Multiple Myeloma Treatment And Prognosis

Multiple Myeloma Definition: Multiple myeloma also known as Myeloma is a blood cancer that develops in the plasma cells found in the soft, spongy tissue at the center of the bones, which is made in the bone marrow. Plasma cells are the type of white blood cell responsible for producing antibodies (immunoglobulins) which are essential for maintaining the body’s immune system, that help the body fight infection and disease. Multiple Myeloma treatment and prognosis depends on the signs, symptoms & stages of myeloma.multiple myeloma treatment and prognosisMultiple myeloma does not normally take the form of a lump or a tumor, the myeloma cells split and expand inside the bone marrow, damaging the bones and affecting the making of healthy blood cells. Through a complicated, multi-step process, healthy plasma cells modify into malignant myeloma cells.

 

Plasma cell neoplasms are conditions in which the body produces too many plasma cells in the bone marrow and these cells are abnormal. Myeloma cells rise in the generation of abnormal antibodies, or M proteins. A large level of M protein in the blood is the hallmark feature of multiple myeloma. Additionally, all myeloma cells are same to each other and produce large amounts of the same specific M protein ( IgG or IgA). The M proteins offer no advantage to the body, and as the amount of M protein rises, it crowds out normally performing immunoglobulins. This eventually causes bone damage or damage the kidneys. Most of the symptoms and complications related to myeloma are produced by the build-up of the abnormal plasma cells in the bone marrow and the presence of the paraprotein in the blood and/or in the urine.

Multiple myeloma is a neoplastic disorder characterized by an abnormal monoclonal proliferation of plasma cells in the bone marrow and overproduction of circulating monoclonal immunoglobulin (paraprotein). The paraprotein is deposited in various tissues including the renal tubules, causing renal impairment, and other organs such as the heart and the gut. At these sites, the paraprotein is significantly impaired organ function. Malignant plasma cells secrete osteoblast-deactivating factors and osteoclast-activating factors leading to destructive, osteolytic bone disease. Malignant plasma cells accumulate within the bone marrow, leading to bone marrow failure manifesting as anemia, leukopenia, and thrombocytopenia as well as impaired cellular and antibody-mediated immunity.

Multiple Myeloma typically occurs in the spine, pelvic bones, ribs, shoulders and the hip joint. In addition, groups of myeloma cells cause other cells in the bone marrow to remove the solid part of the bone and cause osteolytic lesions, resulting in weakened bones and increasing the risk of fractures(osteoporosis). Although these lesions or other manifestations of bone loss do not happen in all patients with myeloma.

Also, Like: Multiple Myeloma Treatment Centers in the U.S

Multiple Myeloma Causes

The multiple myeloma causes have not yet been identified.The myeloma is poorly understood but it is caused by a complex interaction of both genetic and environmental factors.

There are multiple environmental factors which may increase the risk of developing multiple myeloma causes - include exposure to certain types of industrial and agricultural chemicals, exposure to high doses of radiation, viruses and a weakened immune system. However, there are no influential relationships, and, in most cases, multiple myeloma occurs in individuals who have no identified risk factors.

Multiple Myeloma Genetics Facts-

Myeloma is not inherited, in the similarly– such as cystic fibrosis and some forms of breast cancer – which are identified to be caused by a single inherited gene, a somewhat higher percentage of myeloma amongst family members than in the usual population which does betoken an inherited genetic element.

Studies have explained that there are some genetic ‘errors’ which can enhance the probability of a person developing myeloma and that these multiple myeloma genetic errors are inherited. However, their effect is very little. This means that individuals may inherit a certain sequence of genetic errors that put them at higher risk of acquiring myeloma but these are only a small part of the puzzle.

Multiple Myeloma happens while genetic ‘errors’ occur inside the DNA of a plasma cell. Although it is not known what causes myeloma, some risk factors have been distinguished by researchers.The chance of myeloma progress as people get older and myeloma is somewhat more common in men than women and slightly more prevalent in black populations than in white or Asian communities.

