Multiple MyelomaAlan Johns, M.D.Kristine Krafts, M.D.

Richard – A Case Study

Richard S.

51 year old male presented 8/95 with vague 51 year old male presented 8/95 with vague epigastric distress and weight loss of 5 lbs.epigastric distress and weight loss of 5 lbs.

Denies fevers, chills or back painDenies fevers, chills or back pain PMH – neg.PMH – neg. Meds – noneMeds – none Smoking, alcohol – noneSmoking, alcohol – none Works as a carpenterWorks as a carpenter

Physical Exam: BP= 134/84, Pulse = 70Physical Exam: BP= 134/84, Pulse = 70

Temp = 98.4 degreesTemp = 98.4 degrees

HEENT – negHEENT – neg

Neck – no lymphadenophyNeck – no lymphadenophy

Lungs – clear, Heart – no gallop or murmurLungs – clear, Heart – no gallop or murmur

Abdomen – nontender, no organomegalyAbdomen – nontender, no organomegaly

Rectal – normal, stool hemoccult negativeRectal – normal, stool hemoccult negative

Extremities – no edema or deformities, no tendernessExtremities – no edema or deformities, no tenderness

Initial Lab:

Hemoglobin = 6.7Hemoglobin = 6.7 WBC = 8,300WBC = 8,300 Plts. = 166,000Plts. = 166,000 MCV = 94.5 (82-99)MCV = 94.5 (82-99) RDW = 13.0 (11.0-15.0) RDW = 13.0 (11.0-15.0) Reticulocyte Count = 0.9% (0.4-1.8)Reticulocyte Count = 0.9% (0.4-1.8) Hemoccult (stool) – negative for bloodHemoccult (stool) – negative for blood

Other Lab:

Creatinine = 4.5 (0.8-1.3)Creatinine = 4.5 (0.8-1.3) UA – trace protein, no rbc’s or wbc’sUA – trace protein, no rbc’s or wbc’s

Problem List:

1) Severe anemia1) Severe anemia 2) Acute renal failure with proteinurea2) Acute renal failure with proteinurea 3) Epigastric distress3) Epigastric distress 4) Weight loss4) Weight loss

Bone Marrow

Diagnosis – Multiple MyelomaDiagnosis – Multiple Myeloma

Multiple Myeloma

• monoclonal plasma cell proliferation

• monoclonal gammopathy• decreased normal immunoglobulins• osteolytic lesions

Things You Must Know

• M-spike

• Type of IgG • IgG in 60% of cases• IgA in 20% of cases• IgD or IgE in rare cases• Never IgM

• Bence-Jones protein in urine

• Decreased normal Ig

Laboratory Findings

Normal serum protein electrophoresisNormal serum protein electrophoresis

Normal serum protein electrophoresisSerum protein electrophoresis showing monoclonal band (M

protein)

• Blood: anemia, rouleaux

• Marrow: plasma cells, amyloid

Morphology

Multiple Myeloma

Multiple Myeloma

Myeloma, mature type

Myeloma, intermediate type

Myeloma, plasmablastic type

Flame cells

Russell bodies

Dutcher body and Mott cell

Rouleaux

Amyloid

• Solitary plasmacytoma

• Plasma cell leukemia

• Waldenström macroglobulinemia• Lymphoplasmacytoid lymphoma• IgM• Hyperviscosity syndrome

• MGUS (Monoclonal gammopathy of undetermined significance)• Small M spike with no myeloma symptoms• Occasionally transforms into myeloma

OTHER PLASMA CELL TUMORS

Richard

Serum protein electrophoresis:Serum protein electrophoresis: Serum immunoelectrophoresisSerum immunoelectrophoresis Urine immunoelectrophoresisUrine immunoelectrophoresis

Biology of Normal Plasma Cells

Plasmablasts in lymph nodes (IgM)Plasmablasts in lymph nodes (IgM)

Activated B cells in bone marrow (IgG, IgA)Activated B cells in bone marrow (IgG, IgA)

Differentiate into plasma cells (small in Differentiate into plasma cells (small in number, well-differentiated, characteristic number, well-differentiated, characteristic phenotype, die by apoptosis)phenotype, die by apoptosis)

Biology of Malignant Plasma Cells Plasmablasts in lymph nodesPlasmablasts in lymph nodes

Plasmablasts in bone marrow (IgG, IgA)Plasmablasts in bone marrow (IgG, IgA)

Plasmablasts do not differentiate into plasma cells, Plasmablasts do not differentiate into plasma cells, continue to proliferate and accumulate in marrow, continue to proliferate and accumulate in marrow, produce large amounts of immunoglobulins, normal death produce large amounts of immunoglobulins, normal death of cells doesn’t occur, crowds out other cells – rbc of cells doesn’t occur, crowds out other cells – rbc precursors. Suppress antibody synthesis by normal precursors. Suppress antibody synthesis by normal plasma cells.plasma cells.

