Despite the frequent advances in the field of cancer research and medicine, we don’t fully understand how cancer develops and what we know is still restricted to the genetics of many cancers regarding the gene disturbed that led to the uncontrolled proliferation of such cells. In multiple myeloma, there is no exception. The cancer that was first described in 1848 remains a serious problem which we still don’t know everything about.
What is multiple myeloma?
Multiple myeloma is a cancer of the bone marrow which resulted from several genetic defects that lead to increased division of a certain “line” of cells called plasma cells in the bone marrow. As is the case with many cancers, there is a premalignant stage, which means that such cancer doesn’t develop out of the blue but was preceded by a detectable stage in which it was not fully developed. This stage is called MGUS or Monoclonal Gammopathy of Undetermined Significance. The term looks intimidating, but its explanation is quite simple: monoclonal means that those cells resulted from a single “clone” or a mother cell. This is, in fact, the case with most blood cancers where they develop due to a single cell losing control of its proliferating machinery leading to uncontrolled division. The term gammopathy refers to the problem arising from plasma cells. Plasma cells are white blood cells of the B lymphocyte type after their activation. They are responsible for the production of antibodies which are proteins that are also termed “gamma globulins”.
During the stage of MGUS, mutations accumulate which is another key stage in the development of cancer, we need multiple mutations and alterations in DNA to develop the full blown uncontrolled disease because we have inherent defense mechanisms which protect us against such conditions. They include repair genes which repair any defects in DNA during cellular division or in response to external factors as well as “suicide” mechanisms that force the cells to kill and eat themselves from within in case of a fatal error in their genetic material.
After the MGUS stage comes the smoldering myeloma stage which is intermediate between MGUS and multiple myeloma. The differentiation between MGUS, smoldering myeloma and multiple myeloma stages is based on certain criteria including the level of a certain protein called the M protein secreted by the abnormal plasma cells of multiple myeloma.
Cells of multiple myeloma are subject to numerous factors that affect their growth and the disease’s severity. This usually has to do with what we call a “tumor microenvironment” which includes the multitude of chemical substances secreted from cancer cells that further affect their growth and the pattern of their division. This microenvironment is usually independent of the body’s control and therefore the growth of cancer is uncontrollable.
What causes multiple myeloma?
Although we understand the genetics of most cancers, and even though such understanding helps us predict their behavior and develop new drugs for their treatment, it serves little to prevent them. The causes behind such mutations remain unknown in many cases and few are the cancers that we know the exact reasons to their development. In multiple myeloma, we understand the genetics well, but several studies are still needed to affirm the reasons behind such genetic alterations.
Some of the confirmed associations are those between working in the petrochemical industry, agricultural fertilizers exposure and radiation exposure and the development of multiple myeloma. Other studies point out a possible relation between certain infections or autoimmune diseases and multiple myeloma but they remain largely theoretical.
Multiple myeloma symptoms
Multiple myeloma is a cancer that affects different body organs and systems and therefore, the range of symptoms that result from it are diverse. Symptoms include the following:
1) Asymptomatic
Like many cancers, multiple myeloma can present in an asymptomatic patient through routine checkup, lab tests or due to an unrelated problem. The doctor can order a protein measurement of the blood and find that there is an unfilled gap of protein. Our serum, which is the fluid in which our blood cells move, contains 2 main proteins, albumin and globulin. Albumin is our chief protein and is produced by our liver, while globulins or antibodies are produced by our plasma cells. A wide gap between total protein and albumin levels could indicate an excessive secretion of antibodies.
2) Bone pain and fractures
Up to half the patients with multiple myeloma present with problems related to their skeletal system. Due to the rapid growth and division of multiple myeloma, it “eats” through the bone and causes it to weaken, making it susceptible to fracture with minor or no trauma. This is called a pathological fracture. Due to the rapid expansion of the myeloma in the bone marrow cavity, the pain-sensitive covering of the bone “the periosteum” becomes irritated leading to pain which can be severe.