Some people go on to develop myeloma after having been diagnosed with a condition which stands for Monoclonal Gammopathy of Undetermined Significance(designated MGUS). It is usually now believed that all myeloma patients have had MGUS first, whether it did identify or not.

While some study provides evidence of inherited from multiple myeloma genetic susceptivity to myeloma, moreover studies are needed to understand the biology following the risk variants. These studies, administered in coordination with analyses of patients’ practical outcomes, are supposed to lead to additional insights into myeloma biology that encourage the development of new therapeutic agents and personalized medicine approaches to treatment.

Multiple Myeloma Symptoms

During the early stages, multiple myeloma symptoms may not produce and also any complications, and may only be diagnosed following a routine blood or urine test. Multiple myeloma is characterized by several features, which are outlined below-

  • Bone pain
  • Bone fractures and spinal cord compression
  • Fatigue
  • Anaemia
  • Repeated infections
  • Raised calcium levels in the blood
  • Confusion
  • Increased thirst
  • Unusual bleeding
  • Thickened blood
  • Peripheral neuropathy
  • Impaired kidney function

Bone Pain

Multiple myeloma causes pain in affected bones, caused by tiny fractures in the bone (lytic bone lesions) made by the accumulation of plasma cells. Most often the back, ribs or hips. The pain is frequently a persistent dull ache, which may be made worse by movement.

Bone Fractures and Spinal Cord Compression

Multiple myeloma causes may weaken the bones and make them longer likely to fracture. The spine and ribs are several often swayed.Fractures of the spine can occasionally compression of the spinal cord.Compression of the spinal cord can cause pins and needles, insensitivity and weakness in the legs and feet, and sometimes difficulties managing bladder and bowels.

Anaemia

Multiple myeloma can affect the production of blood cells in our bone marrow, which can lead to a lack of red blood cells known as anaemia. Low levels of red blood cells in the blood cause anemia-related fatigue. This can also occur as a side effect of multiple myeloma treatment.

Multiple myeloma infections(Repeated)

People with multiple myeloma are unusually weak to infection because the myeloma and its treatments intervene with the immune system.

Multiple myeloma and hypercalcemia(hypercalcemia)

A high level of calcium in the blood can develop in people with multiple myeloma because too much calcium is released from affected bones into the bloodstream.

Symptoms of hypercalcemia can include changes in urination, restlessness, increased thirst, confusion, nausea and loss of appetite.

Unusual Bleeding

Haemorrhage sometimes occurs in multiple myeloma because the cancer cells in the bone marrow can stop blood clotting cells called platelets being made.

Peripheral Neuropathy

It can be induced by the treatments for myeloma and also the myeloma itself.

Kidney problems(Impaired Kidney Function)

Indications of impaired kidney function may appear on blood tests or urine tests.Kidney damage can result in a number of additional complications and is an effect of the kidneys being overworked by the excess protein and calcium in the blood.  Abnormal proteins generated by the cancer cells can weaken the kidneys, as can other difficulties, such as hypercalcemia. Indications of damaged kidney function may appear on blood tests or urine tests.Some multiple myeloma medications used to treat multiple myeloma can also cause kidney damage.

Signs of kidney failure can include:

  • Swollen ankles, feet or hands
  • Weight loss
  • Shortness of breath
  • Itchy skin
  • Feeling sick

Multiple Myeloma  Diagnosis & Classification

  • Solitary Plasmacytoma

Plasmacytoma regards to a tumor consisting of abnormal plasma cells that develop within the soft tissue or in the bony skeleton. It can be present as a discreet solitary mass of abnormal plasma cells- called multiple myeloma. Multiple myeloma is a prototype of blood cancer of the plasma cells which are found in the bone marrow. The prognosis and treatment of solitary plasmacytomas are very different to multiple myeloma.

Plasma cells are a type of white blood cell that occurs from mature B-lymphocytes in the bone marrow. They play a vital role in protecting the body against infection and disease by producing proteins called immunoglobulins (Ig).

