This document provides an outline and overview of multiple myeloma. It begins with definitions of multiple myeloma and the monoclonal proteins involved. It then discusses the epidemiology, etiology, pathogenesis, clinical manifestations including bone disease, renal failure, neurologic symptoms, and more. It covers the workup, diagnosis involving bone marrow plasmacytosis and monoclonal proteins. It concludes with sections on prognosis, standard therapeutic agents, treatment of relapsed multiple myeloma, supportive care, monitoring response, and reference materials.

1. Seminar presentation on
Multiple Myeloma

2. OUTLINE
• Defination
• Epidemiology
• Etiology and risk factors
• Pathogenesis
• Clinical manifestation
• Work up
• Diagnosis
• prognosis
• Treatment

3. Defination
• Multiple myeloma(MM) is hematologic malignancy
characterized by neoplastic proliferation of single
clone of plasma cell in bone marrow engaged in
production of monoclonal (M) protein.
• The M protein may be IgGκ, IgGλ , IgAκ ,IgAλ ,IgDκ
,IgDλ
IgEκ ,IgEλ , free κ and λ .

4. EPIDEMOLOGY
• An estimated 30,280 new cases of myeloma were diagnosed in
2017,
• The median age at diagnosis is 69 years
• it is uncommon under age 40.
• Males are more commonly affected than females, and blacks
have nearly twice the incidence of whites.
• Myeloma accounts for 1.3% of all malignancies in whites and
2% in blacks, and 13% of all hematologic cancers in whites
and 33% in blacks.

5. ETIOLOGY AND RISK FACTORS
• The cause of myeloma is not known
• Myeloma occurred with increased frequency in those exposed
to the radiation of nuclear war heads in World War II after a
20-year latency
• Myeloma has been seen more commonly than expected among
farmers, wood workers,leather workers, and those exposed to
petroleum products.

6. • A variety of chromosomal alterations have been found in
patients with myeloma:
• hyperdiploidy, 13q14 deletions, translocations
t(11;14)(q13;q32), t(4;14)(p16;q32), and t(14;16), 1q
amplification or 1p deletion, and 17p13 deletions.
• N-ras, K-ras, and B-raf mutations are most common and
combined occur in >40% of patients

7. PATHOGENESIS

8. CLINICAL MANIFESTATIONS
 The clinical manifestations of MM are the direct
consequence of
◦ Marrow infiltration by plasma cells,
◦ Production of monoclonal protein in blood or
urine, and
◦ Immune deficiency

10. CONT….
 Bone Disease
◦ Bone pain, typically in the back (spine) or chest (ribs) and
less often in the extremities, is present at diagnosis in more
than two thirds of patients.
 The most frequent sites of involvement include areas with
active hematopoiesis, such as the vertebral bodies, skull,
thoracic cage, pelvis, and proximal humeri and femor
◦ The pain usually is aggravated by movement.

11. CONT….
 A myelomatous lesion may extend through the cortex of a
vertebral body and cause either nerve root or spinal cord
compression in <2% of patients
 Alternatively, the myeloma can disturb the mechanical
integrity of a vertebral body, resulting in compression
fracture with retropulsion
 either plasmacytoma or bony fragments into the spinal
canal, again causing neurologic deficits

12. RENAL FAILURE
◦ The two major causes of renal insufficiency in MM
are
 Myeloma kidney and
 Hypercalcemia

13. HYPERCALCEMIA
◦ Hypercalcemia occurs in 30% to 40% of patients with MM
and usually is associated with a large disease burden.
◦ Hypercalcemia is the presenting finding in 15% to 30% of
patients
◦ c/m : lethargy, polyuria, polydipsia, constipation, nausea,
and vomiting

14. NEUROLOGIC SYMPTOMS
 Neurologic symptoms usually are the result of compression by a
soft-tissue plasmocytoma or bone fragments of a vertebral body
on the spinal cord or on a nerve.
 The pain usually is in the thoracic or lumbosacral area.
 Compression of the spinal cord must be considered an oncologic
emergency requiring prompt intervention.
 It is best diagnosed by MRI.
 In addition to back pain with radicular features, weakness or
paralysis of the lower extremities and bowel or bladder
incontinence may occur.

15. HYPERVISCOSITY SYNDROME
 In contrast to Waldenström macroglobulinemia,
hyperviscosity is rare in MM, occurring in less than 10%
of patients.
 Among patients with IgG myeloma, those with the IgG3
subclass are most likely to develop hyperviscosity.
 c/m : headache, fatigue, shortness of breath,, visual
disturbances, ataxia, vertigo, retinopathy

16. AMYLOIDOSIS
 Amyloidosis is a clinical syndrome that results from
extramedullary deposition of insoluble fibrillar protein.
 A diagnosis of MM can be made in 20% of patients with
light chain associated amyloidosis.
 The most common clinical manifestations are carpal
tunnel syndrome or generalized edema due to nephrotic
syndrome.

