Multiple Myeloma

Hydroxyurea REF: Harrison 17^th ed chapter 106

Drugs used in chemotherapy of multiple myeloma are:

• Melphan
• Thalidomide
• Lenalidomide
• Cyclophosphamide
• Vincristine
• Doxorubicin (Adriamycin) and liposomal doxorubici

Multiple myeloma is associated with negative bone scan or cold lesions.

The bone scan measures the osteoblastic activity. In multiple myeloma, the osteoblasts doesn’t react much to bone destruction. Bone scans are least useful for diagnosing multiple myeloma because the cytokines secreted by myeloma cells suppress osteoblastic activity.

Ref: Harrison’s Principles of Internal Medicine, 17th Edition, Page 703-705; 16th / 658, 659; Davidson’s principles and practice of Medicine, 20th Edition, Chapter 24, Page 1052-1054

Ans. is ‘d’ i.e., Elevated alkaline phosphatase

• In multiple myeloma, neoplastic plasma cells infiltrate various organs, particularly the bone marrow.
• In the bone marrow, neoplastic plasma cells secret certain cytokines which mediate bone resorption. o In normal conditions, bone resorption is associated with increased osteoblastic activity, so to form new bone & these osteoblasts secrete alkaline phosphatase.

o But in multiple myeloma, bone resorption is not associated with increased osteoblastic activity, so alkaline phosnhatase is not raised.

• Due to increased bone resorption, multiple lytic lesions are produced in the bone which clinically manifest as pathological fracture and bone pain.

o Radiologically these lytic lesions manifest as multiple punched out lesions.

• The increased bone resorption causes hypercalcemia.

Clinical features of multiple myeloma

o Peak age of incidence of multiple myeloma is between 50 and 60 years.

o The clinical features stem from the effects of –

(i)       Infiltration of organs, particularly bones, by the neoplastic plasma cells.

(ii)     The production of excessive immunoglobulin which often have abnormal physiochemical properties.

(iii)    The Suppression of normal humoral immunity.

Clinical features are : ‑

• 1. Bone pain, pathological fracture, osteoporosis, hypercalcemia because of tumor expansion in bone marrow and secretion of osteolytic cytokines by neoplastic plasma cells.
  2. Renal failure because of hypercalcemia, damage by Bence Jones protein, Urate nephropathy, amyloidosis.
  3. Recurrent infections because of hypogammoglobulinemia.
  4. Pancytopenia because of marrow infiltration by tumor cells that results in anemia, neutropenia and thrombocytopenia.
  5. Neurological symptoms because of hyperviscosity and hypercalcemia.
  6. Nausea and vomiting because of renal failure and hypercalcemia.
  7. Bleeding tendency        Platelets get coated by M protein. So, there is impairment in adhesion and aggregation.
  8. Coagulation abnormality M proteins interfere with coagulation factors.
  9. Amyloidosis – AL type.
  10. Cryoglobulinemia

Ans. is ‘a’ i.e., Vertebral column

o Bone lesions are most common in vertebral column.

o The following distribution was seen in large series of case:

Vertebral column –> 66%  Pelvis  —>  28%

Ribs –> 44% Femur –> 28%

Skull –> 4%  Clavicle —> 10%.

Ans. is ‘b’ i.e., Multiple myeloma; ‘c’ i.e., Acute myocardial Infarction

B i.e. Multiple Myeloma

• Old age, male sex & vertebral involvement (lytic lesion) indicate towards diagnosis of Metastasis & Multiple myeloma.
• But Absence of primary and characterestic multiple punched out lesions on X-Ray skull is diagnostic of Multiple myelomaQ.

In children with CRF, the combination of rickets & hyperparathyroidism leads to Rotting Fence Post appearance.Q

Multiple Myeloma: Two cardinal features are:

Generalized reduction of bone density (Osteopenia)

Localized areas of radiolucency (Punched outQ/Rain drop lesionsQ) in red marrow areas i.e. axial skeletal – spine & skull.

In multiple Myeloma lytic lesions of spine are usually associated with some collapse & soft tissue extension i.e. paravertebral soft tissue shadows (differentiation from Metastasis).

Differentiation from inflamatory lesions can be made as the intervertebral disc space & articular surfaces are not affected.

Answer is C (Plasmocytosis > 2%):

Diagnosis of Multiple Myeloma requires plasmacytosis of> 10%.

The classic triad of myeloma is:

a)       Marrow plasmacytosis > 10%

b)       Lytic bone lesions

c)        Serum or urine ‘M’ component

Answer is A(IgG)

The M component in Multiple Myeloma can be made up of the immunoglobulins IgG, IgM, IgD, IgA, and IgE; light chains alone; or heavy chains alone. IgG Myeloma is the most common form of Multiple Myeloma while IgD (2%) and IgE (Rare) are the least common.

Distribution of immunoglobulin types in patients with multiple myeloma

Answer is D (IgD)

The M component in Multiple Myeloma can be made up of the immunoglobulins IgG, IgM, IgD, IgA, and IgE; light chains alone; or heavy chains alone. IgG Myeloma is the most common form of Multiple Myeloma while Ig D (2%) and IgE (Rare) are the least common.

