Multiple Myeloma

 Multiple Myeloma

PKGhatak, MD

Multiple Myeloma (MM) is a cancerous disease of the Plasma cells of the bone marrow. It is a disease of the elderly and the condition is not inherited neither risk factors are known; but hepatitis C, HIV infection and Chronic Lymphocytic leukemia (CLL) patients have a higher incidence of MM.

MM is the final stage of a spectrum of plasma cell dyscrasias which starts as monoclonal gammopathy of unknown significance (MGUS) to overt plasma cell leukemia to extramedullary myeloma and finally to MM with end organ damages.

Epidemiology:

MM is very in people under 35 yrs. old. The annual incidence of MM in the USA is 300,000/yr. and 12,000 people die from MM. The worldwide incidence of MM is 80,000/yr.  New Zealand and Australia have more MM per 100,000 population. In the USA the rate is 8.2 in white men, 5.0 in women, 16.5 in black men and 12.0 in black women per 100,000 population. For Hispanic men and women, the rates are 8.2 and 5.7 respectively and the rare for Asian/pacific islanders at 5.0 in men and 3.2 in women.

Plasma Cell.

                                            Plasma cell..

About 2 to 3% of cells in the normal bone marrow are plasma cells. Plasma cells are large and have an eccentric nucleus, coarse chromatins and large cytoplasm.

In health, the majority of plasma cells are found in the active bone marrow and a few are also found in the spleen, lymph nodes and other tissues. In adults, the most active marrow is located in vertebrae, scapula, sternum, skull bones, ribs and pelvis. The plasma cells are derived from B-Lymphocytes(B-cells). B-cells are activated by a specific foreign antigen which is introduced to them by Dendritic cells. Activated B-cells in lymph nodes survive only 4-5 days. Some activated B-cells move to bone marrow and live for a very long time. Bone marrow plasma cell keeps that antigen memory permanently. When challenged again with the same antigen they quickly produce IgM antibodies (Immunoglobulin) and 10 days later start making IgG antibodies and keep producing antibodies as long as that antigen remains in the body or is reintroduced at a later time. IgA, IgD, IgE antibodies are also produced by plasma cells in various amounts and based on their location in tissue/organ.

Effects of Uncontrolled growth of Plasma cells.

Rapidly multiplying plasma cells displace other blood forming cells, and soon plasma cells number grow to 60 to 80 % of bone marrow blood forming cells. RBC, WBC and Platelet numbers decrease and anemia, recurrent infection and easy bruising develop. The secretory product of plasma cells is immunoglobulins. In MM the immunoglobulins are abnormal in both in structure and amounts. The accumulated immunoglobulin in blood makes blood more viscous and blood circulation in capillaries becomes sluggish, particularly in the retinal vessels, producing retinal hemorrhage and decreased visual acutely. The lambda and kappa light chains of immunoglobulins are excreted in urine and gradually renal function deteriorates. Bone spicules dissolve and lytic lesions are detected in an x-ray. Blood calcium levels rise in proportion to bone lysis and osteoporosis and high serum calcium usually leads to a serious medical emergency.

Symptoms of MM:

In those days before Google search, medical schools came up with mnemonics to help students memorize certain important symptoms of a disease. CRAB stood for symptoms of MM. C=calcium increase in blood, R= renal function deterioration, A= anemia, B=bone pain. Bone pain is worse at dawn and dusk and increases in intensity with physical activities. Another mnemonic is Poem syndrome. P=peripheral neuropathy, O=organomegaly,  E= endocrinopathy. M=macroglobulin levels. S=skin pigmentation changes.

 Various peripheral nerves are involved, the Liver, and spleens are enlarged, and many endocrine secretions are suboptimal. Thicken skin, changes in hair growth over the face, chest, limbs, and edema of legs and feet may develop. Other symptoms are weight loss, weakness, fatigue, confusion, and dementia.

Clinical subtypes of MM:

1. Indolent MM - patients are asymptomatic, plasma cells are up 10% or more of the blood cells in the bone marrow. M protein in blood is 3gm/dl. or more.

2. Solitary Plasmacytoma of the bone -  single tumor is present and no symptoms.

3. Extramedullary Plasmacytoma - plasma cell tumors develop in the upper airways, nose, nasal sinuses, larynx, GI tract, breasts and brain.