There are two main types of solitary plasmacytomas:

Solitary bone plasmacytoma (SBP) - abnormal plasma cells is build-up in the bone. Usually, these tumors develop in the spinal column, may also happen in the pelvis, femur,  ribs, arms, face, skull, and sternum.Some people(around 50-70% ) with SBP may go on to develop multiple myeloma over 10 years .so regularly monitored with blood tests and x-rays and/or MRI scans.

Solitary extramedullary plasmacytoma (SEP) - abnormal plasma cells occurs outside the bone in soft tissue. These plasmacytomas usually occur in the head and neck region, particularly in the nose, throat, and sinuses, but may also occur in the gastrointestinal tract, lymph nodes, lung, bladder other organs. There is less than a 10% chance of this disease progressing to myeloma.

Solitary plasmacytomas do not have the characteristic features of myeloma, which include low red blood cell counts, raised calcium levels in the blood, or diminished kidney function. And although 75% of people with SBP and 25% of people with SEP have an M-protein (cancerous plasma cells), they are usually small and disappear following treatment.

  • Multiple Myeloma

It is necessary to multiple myeloma diagnosis as quickly as possible. Myeloma can be gradual-moving or more aggressive.To get the exact myeloma diagnosis, you require undergoing a variety of tests-

  • Possible low white blood cells or blood platelets
  • Anemia
  • Elevated blood calcium
  • Raised blood creatinine and/or blood urea nitrogen
  • Risen protein level in the blood and/or urine

Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma and any one or more of the following CRAB features –

  • C for a rise in blood calcium, known as hypercalcemia: serum calcium >0.25 mmol/L (>1 mg/dL) greater than the upper limit of normal or >2.75 mmol/L (>11 mg/dL)
  • Renal insufficiency: creatinine clearance <40 mL per minute or serum creatinine >2mg/dL (>177µmol/L)
  • Anemia: hemoglobin value of >20g/L below the lowest limit of normal, or a hemoglobin value <100g/L
  • Bone lesions: If bone marrow has <10% clonal plasma cells, more than one bone lesion is required to identify from solitary plasmacytoma with minimal marrow involvement.osteolytic lesion on skeletal radiography, CT, or PET/CT.

Anyone or more of the following biomarkers of malignancy (MDEs):

  • Serum involved / uninvolved free light chain ratio of 100 or greater, provided the entire level of the involved light chain is at least 100mg/L
  • 60% or greater clonal plasma cells on bone marrow examination.
  • More than one focal lesion on MRI that is at least 5mm or greater in size.

 

  • Osteosclerotic Myeloma

A rare syndrome described by POEMS, POEMS syndrome is designated by- polyradiculoneuropathy, organomegaly, endocrinopathy, M protein, and skin changes (S). Other characteristics include papilledema, sclerotic bone lesions, extravascular volume overload, thrombocytosis/erythrocytosis, and elevated VEGF levels.

  • Sensory symptoms manifest first and then are followed by motor weakness.
  • Neurologic symptoms are symmetric and begin distally and migrate proximally.
  • Neurological symptoms usually do not improve.
  • Skin lesions are characteristic and occur predominantly in the trunk, 25-50% of skin lesions occur in the extremities.
  • Sclerotic bone lesions occur in both the axial and appendicular skeleton.

Multiple Myeloma Tests

Blood Tests

Various blood examinations are administered to attend multiple myeloma diagnosis - Complete Blood Count, Beta 2 Microglobulin, Electrophoresis, or Free Light Chain Assay. Each blood test examines various chemicals in the blood, looking for anomalies of the myeloma disease.

Urine Tests

Urinalyses, are commonly conducted to help identify signs and symptoms of multiple myeloma. Urine tests conducted to diagnose myeloma-Bence-Jones Protein Test or Urine Protein Electrophoresis. Both analyses estimate the abnormal immunoglobulins or M protein found in the urine. Abnormal levels of M proteins may symbolize multiple myeloma.