3) Fever, fatigue and weight loss
Those symptoms are general in nearly all types of cancers due to the rapid destruction and formation of cells. The destruction of cancer cells does occur at a rapid rate but is always overshadowed by their rapid division. This destruction releases many chemical mediators which cause the fever. The diversion of nutrition from normal cells causes the weight loss and fatigue.
Having a fever, however, is not indicative of malignancy at all, and many other causes for fever and weight loss are excluded by a brief history taking by your physician. Common causes like infections can cause both especially if they involve the gastrointestinal system like gastroenteritis. Tuberculosis is also known to cause both and to have a chronic course similar to cancer. Tuberculosis is also characterized by night sweating, coughing and bloody sputum in some cases.
4) Back and neurological symptoms
Involvement of the spine can affect the spinal cord which runs in the spinal canal. The spinal cord contains nerve fibers which are responsible for sensation and movement of muscles as well as sphincteric control. The severity of affection depends on the extent of the disease as well as the level of affection, the higher the lesion, the greater the affection. It can present by loss of sensation beneath the level of affection, muscle weakness and paralysis as well as incontinence of urine and stool.
5) Gout and gouty arthritis
One of the chemical substances released when cancer cells are destroyed is uric acid. It is the end product of the genetic material of the cell and is normally excreted by the kidney in urine, however, if its level rises high enough, the kidney can’t excrete it effectively and it will crystallize in joints especially those of the feet like the big toe and the small joints of the hand causing significant pain and discomfort.
6) Urinary stones and renal failure
Uric acid crystals can also cause stones of the ureters and the kidney and, in severe cases, can cause renal failure.
There are many causes for renal failure in multiple myeloma including excessive excretion of calcium from bones, increased excretion of abnormal proteins which can also impede the kidney’s ability to properly filter blood and lastly, increased uric acid production as mentioned above.
7) Manifestations of hypercalcemia
When the bone is destroyed, large amounts of calcium are released into the blood which can cause several problems. The patient feels tired, weak and thirsty. Patients also suffer from constipation and it can be a precipitating factor for kidney stones.
8) Swellings at various body sites
This is a peculiar symptom in multiple myeloma. Plasma cells numbers increase rapidly that they are deposited in tissues in the form of swellings in the mouth, throat, ear canal and face. They are usually not painful but can cause a significant cosmetic discomfort.
9) Anemia
One of the most common complications of multiple myeloma is the encroachment of plasma cells on the normal cells of the bone marrow leading to deficiencies of blood cells. This can involve red cells causing anemia. Anemia is a laboratory term but symptoms include: generalized weakness and fatigue, breathlessness, pallor, awareness of heart beats due to the rapid heart rate, and in severe cases, attacks of syncope or dizziness -because not enough oxygen is reaching the brain.
10) Infections
Although multiple myeloma originates from cells which are essentially immune cells, those cells are dysfunctional. Cancer cells are like zombies and never perform their main function as healthy cells.
The rapid division of such cells also encroaches upon healthy white blood cells in the bone marrow causing their death and therefore decreased number of white blood cells in the circulation. This leaves the body highly susceptible to infections especially what we call “opportunistic infections” which are infections caused by organisms that are normally weaker than the body’s immunity, so they take the opportunity and infect when the body is vulnerable. Infections also become more severe and can be life-threatening.
11) Bleeding, petechiae and bruises
Our hemostatic mechanisms are those which protect us against excessive bleeding and they include: blood vessels that contract when they are injured to limit blood loss, platelets which aggregate and plug the defect and the coagulation which forms the blood clot. Platelets originate from their mother cells “megakaryocytes” in the bone marrow. Due to the rapid growth of multiple myeloma, those mother cells are decreased in number and consequently, platelet number falls. In some other cases, coagulation factors can be affected due to their destruction by the deformed antibodies produced by plasma cells of multiple myeloma. This disorder can manifest by bleeding from surfaces including the skin in the form of small red dots called purpura or large bruises in response to minor or no trauma at all. Bleeding can also occur from the lips, gums and vagina. It can also appear in urine or feces. If platelet count falls too low, bleeding can occur within the cranial cavity and into the brain. This becomes life threatening and has to be managed rapidly and meticulously.