4. Bence Jones proteinuria or presence of light chains in urine.

5. Nonsecreting Myeloma.

6. Waldenstrom macroglobulinemia. Both B-cells and Plasma cells produce excess Macroglobulin. Various symptoms develop due to high blood viscosity from the excess macroglobulin.

7. Rare IgD and IgE myeloma. IgD myeloma is seen at relatively younger age. IgE myeloma is an aggressive type.

Diagnosis of MM:

A bone marrow biopsy is essential. MM diagnosis is made when the Plasma cell population is over 10%, usually at the time of diagnosis plasma cells are over 50%. Other positive findings are high microglobulin in blood and urine. Bone x-ray show lytic lesions and pancytopenia but these additional findings are not required for the diagnosis of MM.

Staging:

The international staging system categorizes MM into 3 stages based on blood tests:

Stage I. - Serum beta-2 microglobulin over 3.5 mg/L and serum albumin at/ over 3.5 g/dL. 

Stage II. serum levels are in between values of stage I and stage III.

Stage III. - Serum beta -2 microglobulin at or over 5.5 mg/L and high LDH (lactic dehydrogenase).

Revised International staging system (R-ISS):

Stage I. B-2 microglobin  < 3.5mg/L, albumin > 3.5d/L, no cytogenic abnormalities in iFISH (interphase fluorescence in situ hybridization).

Stage III. B-2 microglobin  >3.5 mg/L, High LDH, Presence of iFISH abnormalities. In MM the iFish cytogenic abnormalities are - deletion of 17p and/or t 4;14, and/or t 14;16. (p= short arm of chromosome 17. t=translocation of oncogene at 14;4 location).

Treatment of MM:

The current trend in the treatment of hematology malignancy is to perform Stem Cell Transplantation early. In MM the preferred age for stem cell transplant is below 75 yrs. Two different stem cell transplants are possible in MM. These are Autologous (patient's own stem cells) and Allogenic (HLA matched stem cells from the donors).

Targeted Therapy.

  - Proteasome inhibitor therapy. Proteasome is a protein that clears unused protein molecules from a dividing cell. If that clearing protein is blocked, then the dividing cells are choked with proteins and die. That is the basis of proteasome treatment. Drugs available are Bortezomib, Carfilzomib and Ixazomab.

- Monoclonal antibody therapy (mAb). The commonly use mAbs are Daratumumab for bone pain, Elotuzumab for accelerated killing by phagocytes.

- Histone Deacetlase (HDAC) inhibitors. These drugs block cell division. The available drug is Panobinostat.

- BCL-2 Inhibitor. Helps to kill cancer cells. Drugs available is Veneloclax.

Immunotherapy. Thalidomide accelerates the killing of rapidly dividing malignant cells. Derivatives of thalidomide are more powerful than thalidomide. Available drugs are Lenalidomide and Pomalidomide.

CART Therapy.  Surveillance T-cells have surface receptors by which T-cells attach to the foreign antigen. Because cancer cell antigen closely resembles the normal cell of the body, at times the receptors fail to bind with the cancer antigen. Mutated cancer cells have acquired this strategy and evade detection and death. In the CART therapy laboratory engineered Chimeric Antigen Receptors and T-cells from the patient are incubated together. These special T-cells are made to multiply in the laboratory and later transfused to patients to enhance tumor killing.

Chemotherapy. - A combination of 4 to 6 chemotherapeutic agents is administered in 4 to 6 cycles over 6 months to induce remission. Cyclophosphamide, Doxorubicin and Etoposide are commonly used in MM.

Treatment strategy for MM. - The first step is to induce remission through a combination of immunotherapy, targeted therapy and chemotherapy. The number of agents used in the combination varies according to the disease stage of patients. Then Watchful Waiting. Maintaining remission is usually achieved by immunotherapeutic agents.

If a recurrence of MM is detected, a Stem cell transplant is advised provided there is no contradiction.

Then again, a watchful Waiting with maintenance therapy, and surveillance.

Prognosis:

The prognosis: Survival used to be 5 years for stage I, and for stage II and stage III rates were 3.5 yrs. and 2.5 yrs. respectively. In a 2021 publication, the 5-year survival rate was noted to be 75% in early cases, and in late diagnosed cases the rate was 48%.

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