.Manifestations:

– Proteinuria by release of the free light chain or glomerular disease (amyloidosis);

– Risk of kidney failure by amyloidosis, hypercalcemia (in fact rarely involved alone), especially precipitation in the tubules of the Bence Jones protein in the course of dehydration or radiological opacification by iodinated .

Neurologic Manifestations:

– Signs of hyperviscosity (visual or vestibular disorders, apathy, drowsiness, coma);

– Spinal cord or nerve compression;

– Peripheral neuropathies by plasma cell infiltration, or amylose or anti-myelin activity of the monoclonal immunoglobulin, or paraneoplastic syndrome.

Hematologic Events: signs of anemia, and rarely late pancytopenia, often also increased by chemotherapy;thrombopathy.

Infectious events: especially pneumonia, which require dosing rates of the various serum immunoglobulins.

Events related hypercalcemia: nausea, vomiting, polyuria-polydipsia, even coma. Events related amyloidosis: nephrotic syndrome “big kidney”, joint pain (including shoulder), macroglossia, hepatosplenomegaly, biochemical failure cardiaque.Manifestations: elevated erythrocyte sedimentation rate (above 100) revealing the monoclonal peak electrophoresis of proteins, hypercalcemia, hyperuricemia. The protein electrophoresis is essential but must be complemented by typing monoclonal immunoglobulin it has identified more often used today immunofixation as immuno-electrophoresis. Always seek proteinuria with urinary protein electrophoresis if necessary.

Differential diagnosis:

1- This is not a myeloma:

Benign plasmocytoses spinal cord, which can be seen in viral infections (rubella, hepatitis, cytomegalovirus, etc.), up to 40 to 50%, or even cirrhosis: they are made of plasma cells with nuclei “mature” sometimes rich cytoplasmic anomalies, but still polyclonaux.Les other hypergammaglobulinémies sometimes revealed by very strong increases in sedimentation rate:

– Polyclonal, easily distinguished from the protein electrophoresis, in chronic infections (such as hepatitis), diseases dysimmune (lupus, Sjögren’s syndrome, sarcoidosis), cirrhosis;

– Monoclonal: benign, that can be seen in some viral infections, cytomegalovirus (CMV) including or immunoallergic reactions are reversible spontaneously within a few weeks; Malignant: Waldenstrom’s macroglobulinemia, characterized by the secretion of a monoclonal IgM by lymphocytes and plasma cells (plasma cell and not merely, as in the exceptional myeloma IgM) without bone lesion (usually), but with great frequency a frank splenomegaly, sometimes deep lymph nodes, and a tendency to hyperviscosity; one can also observe small peaks in certain lymphomas with monoclonal plasma cell differentiation, chronic lymphocytic leukemia, certain T-cell lymphomas, amyloidosis primitive.Les other osteolytic lesions:

– It is rare, but possible, that cancer metastasis give microlacunaire appearance of a skull, for example; – Is a most difficult aspects of osteoporosis in a subject over 70 years old to common senile osteoporosis and myeloma: biology, bone marrow aspiration, possibly a spinal biopsy help in diagnosis.

2- What goes under the myeloma:

Monoclonal gammopathy of undetermined significance is as a plasma cell clone small amount and not scalable (immunoglobulin levels below 20 or 30 g / L for IgA and IgG, absence of bone symptoms, hematologic, renal, absence hypercalcemia, and stable peak), but it is potentially myeloma and should be checked once or twice a year the absence of évolutivité.Le POEMS syndrome is a rare combination: a secreting monoclonal plasma cells, peripheral polyneuropathy, often an aspect of “condensing myeloma,” and multiple manifestations of paraneoplastic types: cutaneous, hematological (thrombocytosis), hepatosplenomegaly, endocrine disorders surrénaux.Le solitary plasmacytoma: proliferation remains limited in the same site (bones or digestive lymphoid structure), made of highly adhesive cells and often low proliferation kinetics. The tumor may be large. His seemingly isolated nature makes lawful localized treatment (surgery if possible or radiation) with long survivals. It is a position close enough to those of solid cancers with the same term risk (often years long) is isolated relapse again, either by spinal dissemination multiple.La myeloma plasma cell leukemia: cells circulate in abundance in the blood and the picture is that of a fast acute leukemia, with pancytopenia. The prognosis is generally very poor.