Interleukin – 6

Essential for survival and growth of Essential for survival and growth of myeloma cellsmyeloma cells

Growth factor for myeloma cellsGrowth factor for myeloma cells Also promotes survival of myeloma cells by Also promotes survival of myeloma cells by

preventing spontaneous apoptosis.preventing spontaneous apoptosis. Increased levels in myeloma patientsIncreased levels in myeloma patients

Clinical Features

80% of patients present with bone pain 80% of patients present with bone pain

(low back, pelvis, or ribs). Pain is (low back, pelvis, or ribs). Pain is associated with multiple lytic bone lesions.associated with multiple lytic bone lesions.

• Bruising or bleeding from decreased Bruising or bleeding from decreased plateletsplatelets

• Infections from decreased levels of normal Infections from decreased levels of normal immunoglobulins immunoglobulins

Clinical Features – con’t

Hypercalcemia from bone destructionHypercalcemia from bone destruction 50% of patients present with renal failure50% of patients present with renal failure Hyperviscosity syndrome – caused by large Hyperviscosity syndrome – caused by large

amounts of circulating immunoglobulins amounts of circulating immunoglobulins causing purpura, confusion, decreased visioncausing purpura, confusion, decreased vision

Major causes of death – infection, renal failureMajor causes of death – infection, renal failure Classic triad – anemia, bone pain, renal failureClassic triad – anemia, bone pain, renal failure Average age of diagnosis – 69 yearsAverage age of diagnosis – 69 years

Criteria for Diagnosis

1) Bone marrow with >20% plasma cells OR1) Bone marrow with >20% plasma cells OR

2) Plasmacytoma plus one of the following:2) Plasmacytoma plus one of the following:

monoclonal protein in serum > 3 g/dlmonoclonal protein in serum > 3 g/dl

monoclonal protein in urinemonoclonal protein in urine

lytic lesionslytic lesions

3) Usual clinical features of myeloma3) Usual clinical features of myeloma

4) Exclude connective tissue diseases, chronic 4) Exclude connective tissue diseases, chronic infections, carcinoma, lymphoma, leukemiainfections, carcinoma, lymphoma, leukemia

Therapy

Conventional Dose ChemotherapyConventional Dose Chemotherapy

Classic combination – melphalan and Classic combination – melphalan and prednisone (1962)prednisone (1962)

Complete Remission - < 5%Complete Remission - < 5% Median Survival – 3 years Median Survival – 3 years

Conventional Chemo-con’t

VAD – vincristine, doxyrubicin and VAD – vincristine, doxyrubicin and dexamethasonedexamethasoneVAMP – vincristine, doxyrubicin and VAMP – vincristine, doxyrubicin and methyprednisolonemethyprednisoloneDid not prolong survival more than other Did not prolong survival more than other

regimensregimensExcessive morbidity and mortality from Excessive morbidity and mortality from

prolonged myelosupressionprolonged myelosupression

Autologous Peripheral Blood Stem Cell Transplant - PBSC Hematopoietic stem cells from peripheral Hematopoietic stem cells from peripheral

blood blood Growth factors are given after Growth factors are given after

transplantationtransplantation Safe – 1-2% death rate from the transplantSafe – 1-2% death rate from the transplant Problem – contamination of the autologous Problem – contamination of the autologous

graft by myeloma cellsgraft by myeloma cells

High-Dose Therapy with Stem-cell Transplant (1992)

Melphalan in high doses can induce complete Melphalan in high doses can induce complete remissions in 20-30%. Death from remissions in 20-30%. Death from treatment alone is 10-30%.treatment alone is 10-30%.

Stem-cell transplant after high dose Stem-cell transplant after high dose Melphalan (with or without radiation) can Melphalan (with or without radiation) can produce a 30-50% complete remission in produce a 30-50% complete remission in newly diagnosed patients. Problems – only newly diagnosed patients. Problems – only 58% of patients over 60 could tolerate.58% of patients over 60 could tolerate.