Bone Marrow Tests

Bone marrow tests-A tiny bone fragments or soft tissue from the bone is called bone marrow. Common bone marrow tests for myeloma include-Bone Marrow Biopsy, Flow Cytometry or Cytogenic Analysis.

Multiple Myeloma Pathology

Multiple Myeloma is designated by neoplastic proliferation of plasma cells comprising more than 10% of the bone marrow. Progressing evidence suggests that the bone marrow microenvironment of tumor cells plays a crucial role in the Multiple Myeloma Pathology.  This determination has resulted in the expansion of treatment options.

The malignant cells of Multiple Myeloma, plasma cells, and plasmacytoid lymphocytes are the numerous mature cells of B-lymphocytes. B-cell maturation is correlated with a planned rearrangement of DNA progressions in the process of encoding the structure of mature immunoglobulins. It is distinguished by an excess production of monoclonal immunoglobulin G (IgG), immunoglobulin A (IgA), and/or light chains, which may be recognized with serum protein electrophoresis (SPEP) or in the urine protein electrophoresis (UPEP).

The function of cytokines in the pathogenesis of Multiple Myeloma is an extensive area of research. Interleukin (IL)-6 is further an important factor encouraging the in vitro growth of myeloma cells. Other cytokines are tumor necrosis factor and IL-1b.

The pathophysiologic background for the clinical sequelae of Multiple Myeloma involves the skeletal, renal, hematologic, and nervous systems, as well as general processes.

Skeletal processes

Plasma-cell proliferation creates extensive skeletal damage with osteolytic lesions, hypercalcemia, and anemia. Mechanisms for hypercalcemia involve bony involvement and, perhaps, humoral mechanisms. Isolated plasmacytomas (affect 2-10% of patients) commence to hypercalcemia throughout the creation of the osteoclast-activating factor.

Disruption/damage of bone and its replacement by the tumor may commence to pain, pathologic fracture, and spinal cord compression.

Multiple Myeloma Stages

This Multiple Myeloma staging system is beneficial for estimating the extent of the disease and/or size of the tumor and further help for the Multiple Myeloma treatment protocol. According to this system, there are 3 stages-

Multiple Myeloma Stage I:

Many patients with Multiple Myeloma stage I  show no Multiple Myeloma symptoms because there are fewer cancer cells in the body. If cancer has affected kidney function, the Multiple Myeloma prognosis may be worse regardless of the stage. Factors characteristic of stage I include:

  • Number of red blood cells is within or slightly below normal range, Hemoglobin >10 g/dL
  • Normal amount of calcium in the blood
  • Low levels of M protein in the blood or urine-M protein<3 g/dL for IgA; <5 g/dL for IgG; <4 g/24 h for urinary light chain
  • Urine monoclonal protein excretion <4 g/day
  • No generalized lytic bone lesions, no bone damage on x-rays or only 1 bone lesion is visible

Multiple Myeloma Stage II:

Intermediate between stages I and III.More cancer cells are present in the body in stage II. Again, if kidney function is affected, then the prognosis worsens regardless of the stage.

Multiple Myeloma Stage III:

Many cancer cells are present in the body at stage III. Factors characteristic of this stage include:

  • Anemia, Hemoglobin <8.5 g/dL
  • Hypercalcemia, Serum calcium >12 g/dL
  • Urine monoclonal protein excretion >12 g/day
  • Advanced lytic bone lesions (3 or more bone lesions)
  • High levels of M protein in the blood or urine,M protein >5 g/dL for IgA; >7 g/dL for IgG; >12 g/24 h for urinary light chain.

Multiple Myeloma Treatment

Multiple myeloma treatment opportunities have significantly developed over the recent 10 years. Current multiple myeloma treatments have improved survival rates in patients with myeloma. There are many supportive new therapies under research now, but by seeking to customize treatments strategies based on our mapping of the patient’s genome.