12) Symptoms due to increased blood viscosity
Blood has a degree of viscosity dependent on the number of cells and amount of protein present in the serum. Increase in the number of cells or proteins can cause hyper viscosity. In multiple myeloma, this results due to the excess protein produced by multiple myeloma cells. Increased blood viscosity present by:
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- Headache and sleepiness: The explanation is that when the blood is viscid, the circulation becomes sluggish and not enough oxygen reaches the brain. This can also be associated with tinnitus – a persistent buzzing or ringing sound in the ears-.
- Chest pain: The chest pain associated with hyper viscosity is similar to that of angina and heart attacks. Sluggish circulation deprives the tireless heart muscle of the most needed oxygen causing the chest tightness felt in angina. This tightness or pain usually involves the entire chest and especially behind the breastbone, becomes worse on effort and is partially or completely relieved on rest.
- Calf pain: This condition is called intermittent claudication and is usually found in patients with vascular diseases. This also results from the inadequate oxygen delivery to calf muscles. It presents as a cramping pain on walking and is usually relieved on resting.
- Neurological problems: The same mechanism that caused heart attacks can cause strokes in hyper viscosity and presents by weakness on one side of the body, loss of sensation, inability to speak or numbness of the face, tongue and lips.
- Eye manifestations: Hyper viscosity can cause blurry vision retinal detachment, retinal bleeding and permanent loss of vision.
13) Symptoms of amyloidosis
Amyloidosis is a clinical condition in which an abnormal protein called amyloid is deposited in tissues and can be a result of old age in some cases or due to a large number of diseases including cancers in other cases. In the case of multiple myeloma, it can produce an enlarged tongue, skin swellings and swellings around the shoulder joint when they deposit around it, a sign known to clinicians as shoulder pad sign. Amyloidosis can also occur in the wrist leading to a syndrome known as carpal tunnel syndrome, where the median nerve which supplies some hand muscles and carries the sensation of your first 3 and half fingers is affected. This causes pain and numbness of the hand as well as difficult movement and weakness of the muscles supplied by the nerve.
Diagnosis
Diagnosing multiple myeloma is no easy task and the doctor will almost always require special investigations to confirm their diagnosis. It will include careful noting of symptoms and asking whether more are present then, a physical examination is carried out which includes vital signs such as checking your fever, pulse and blood pressure, palpating the tender bone as well as a careful abdominal examination which includes checking the liver and spleen for enlargement -as is the case in some blood cancers-, checking the skin, gums and lips for signs of bleeding, careful fundus examination of the eyes for signs of hyper viscosity as mentioned earlier and a thorough neurological examination including checking sensation and motor functions of your upper and lower limbs to ascertain spinal cord involvement.
A) Laboratory investigations
Laboratory investigations are essential to confirm the diagnosis of multiple myeloma. It includes tests done on the patient’s blood to detect some of the products of plasma cells responsible for multiple myeloma as well as the level of such products.
B) Blood tests
- Complete blood count: A complete blood count is the most basic of lab investigations and in multiple myeloma, it can show a decrease of all blood elements, a condition termed pancytopenia which, if combined with a normal sized spleen, almost always points towards an abnormally functioning bone marrow -due to plasma cells invasion-.
- Coagulation tests: Coagulation tests are done to detect the effectiveness of your coagulation factors. As mentioned earlier, it can be affected, and this will result in a prolonged coagulation time.
- Protein level: As mentioned above, a significant difference or “gap” between total protein and albumin levels reflect a high globulin level and could point towards multiple myeloma.