Answer is A (t(11;14))

The most common translocation seen in patients with Multiple Myeloma is 01;14).

`The most common translocation seen in patients with Multiple Myeloma is t(11;14)(q13;q32) involving the BCL1 locus on chromosome 11g13 and the immunoglobulin heavy (IgH) chain locus on chromosome 14q13 which leads to overexpression of Cyclin D1 ‘- The Washington Manual of Surgical Pathology

`The two most common translocation seen in patients with Multiple Myeloma are t(11;14)and t(4; 14). Both these translocations occur with almost similar frequencies, however the incidence of translocation 1(11; 14) appears to be marginally higher. Patients with t(4; 14) fall within a poor prognosis subgroup, while those with 1(11; 14) have a standard risk’ – The Principles of Clinical Cytogenetics

The two most common translocation seen in patients with Multiple Myeloma

• t(11;14)(q13;q32) : Associated with standard prognosis
• t(4;14) (p16;q32) : Associated with aggressive behaviour and poor prognosis
• The most common translocation in multiple myeloma associated with a poor prognosis is translocation t(4;14)

Answer is D (Renal failure)

Renal failure occurs in nearly 25% of Myeloma patients and some renal pathology is noted in over half.

Multiple Myeloma is associated with Lvtic bone lesion and Bone Resorption

The bone lesions of Myeloma are caused by activation of osteoclasts that destroy bone and suppression of osteoblasts that form bone.

Bone lesions are thus lytic in nature and not sclerotic.

There is a net resorption of bone and not bone deposition.

Multiple Mveloma is associated with Hypercalcemia and not Hypocalcemia

Hypercalcemia is caused by substantial mobilization of calcium from bone due to associated bony lysis.

Answer is B (Increased in alkaline phosphatase)

Serum alkaline phosphatase is usually normal even with extensive bone involvement because of the absence of aslet)hractfr fictivity – Harrison 16^th/ 659

• Anaemia: Normocytic normochromic
• ESR : markedly increased
• Hypogammaglobulinemiae
• Monoclonal spike on Serum protein electrophoresis – Monoclonal Gammopathy (M Band)
• Bone marrow replacement of normal marrow elements by plasma cells.
• Bence Jones Proteinuria: Light chain proteinuria (inclomplete IgG)
• Uric Acid level : Elevated due to increased cell turnover
• Serum calcium : Elevated
• Alkaline phosphatase : Normal
• Neutropenia & Thrombocytopenia rare

Answer is D (Plasmacytosis < 10%)

Multiple myeloma is characteristically associated with Plasmacytosis >10%.

Multiple myeloma may be associated with both Hypogammaglobulinemia and Hypergammaglobulinemia.

Electrophoresis Pattern in Multiple Myeloma

Monoclonal Hypergammaglobulinemia (M spike) This is the characteristic electrophoresis pattern in Myeloma

Hypogammaglobulinemia

• About 10-20% of multiple myeloma patients present
  with Hypogammaglobulinemia on electrophoresis.
• This configuration is suggestive of light chain variant of multiple myeloma in which Bence Jones proteins are excreted into urine without a serum myeloma protein being evident with routine electrophoresis techniques.

`Multiple Myeloma results in hypergammaglobulinemia of a specific class of immunoglobulins.

Hypogammaglobulinemia also justifies a search for myeloma especially for the possibility of light chain disease. ‘

Multiple Myeloma may be with Bence Jones Proteins, Amyloidosis & Renal failure

Answer is A (multiple mycloma):

Russell bodies are intracytoplasmic inclusion bodies seen in within plasma cells in multiple mycloma

Characteristic Pathological features of multiple myeloma
(Not specific for multiple myeloma and may also be seen in benign disorders)

Cell types/shapes

• Plasma blasts
• Bizzare multinucleated cells
• Flame cells (cells with cherry red cytoplasm)
• Mott cells (cells with multiple blue grape like cytoplasmic droplets)

Inclusion Bodies

• Russell bodies (intracyloplasmic)
• Dutcher bodies (nuclear)
• Inclusions of fibrils, crystalline rods and globules

Answer is C (Multiple myeloma)

Backache and Recurrent infections in the backdrop of normal alkaline phosphatase levels and a reversed albumin globulin ratio (A : G ratio) is highly suggestive of the diagnosis of multiple myeloma.

 Both clinical findings and laboratory data suggest the diagnosis of Multiple Myeloma

• Serum Alkaline Phosphatase is usually normal even with extensive bone involvement.— Harrison
• Serum Albumin is normal or low, Total protein is normal or raised.— Kumar 5th/501

Answer is A (Multiple Myeloma):

Plasmacytoma on tissue biopsy and Bone marrow plasmacytosis with >30 percent plasma cells are two major criteria for the diagnosis of Multiple Myeloma. Presence of ant’ two major criteria is believed to confirm the diagnosis of multiple myeloma.