Researchers are working on better understanding the biology of multiple myeloma. Through genomic studies of the tumor cell DNA, there are many DNA alterations in myeloma cells, and these generally differ from patient to patient. The concluding aim of the genomic study is developing personalized treatments based on the DNA in the myeloma cells of a particular patient.

DNA alterations indicate how aggressive the myeloma is and, can help guide treatment decisions or determine eligibility for multiple myeloma clinical trials.

DNA alterations and treatment

For most DNA alterations, there are not satisfactorily data to conduct treatment decisions. An exception is t(4;14). This is a type of chromosomal abnormalities called translocation in which chromosome splits and a portion of it attaches to another chromosome.

Researchers have designated that patients among t(4;14) have better results when treated with a proteasome inhibitor, such as Velcade.

There is no one standard multiple myeloma treatment. A patient’s individual treatment plan is based on-

  • Results of laboratory and cytogenetic (genomic) tests
  • Age and general health
  • Symptoms and disease complications
  • Patient’s lifestyle, goals, views on quality of life, and personal preferences

Treatment Options for Multiple Myeloma, by Stage

Solitary plasmacytoma Treatment

The treatment applied most commonly to both types of plasmacytoma is radiotherapy. The treatment is generally given over several days to reduce side-effects.Radiotherapy generally provides excellent local and often durable control of the plasmacytoma.All people with plasmacytomas require life-long follow-up. This generally involves physical examination, blood and urine tests, and x-rays, MRI or PET scans at regular intervals for at least the first five years after treatment has been completed.

Although chemotherapy is generally not used in addition to radiotherapy.

Surgery is rarely necessary but may be required in situations where plasmacytoma involvement of the bone causes skeletal instability and high risk of fracture.

Treatment for Multiple Myeloma Stage I /Early myeloma

Patients with early stage I disease myeloma or early myeloma can do well for years without treatment. If you stage I  multiple myeloma but aren't experiencing any symptoms, starting treatment early does not seem to help them live longer. These patients are usually followed closely without starting chemo or other strategies for myeloma. They may be started on a bisphosphonate if have bone disease.

Based on how abnormal the plasma cells of immunoglobulins, some patients with stage I myeloma have a high risk of progressing to active myeloma and needing treatment. The study suggests that, treating these patients with dexamethasone and lenalidomide (Revlimid)  before they developed symptoms helped them live longer.

Treatment for Multiple Myeloma StageII /III(Active Myeloma)

Patients whose myeloma is stage II or higher or who have light chain amyloidosis are often given drug therapy. If you exhibit multiple myeloma symptoms, you and your physician may decide to begin treatment.The drugs chosen depend on the patient’s health ( kidney function) and whether a transplant is planned.

Often, a combination containing bortezomib (Velcade), dexamethasone and thalidomide or lenalidomide,  is used. Combinations containing bortezomib are particularly helpful in patients who have kidney difficulties and those whose myeloma cells contain chromosome abnormalities.

Other combinations may be considered such as vincristine, dexamethasone (VAD), and doxorubicin (Adriamycin). If the patient is not demanded to have a transplant, chemotherapy with melphalan and prednisone may be practiced, and that can be combined with thalidomide.

Bisphosphonate treatment is often started along with chemo. If the damaged bone continues to cause symptoms, radiation therapy may be used.

Patients with multiple myeloma further receive supportive treatments, such as transfusions to treat lowering level of blood cell counts,  antibiotics and sometimes intravenous immunoglobulin (IVIG) is used for infections.

Chemo drugs that may be used to multiple myeloma treatment include-

  • Vincristine (Oncovin)
  • Melphalan
  • Cyclophosphamide (Cytoxan)
  • Doxorubicin (Adriamycin)
  • Etoposide (VP-16)
  • Bendamustine (Treanda)
  • Liposomal doxorubicin (Doxil)

 

Combinations of these drugs are more effective than any single drug. Often these drugs are combined with different types of medications like corticosteroids or immunomodulating agents.

