Blood Hematopoietic Disease: Multiple Myeloma and related diseases

• Intractable hematopoietic malignancy
• Abnormal proliferation of Tumor plasma cells
• Common symptoms are hypercalcemia and anemia
• Adverse prognosis in high risk group
• CT and MRI are the must since bone lesion appears on entire body.
• Treatment is different depend on Transplant adaptation or Non-transplant adaptation.

Intractable hematopoietic malignancy

Multiple Myeloma is a kind of blood malignancy, and it is an intractable hematopoietic malignant tumor which indicates diverse symptoms. Plasma cell neoplasm (there are forming a mass outside marrow type and appearing isolated to bone type), Plasma cell leukemia, Primary macro globulin (LPL) and Immunoglobulin-mediated (AL) amyloidosis are the relative disease. (Fig.1). There is a case which is diagnosed at medical checkup from abnormally high value of total protein or high value of ZTT (Kunckel Turbidity Test). It shows undetermined disorder of kidney so that there is a case which is diagnosed by Bence Jones protein (BJP) positive since kidney dialysis implementation. This disease becomes common for aged person over 60, but it may be seen in 30 to 40 years younger person.

Abnormal proliferation of Tumor plasma cells

There are, case which total protein is increased due to the production of monoclonal abnormal gamma globulin (M Protein) by abnormally proliferated myeloma cells, and case which total protein is under normal, but light chain of gamma globulin (κ chain or λ chain) is abnormally produced so that they are detected in blood/urine as Bence Jones protein (BJP). There is a case which both M protein and BJP protein are detected. When myeloma cell infiltrates bone marrow, it disorders hematopoietic capacity then develops the anemia. And when it infiltrates bone and develops bone lysis, it presents with bone ache and hypercalcemia symptoms.

Common symptoms are hypercalcemia and anemia

As above onset mechanism, primary symptoms of the disease are CRAB symptoms (hypercalcemia, kidney disorder, anemia and bone lesion). In case of nervous symptom, fatigability, languor or altered mentation caused by hypercalcemia are seen. Because of blood viscosity increased by high protein (especially lgM) (Hyperviscosity Syndrome), headache, impaired vision and retinopathy are shown. There is a case where altered mentation is shown by hyperammonemia. When myeloma cell is infiltrated into vertebral canal, it develops guts pain and bladder rectal disorder by cord compression, and when further advanced, it develops quadriplegia. And there is a case where peripheral neuropathy is onset due to the accumulation of amyloid protein. (AL amyloidosis).

Adverse prognosis in high risk group

Serum single-clone protein content、percentage of myeloma cell in bone marrow, MGUS（Monoclonal gammopathy of undetermined significance）depend upon the level of myeloma-related organ disorders, Smoldering or indolent myeloma and Symptomatic multiple myeloma are distinguished. Diseases may possibly be advanced in this sequence as time proceeds. In stage classification since 2005, IMWG International Staging System：ISS, judged from βMG and albumin value in blood serum, are generically used to distinguish stage I, II and III. With conducting the treatment, long-term survival is possible in low risk group regarding to prognosis, but in high-risk group, there are adverse prognosis case despite of therapeutic advance.

CT and MRI are the must since bone lesion appears on entire body.

Examination for the diagnosis are as follows.

Universal Testing

Peak of M protein (Fig.2) is verified by ordinally protein fraction inspection in blood serum. By immune electrophoresis, single-chronic protein is confirmed in either IgG, IgA, IgM or IgD, and either κ chain or λ chain (IgG-κ, igG-λ, IgA-κ, IgA-λ etc.). BJP is tested by Urine Test. Check protein urea. Existence or non-existing of anemia or platelet depletion are checked by CBC. Albumin and β2 micro-globulin are tested by biochemical examination. Also, calcium and ammonia are measured because of the cases which shows hypercalcemia or hyperammonemia. In about 30 to 40% cases, some sort of kidney disorder symptom is shown, so that existence or non-existence of kidney disorder in Kidney function test. In the image test (simple X-ray), bone lysis image called as punched out lesion is seen. Since bone lesion can be seen at entire body bones like cranial bone, vertebral body or long bone, CT, MRI and when necessary PET-CT test are necessary.

Free-Light Chain Test

Generally speaking, immune protein is consists of heavy chain and light chain (κ chain and λ chain). Plasma cell produces more light chain than necessary, and over produced light chain flow out into blood as Free-Light chain: FLC because it is unable to connect with heavy chain. They exist under normal condition, but under myeloma or myeloma related diseases, ratio of κ/λ has an great gap so that their evaluation becomes necessary to reflect disease activity.

Bone-Marrow Examination

Not only evaluating the percentage of myeloma cell at smear, but also abnormal karyotype of translocation, such as t(14;16) or t(4;14) recognized as high risk group, are identified by chromosomal study or fluorescence in situ hybridization (FISH). Also, [CD38 Multi Analysis] for SRL by Flowcytometry, and Marrow Plasma 38 (bone myeloma-CD20 Analysis set) for BML are requested. They are classified with Immature, intermediate, matured type by the expression result of various character (MPC-1, CD45, CD49e) of myeloma cell. And there exists possible receptivity difference by its degree of differentiation, differentiation evaluation is also important.

Treatment is different depend on transplant adaptation or non-transplant adaptation.

Replacing with conventional MP Treatment or VAD treatment, current treatment has undergone a radical transformation by the implementation of new treatment drugs. Lenalidomide (Revlimid), Bortezomib (Velcade), Thalidomide (Thaled), Pomalidomide (Pomalyst) and Calfilzomib (Kyprolis) can be used.

Depend on transplant adaptation (usually under age of 65) or non-transplant adaptation (over 65 years old), the treatment method is different. In former case, remission introduction therapy or reinforcement therapy by autologous hematopoietic stem cell transplantation (ASCT) + high dose chemotherapy (HDT) can build in, but for latter case, chemotherapy is a primary treatment. At present, standard treatment for first-time case of non-transplant adaptation, MPT (Melphalan = Alkeran + Prednisolone + Thalidomide), MPB (Melphalan = Alkeran + Prednisolone + Bortezomib) or Ld (Lenalidomide + Dexamethasone in low dose) are recommended. First-time treatment may have started with Bortezomib hypodermic injection only for aged person in oral difficult cases. For the example of positive bone lesions, Zoledronic acid (Zometa) is adequate, but need to pay attention for onset of necrosis of the jaw bone or osteomyelitis of the jaw. There are many cases where cingulum appears in high frequency during chemotherapy so that the nerve pain after cingulum becomes a major concern on the treatment.

Fig.1: Multiple myeloma and its relative disease

Fig.2: Comparison of monoclonal (M protein) and Polyclonal protein by Fractionation of Protein