The clinical complex of bone pain and renal failure together with diagnostic observation of skeletal destruction, hypercalcemia, monoclonal ‘Al’ spike, tissue plasmacytoma and bone marrow plasmacytosis >30 percent confirms a diagnosis of Multiple Myeloma

MGUS is typically associated with < 10 % plasma cells on bone marrow biopsy.

Solitary Plasmacytoma and Smoldering myeloma are by definition/criteria not associated with any myeloma related symptoms (Anemia, Hypercalcemia, and Renal Failure)

Ans: A: Raised Serum Calcium

Multiple myeloma/ MM/ myeloma/ plasma cell myeloma/Kahler’s disease is a type of cancer of plasma cells which are immune system cells in bone marrow that produce antibodies.

The peak age of onset of multiple myeloma is 65 to 70 years of age.

Multiple myeloma affects slightly more men than women.

A mnemonic sometimes used to remember the common tetrad of multiple myeloma is CRAB ‑

C = Calcium (elevated), R = Renal failure, A = Anemia, B = Bone lesions.

Myeloma bone pain usually involves the spine and ribs, and worsens with activity.

Myeloma bone disease is due to proliferation of tumor cells and release of IL-6, which stimulates osteoclasts to break down bone. The breakdown of bone also leads to release of calcium into the blood, leading to hypercalcemia and its associated symptoms.

These bone lesions are lytic in nature and are best seen in plain radiographs, which may show “punched-out” resorptive lesions.

The anemia found in myeloma is usually normocytic and normochromic.

The presence of unexplained anemia, kidney dysfunction, a high erythrocyte sedimentation rate (ESR) and a high serum protein (especially raised immunoglobulin) should raise the suspicion.

Protein electrophoresis of the blood and urine may show the presence of a paraprotein (monoclonal protein, or M protein) band, with or without reduction of the other (normal) immunoglobulins (known as immune paresis).

One type of paraprotein is the Bence Jones protein which is a urinary paraprotein composed of free light chains.

Multiple myeloma can produce all classes of immunoglobulin, but IgG paraproteins are most common, followed by IgA and IgM. IgD and IgE myeloma are very rare.

Myeloma activity sometimes appear as “lytic lesions” (with local disappearance of normal bone due to resorption), and on the skull X-ray as “punched-out lesions” (pepper pot skull).

Ans. C: Multiple Myeloma

I. Increased alkaline phosphatase levels:

• Increased calcium deposition in bone
• Hyperparathryroidism
• Pagets disease
• Osteomalacia / rickets: in both cases there is failure of mineralization;
• Caffey’s syndrome (infantile cortical hyperostosis)
• Osteoblastic bone tumors (metastatic or osteogenic sarcoma) alkaline phosphatase level is high in about 1/2 of patients with osteosarcoma & in smaller fraction of those with another type of primary malignant bone tumor;
• Pregnancy
• Childhood
• Liver disease such as biliary obstruction
• Total Parenteral Nutrition (TPN)

II. Decreased alkaline phosphatase levels: Malnutrition

• Excess Vit D ingestion;
• Hypophosphatasia

Ans. C: 30%

Manifestations of multiple myeloma includes bone marrow plasmacytosis of more than 30% Multiple myeloma:

• MC symptomatic monoclonal gammopathy
• Histology: Russel bodies, flame cells, Mott cells, Dutcher bodies
• Presents as pathological fractures with hypercalcemia, M-spike and Bence-Jones proteins (light chains)
• TL-6 is associated with poor prognosis
• Raised calcium and raised uric acid

WHO criteria (major):

• Bone marrow plasmacytosis more than 30%
• Plasmacytoma on biopsy
• Presence of monoclonal M protein (M component) in urine/serum
• Serum IgG more than 3.5 g/ dl, or
• Serum IgA more than 2 g/ dl, or
• Urine Bence-Jones protein more than 1 gm/day

WHO criteria (minor):

• Bone marrow plasmacytosis of 10 – 30%
• Presence of monoclonal M protein (M component) in urine/ serum, but less than the above concentration
• Presence of lytic bone lesions
• Reduced normal immunoglobulins to less than 50% of normal
• IgG less than 600 mg/ dl, or
• IgA less than 100 m/ dl, or
• IgM less than 50 mg/ dl

Diagnostic requirement:

• Minimum of 1 major criterion and 1 minor criterion, or
• 3 minor criterion which must include bone marrow plasmacytosis of 10 – 30% and the presence of a monoclonal rotein
• These criteria must be manifested in a symptomatic patient with progressive disease

Ans. Multiple myeloma

Ans. is ‘a’ i.e., Multiple myeloma

Uses of bortezomib:

• The prime indication of bortezomib is multiple myeloma, both for first line combined therapy as well as for replapsed disease.
• It is also used for refractory mantle cell lymphoma.

Note: The most prominent adverse effect of bortezomibis peripheral neuropathy. Others are diarrhea, fatigue, bone marrow depression especially thrombocytopenia.