Side effects of Chemotherapy

Chemo drugs are given carefully to avoid or reduce the side effects of chemotherapy. These side effects depend on the dose of drugs given and the length of time they are taken.

  • Hair loss
  • Loss of appetite
  • Mouth sores
  • Nausea and vomiting
  • Low blood counts

Chemotherapy often leads to low blood counts, which can cause -serious infection, bleeding ( thrombocytopenia), short of breath (from anemia).

Most of the side effects are temporary and go away after treatment is finished.

Corticosteroids

Corticosteroids, such as dexamethasone and prednisone, are an important part of the multiple myeloma treatment. Corticosteroids used singly or combined with other medications as a part of treatment. Corticosteroids are also managed to help decrease nausea and vomiting that chemo may produce.

Common side effects of Corticosteroids

  • Increased appetite and weight gain
  • High blood sugar
  • Sleeping Problems
  • Changes in mood become irritable

Using Corticosteroids for a long time, these drugs suppress the immune system, can lead to increased risk of serious infections.Corticosteroids can also weaken bones.

Side effects of Corticosteroids go away over time after the drug is stopped.

Bone Marrow Transplant

A stem cell transplant may be part of treatment. Options for stem cell transplant are discussed in Stem Cell Transplant for Multiple Myeloma.

multiple-myeloma-bone-marrow-transplantation

Some patients are given additional cycles of treatment after transplant. This is designated as the consolidation treatment and increases the chance of a complete response (where signs and symptoms of the disease go away).

Some patients ( didn’t have a stem cell transplant) may be given long-term treatment with lenalidomide, thalidomide, or bortezomib. This is known as sustaining treatment and supports delay the return of the myeloma, but it can cause severe side effects.

Many drug combinations can be useful in multiple myeloma treatment. If a drug stops working on myeloma others can be tried.Treating multiple myeloma using these drugs -

  • Melphalan and prednisone (MP), with or without thalidomide or bortezomib
  • Thalidomide (or lenalidomide) and dexamethasone
  • Vincristine, doxorubicin (Adriamycin), and dexamethasone (called VAD)
  • Bortezomib, dexamethasone, and thalidomide (or lenalidomide)
  • Bortezomib, doxorubicin, and dexamethasone
  • Liposomal doxorubicin, vincristine, dexamethasone
  • Dexamethasone, cyclophosphamide, etoposide, and cisplatin (called DCEP)
  • Carfilzomib, lenalidomide, and dexamethasone
  • Dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, and etoposide (called DT-PACE), with or without bortezomib
  • Ixazomib, lenalidomide, and dexamethasone
  • Panobinostat, bortezomib, and dexamethasone
  • Elotuzumab, lenalidomide, and dexamethasone

Multiple Myeloma Prognosis

The prognosis of multiple myeloma as well as survival rates is usually based on the signs, symptoms, and have improved due to myeloma research. The multiple myeloma prognosis is also subordinate on the stage of the disease. Survival rates are sometimes used by physicians to explain a patient’s prognosis.

Multiple myeloma Prognosis depends on several clinical and laboratory findings that contribute important data. These prognostic indicators are how fast the tumor is spreading, the biologic makeup of the tumor, the extent of disease, the response to the therapy, and the overall health status of the individual patients.

Survival Rates by Stage for Multiple Myeloma

Physicians often use survival rates as a standard way of addressing a person’s prognosis (outlook). Some patients with cancer may want to know the survival statistics for people in similar situations. Many other factors can affect your outlooks, such as your age and general health, the treatment you received, and how well your cancer responds to treatment.

The numbers below are the estimated overall median survival applying the International Staging System.

Stage I-Median Survival-62 months

Stage II-Median Survival-44 months

Stage III-Median Survival-29 months

These survival times are timed from the point that treatment, such as chemotherapy, first started. Many patients, such as those with indolent or smoldering myeloma, have a good deal of time after diagnosis before treatment is started. Also, these patients have treated anywhere from 5 to 25 years ago. Treatment considering then has improved considerably and present results are likely to be better.