17. INFECTIONS
 Patients with MM have an increased susceptibility to develop infections
because of the associated hypogammaglobulinemia.
 Myeloma patients are not able to mount a vigorous primary immune
response and have an impaired secondary antibody response to
antigens.
 The additional immunosuppressive effect of chemotherapy, especially
with corticosteroids, further increases the infection risk

18. EXTRAMEDULLARY DISEASE
◦ Extramedullary plasmacytomas have been found in the
lymph nodes, skin, liver, and spleen and occasionally in the
kidneys, breast, testis, and meninges.
◦ The finding usually is associated with high serum LDH
levels and plasmablastic morphology (end-stage myeloma)
◦ Patients usually have poor outcomes even with more
aggressive treatment approaches

19. ANEMIA
 Normocytic and normochromic anemia occurs in ~80%
of myeloma
 Anemia occurs in approximately 75% of
patients
 Due to:-
 Increased IL-6 production by the microenvironment
 IL-6 increases hepcidin level & block microphage
iron cycling
 MIP-1α secretion by myeloma cells, and
 Macrophage inflammatory protein inhibits
erythroid progenitors
 Fas ligand expression on their membranes
 Induces apoptosis of red cell precursors

20. Work up

23. DIAGNOSIS
• The diagnosis of myeloma requires :
• marrow plasmacytosis (>10%),
• a serum and/or urine M component, and
• at least one of the myeloma defining events

26. TREATMENT
 Prior to the development of effective therapies, median overall
survival was less than one year among patients with
symptomatic MM, with the majority of patients being standard
risk
 Melphalan and prednisone (MP), the previous standard
chemotherapy for non-transplant candidates, improved median
overall survival of such patients to approximately three years

27. CONT….
 The addition of thalidomide or bortezomib to the MP regimen
has resulted in an even longer median overall survival of
approximately four years.
 Besides these MP-based regimens, other options include those
in which
◦ Cyclophosphamide is used instead of melphalan
 Eg, bortezomib, cyclophosphamide, dexamethasone, VCd,
and
◦ Non-alkylator containing regimens
 Such as lenalidomide and low-dose dexamethasone (Rd).

28. CONT…
 The most important phases of therapy are
◦ Initial therapy,
◦ Stem cell transplant (if eligible),
◦ Consolidation/maintenance therapy, and
◦ Treatment of relapse.
 Transplant-eligible patients typically receive approximately 4
cycles of initial therapy followed by stem cell collection and
ASCT.

29. STANDARD THERAPEUTIC AGENTS IN
MYELOMA

31. Treatment of Relapsed MM
 The approach to treatment of relapsed MM is complicated.
 Numerous effective regimens are available, and the choice of
treatment depends on numerous factors such as
◦ Drug availability,
◦ Response to previous therapy,
◦ Aggressiveness of the relapse,
◦ Eligibility for ASCT, and
◦ Whether the relapse occurred while the patient was
receiving or not receiving therapy

32. SUPPORTIVE CARE
 Hypercalcemia
◦ The mainstay of therapy for hypercalcemia is
hydration, corticosteroids, and bisphosphonates
(pamidronate or zoledronic acid)
◦ In patients with refractory disease, calcitonin* can
be used

33.  Skeletal Lesions
◦ The most important element in supportive care is
the use of bisphosphonates to prevent or reduce the
number of skeletal lesions

34. CONT….
 Prevention of Infections
◦ Patients with MM should receive pneumococcal and
influenza vaccinations
◦ Intravenously administered gamma globulin every 3 to 4
weeks is indicated if patients have recurrent serious
infections associated with severe
hypogammaglobulinemia.
◦ The role of prophylactic antibiotics in patients receiving
chemotherapy for MM has not been settled.
 Randomized trials have not found significant benefit

35. CONT..
◦ Acyclovir is recommeded for all patients receiving bortezomib or
carfilzomib to prevent herpes zoster activation.
◦ Prophylaxis against Pneumocystis jiroveci should be considered in
all patients receiving long-term corticosteroids.
◦ However, there is a risk of serious skin toxicity in patients receiving
an immunomodulatory agent (thalidomide, lenalidomide) and
trimethoprim-sulfamethoxazole.
 In such patients, alternative antibiotics (such as levofloxacin) and
alternative agents for Pneumocystis prophylaxis should be
considered

36. MONITORING RESPONSE
 Patients should be evaluated before each treatment cycle to
determine how their disease is responding to therapy.
 The preferred method is the measurement of monoclonal (M)
protein in serum or urine.
 Free light chain (FLC) measurements are reserved for patients
with unmeasurable protein in the serum and urine.
 Among patients without an M protein in serum or urine and
normal FLC ratio, further evaluation includes bone marrow
immunohistochemistry or immunofluorescence and plasma
cell labeling index.

37. CONT…
 The principal reasons to monitor disease response are to
identify when patients
◦ Enter a plateau phase,
◦ Experience a relapse, or
◦ Have resistant disease
 Chemotherapy is usually stopped when patients enter the
plateau phase.
 Salvage regimens with other chemotherapeutic agents are
administered to patients with relapsed or resistant disease.

38. INTERNATIONAL MULTIPLE
MYLOMA WORLD GROUP
RESPONSE CRITERIA
 The updated IMWG criteria should be used to assess response
every 30 to 60 days during treatment (grade C/IV).
 Monitoring includes
◦ Clinical And Imaging
◦ Serum/Urine M Protein
◦ Serum FLC Ratio
◦ BM Morphology And Flow Cytometry

40. References
• Harrison 21st edition
• William heamatology 9th
• Uptodate 2021
• IMWG diagnostic and risk stratification guidelines
2014

41. THANK YOU!