Single vs. double autologous stem-cell transplantation (2003)

New Agents

Thalidomide Thalidomide

First used with advanced and refractory First used with advanced and refractory myeloma (2001)myeloma (2001)

Now used for newly diagnosed disease in Now used for newly diagnosed disease in combination with high-dose melphalan and combination with high-dose melphalan and double stem-cell transplant (2005)double stem-cell transplant (2005)

Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

Barlogie, B. et al. Blood 2004;103:20-32

Figure 3. Thalidomide in advanced and refractory myeloma

Bortezomib (Velcade)Bortezomib (Velcade)

Proteasome inhibitorProteasome inhibitor

Copyright ©2004 American Society of Hematology. Copyright restrictions may apply.

Barlogie, B. et al. Blood 2004;103:20-32

Figure 6. PS 341 (Velcade) plus thalidomide for posttransplantation relapse in 46 patients

New Supportive Therapies

Biphosphonates – inhibit bone resorption, Biphosphonates – inhibit bone resorption, treats bone lesions and hypercalcemia.treats bone lesions and hypercalcemia.

Erythropoietin – helps anemia and Erythropoietin – helps anemia and decreases need for transfusions.decreases need for transfusions.

Future Approaches

Interleukin-2, Interleukin-4, Interferon Interleukin-2, Interleukin-4, Interferon gamma- pilot studies show no benefit.gamma- pilot studies show no benefit.

Anti-interleukin-6 Anti-interleukin-6

Initial studies produced some effect but no Initial studies produced some effect but no lasting benefit.lasting benefit.

Further trials underwayFurther trials underway

Future approaches – con’t

ImmunotherapyImmunotherapy Monoclonal immunoglobulins in an individual Monoclonal immunoglobulins in an individual

patient may have a tumor-specific antigen.patient may have a tumor-specific antigen. T-cells seem to recognize the idiotypes of the T-cells seem to recognize the idiotypes of the

patients myeloma protein.patients myeloma protein. IgG from patient transferred to a bone marrow IgG from patient transferred to a bone marrow

donor then patient received transplant. Two donor then patient received transplant. Two years later patient has remained well with years later patient has remained well with minimal M component.minimal M component.

Prognosis

15 % die within 3 months of diagnosis15 % die within 3 months of diagnosis Subsequent death rate 15% per yearSubsequent death rate 15% per year Causes of death- marrow replacement with Causes of death- marrow replacement with

pancytopenia (16%), renal failure (10%), pancytopenia (16%), renal failure (10%), sepsis (14%), acute leukemia (5%), other sepsis (14%), acute leukemia (5%), other chronic illnesses unrelated to myeloma chronic illnesses unrelated to myeloma (23%)(23%)

Richards’ Treatment

8/95 Melphalan and Prednisone cycles 8/95 Melphalan and Prednisone cycles started. M = 6.6 g%started. M = 6.6 g%

9/95 M = 3.96 Creatinine = 1.29/95 M = 3.96 Creatinine = 1.2 4/96 M = 1.954/96 M = 1.95 5/96 M = 2.4 Bone Marrow 7% plasma 5/96 M = 2.4 Bone Marrow 7% plasma

cellscells 8/96 M = 1.858/96 M = 1.85

Richards’ Treatment Cont’

2/97 M = 2.52/97 M = 2.5 4/97 M = 4.05 Bone Marrow shows 44% 4/97 M = 4.05 Bone Marrow shows 44%

plasma cellsplasma cells 5/97 VAD started5/97 VAD started 7/97 M = 3.87/97 M = 3.8 8/97 Bone lesions noted pelvis and femur8/97 Bone lesions noted pelvis and femur 1/98 M = 3.9 Bone marrow shows 20% 1/98 M = 3.9 Bone marrow shows 20%

plasma cellsplasma cells

Richards’ Treatment Cont’

4/98 M = 5.2 4/98 M = 5.2

Allogenic bone marrow transplant after Allogenic bone marrow transplant after Cytoxan and whole body radiation at Mayo Cytoxan and whole body radiation at Mayo Clinic (brother was donor)Clinic (brother was donor)

Post-transplant renal failure and Post-transplant renal failure and pulmonary hemorrhage. pulmonary hemorrhage.

Died 6/6/98Died 6/6/98