- Kidney function tests: Urea and creatinine may be needed to check for kidney functions which may be impaired due to the monoclonal antibodies secreted by plasma cells, high uric acid levels or amyloidosis. Uric acid level is also essential especially in patients with symptoms of gouty arthritis.
- Serum electrophoresis for proteins: One of the tests done in multiple myeloma is electrophoresis which is a physical process in which proteins in the blood are separated depending on their molecular weight and electric charge. This is then represented on a graph and a specific pattern of protein distribution is characteristic for multiple myeloma. This can also be followed by immunofixation which is another physical process where proteins are separated according to the shape of their surface using antibodies.
- C reactive protein: C reactive protein is one of the inflammatory markers of the body and its measurement in cases of multiple myeloma can serve as a prognostic marker, which means that cases with high levels of CRP can be predicted to have a worse outcome and vice versa.
C) Urine analysis and tests
Urine tests may not look as important as blood tests, but one test in particular is of great importance which is the detection of Bence Jones proteins that are also products of plasma cells that are filtered in urine. The level of such proteins can also serve to detect the severity of the condition and to categorize it as being in the MGUS, smoldering stage or multiple myeloma stage. Kidney functions can also be estimated by the level of creatinine in urine collected for 24 hours.
D) Radiological investigations
Radiology is also crucial in diagnosing multiple myeloma, and this can be attributed to the destructive effect the disease has on the skeletal system. It can also be essential to predict which bones are more liable for fractures in the near future and to provide the best care needed to avoid that fracture.
Xray remains the most basic and commonly used radiological investigation in multiple myeloma. The most radiographed bones are the skull, the vertebrae and the pelvis. The skull usually looks “moth-eaten” on x-rays, which can only be seen in a handful of diseases. This method of investigation can also be of particular importance in cases under on follow up to detect disease recurrence.
Magnetic resonance imaging or MRI is also frequently used for a different reason than Xrays. MRI has the advantage of showing soft tissues like ligaments, cartilage and nerves with a better accuracy than x ray and CT scan. It is used particularly for cases with neurological symptoms to detect spinal cord compression.
E) Bone marrow biopsy
Bone marrow biopsy is an investigation commonly requested for patients presenting with symptoms of decreased blood cells or showing pancytopenia on complete blood count test. The procedure is usually done in an outpatient setting in clinics and in some cases in hospitals. A specimen of the bone marrow commonly taken from the hip bone is obtained using a special needle and examined under the microscope. In case of multiple myeloma, the specimen will show an excessive plasma cell count.
Multiple myeloma treatment
Cancer therapy has taken long strides in the past century, and this has reflected on the complexity of therapeutic regimens. Cancer was originally treated in a crude manner with limited chemotherapeutic agents and surgery for solid tumors. This, however, is no longer the case and more complex and specific therapies are discovered on a near-daily basis. Multiple myeloma therapy is no different and for best results, therapy is tailored according to the patient’s condition’s severity, their age and their overall health. For best outcome, it is ideal to obtain as much response from the first round of therapy -as is the case in most malignancies-. Recurrence is usually more sever and second-line therapies are never as effective.
Generally speaking, multiple myeloma is not completely curable, but current therapies -if successful- can cause a remission and improve lifespan for patients through avoiding complications. Treatment lines include chemotherapy, immunotherapy, radiotherapy, stem cell transplantation and surgical care for select patients.
A) Chemotherapy
For diseases which have no cure, the general consideration is to improve the patient’s quality of life, which means that early initiation of therapy may not be the best course of action, so if you have multiple myeloma with no symptoms -as is the case in up to third of patients-, your doctor may recommend postponing your chemotherapy. Chemotherapy’s role in multiple myeloma is largely as a symptomatic treatment. It serves to decrease the number of cells of multiple myeloma “the tumor burden” to relieve symptoms resulting from their proliferation. This can be monitored by the level of protein in urine (Bence Jones proteins) or M protein in the serum.