Multiple myeloma remains an incurable disease, average to poor survival: with conventional treatments, median survival is approximately 3 years and a half, all groups. Generally, under treatment, an improvement appears exceptionally complete (<5%), usually partial (reduction of at least half of the tumor mass, particularly appreciated by the monoclonal peak or proteinuria 24), with installation a phase called “plateau”. At this point, continuing treatment is not useful. This phase can last from several months to several years, then comes a relapse, often less easy to master. Gradually the disease becomes increasingly resistant, sometimes accelerated by a fatal intercurrent complications. When survival was prolonged (approximately 10 years in some cases), it can be seen occur acute leukemia induced by alkylating. Several reasons combine to explain the particularly disappointing results of conventional treatment of myeloma – the low rate of cell division cycle, which brings the other lymphoid malignancies slow kinetics (LLC, low grade lymphomas) where complete remissions are not the rule and where healing is exceptional; – The frequent acquisition of resistance to chemotherapy (including by gene transcription MDR), which explains that the effectiveness of chemotherapy is limited in time; – The specific gravity of complications of the disease (bone lesions, neurological and kidney); – The age of the patients (65 on average) and their particular vis-à-vis fragile infections (especially by the collapse of humoral immunity), which have long limited the use of high doses of chemotherapy.

The Durie and Salmon
The Durie and Salmon

Prognostic classification:

It appeared for a long time that there was great variation in survival rates from one patient to another. The concept of “tumor mass”, diagnosis, has emerged as the major prognostic criterion. The clinic Durie and Salmon, universally used, distinguishes three stages ranging from the lowest to the highest weight (table). Currently this classification appears insufficient, although still used. All authors agree to add to the estimate of the tumor mass (at best evaluated today by the b2-microglobulin), the kinetics of tumor proliferation, evaluated by the classical mitotic index (or labeling index) , or LDH, or serum C-reactive protein according to the authors. Other prognostic factors seem to bring predictive of survival: the result of the karyotype (discovery of translocations), the response to initial chemotherapy, renal function. Finally, the age now has an important value, since it allows or not the practice of intensive treatment with autologous bone marrow or peripheral stem cells, attitudes which almost doubled the hope of survival in patients under 60.

Indications of treatment:

In stages II and III of Durie and Salmon, treatment is required: – in subjects 60 to 65, increased with high dose melphalan (Alkeran) and intravenous (or) total body irradiation (TBI) with “autologous bone marrow transplantation”;– In the older subject: periodic chemotherapy as an outpatient if possible, often limited to very old combination of melphalan and oral corticosteroids, is raisonnable.Dans stage I, low tumor mass, where the average survival can be prolonged (6-7 years), many authors agree not start chemotherapy until there is no sign of scalability: the appearance of a bone lesion (possibly just talking and objectified resonance magnetic), cytopenias or steady rise of the monoclonal peak. In all cases, symptomatic treatment should be provided with vigilance alkalizing beverages, especially if there is proteinuria; opioid analgesics possibly even radiation for analgesic if total body irradiation is not an option; monitoring of the kidney, not hesitating to offer hemodialysis in patients with renal insufficiency; treatment of hypercalcemia bisphosphonate pamidronate infusions (Aredia) or taken etidronate (Clastoban); Surgical decompression of a spinal lesion causing paraparesis; optionally, polyvalent immunoglobulins infusion to prevent lung disease recurrence; plasma exchange in case of hyperviscosity.


It includes:

– The search for signs of new bone by the examination, x-rays at the slightest sign, possibly an MRI, depending on the clinical and biological evolution;

– A standard laboratory tests routinely performed at each cycle of treatment, and at least every two months in case of discontinuation, with: blood count, protein electrophoresis, b-2 microglobulinemia, calcium, creatinine, LDH or protein C-reactive and, as the case and evolution, proteinuria of 24 hours and bone radiographs (including the head). The myelogram is not useful in monitoring, except in case of suspicion of a preleukaemic myelodysplasia.

Highlights to include:

• Multiple myeloma is a hematologic malignancy developed portion of a clone lymphoid B, resulting in a proliferation of monoclonal plasma cells in the marrow. Its impact can be estimated, in France, 2 to 3/100 000 per year in its symptomatic form, somewhat larger in the United States and in the black population.

• Its frequency is increasing and increases with age: very low before age 40, it is around 1% after 90 years, with a median age of 65 years.

• There is no cure, but recent use of intensive treatment with autologous bone marrow transplantation has dramatically improved the prognosis in young patients.

Strong Points to remember:

• Multiple myeloma is due to monoclonal proliferation of B lymphoid cell undifferentiated and therefore belongs, strictly speaking, of “lymphoma” persistently matured to the plasma cell, initially, including many products secretion, the wide variety of symptoms of this highly polymorphic disease.

• Diagnosis is facilitated by the existence of a specific tumor marker, the monoclonal immunoglobulin peak, sometimes replaced by the only light chain or only observable by immunofluorescence study of spinal cord plasma.