The most commonly used chemotherapy regimen is a combination of three drugs: Vincristine, doxorubicin and dexamethasone. The last one is a steroid which is typically used in most chemotherapeutic regimens to decrease the inflammation produced from the destruction of cancer cells. Another effective triad of drugs is Thalidomide, doxorubicin and dexamethasone. Those chemotherapeutic drugs can only be used in young, overall healthy individuals.
As for old or frail individuals, therapy is mainly restricted to Thalidomide, lenalidomide, and bortezomib. They have a better safety profile and are better tolerated. The previous drugs are used to create what we call an induction therapy, that is to hit the cancer and rapidly reduce its cells, but even if induction therapy is successful, the risk of recurrence is still high, and that’s why it has to be followed by a maintenance therapy. Several regimens can be used for maintenance therapy or even for recurrent disease. They include drugs like bortezomib and thalidomide with or without corticosteroids.
B) Stem cell transplantation
Stem cell transplantation remains one of the best therapies for most blood malignancies and many other blood disorders like thalassemia. It is an invasive and risky process, but its effectiveness in the treatment of multiple myeloma is unparalleled. The process usually used in multiple myeloma is called autologous stem cell transplantation in which cells of the same patient are harvested and this is followed by high doses of chemotherapy or radiotherapy to kill any cancer cells along with the bone marrow of the patient, then the harvested cells are reinfused and created the “new marrow”. The process can also be done without ablating the old marrow completely which, in some studies, has shown greater results in fighting off myeloma cells, but has also increased the risk of graft-versus-host disease.
Graft-versus-host disease is considered the most serious complication of stem cell transplantation in which the transfused bone marrow attacks the body and can cause death in severe cases. This, however, has been greatly minimized with modern techniques and autologous stem cell transplantation rather than the use of donor cells “allogenic stem cell transplantation”.
C) Radiotherapy
Radiotherapy is one of the lines of treatment of many bone cancers and multiple myeloma is highly susceptible to radiation that it basically melts by it. It is usually used in patients with symptoms especially those related to the skeletal system and those with impending fractures. It shouldn’t, however, be used in severely affected bones as it can accelerate its destruction in such cases.
D) Surgical treatment
The role of surgery in cancer is diverse. It can be used as a definitive surgery in some cancers like colon cancer, but in multiple myeloma, it is mainly used to protect against or treat fractures induced by bone destruction caused by multiple myeloma. Bones that are liabel for fracture are fixated and those fractured are reduced and fixated. Spinal cord fractures can occur in the form of compression fractures that need decompression.
E) Medical therapy for bone disease
Some drugs have been advocated for the skeletal disease in multiple myeloma. They function to decrease the normal osteoclastic activity of the bone. Our bones are in a continuous state of destruction and formation. Destruction is carried out by cells called osteoclasts while formation is done by cells called osteoblasts. On decreasing osteoclastic activity, the rate of bone destruction decreases, and the amount of calcium released into the circulation is decreased. Two main drugs serve this purpose: bisphosphonates and denosumab.
F) Treatment of complications
Some of the complications of multiple myeloma may need to be treated separately, for example:
- Renal or ureteric uric acid stones may need to be treated whether medically or surgically
- Severe anemia may respond well to erythropoietin or erythropoietin analogues which function to stimulate the bone marrow to produce more red cells.
- Vaccinations may be necessary in some cases to avoid infections.
- Plasmapheresis may be needed in renal impairment due to excess antibodies. It helps wash out the excess antibodies from the circulation.
Outcome
It is no easy task to predict the general outcome of the disease in multiple myeloma since it differs widely between individuals depending on the severity of the disease, their age and their overall health status prior to the disease. Speaking in broad terms, however, the disease has a survival rate ranging from 1-10 years depending on the choice of therapy and the response to initial therapy. Patients who receive stem cell transplantation remain the best in terms of survival and those who develop severe kidney affection or multiple fractures have the worst outcomes.