Myeloma guidelines diagnosis and treatment Serum protein electrophoresis interpretation

1. Protein
electrophoresis

2.  Serum is placed on a specific medium,
and a charge is applied.
 Differentiation :net charge (positive or
negative) and the size and shape of the
protein
 Total protein - 6.4-8.3 g/dL
 Albumin - 3.5-5 g/dL
 Globulin - 2.3-3.4 g/dL
 Alpha-1 globulin - 0.1-0.3 g/dL
 Alpha-2 globulin - 0.6-1 g/dL
 Beta globulin - 0.7-1.1 g/dL

3. Components
 ALBUMIN
 ALPHA FRACTION:
 alpha1-protein fraction is comprised of
alpha1-antitrypsin, thyroid-binding
globulin, and transcortin.
 Ceruloplasmin, alpha2-macroglobulin,
and haptoglobin contribute to the
alpha2-protein
Liver disease
Acute inflammation, malignancy

4.  BETA FRACTION: two peaks labeled
beta1 (transferrin) and beta2 (beta-
lipoprotein)
+/- IgA, IgM, and sometimes IgG,
complement
Cirrhosis /Carcinoma/Cushing’s
Diabetes mellitus /Hypothyroidism
IDA/ Malignant hypertension
Nephrosis /Polyarteritis nodosa
/Obstructive jaundice /3rd tri pregnancy

5.  GAMMA FRACTION: immunoglobulins
IgG type. The gamma-globulin zone is
decreased in hypogammaglobulinemia
and agammaglobulinemia.
monoclonal gammopathy :
Myeloma Waldenström’s
macroglobulinemia, solitary
plasmacytoma, smoldering multiple
myeloma, MGUS, plasma cell leukemia,
heavy chain disease, and amyloidosis

6.  Polyclonal Gammopathy
1. Viral hepatitis, HIV, mononucleosis,
and varicella
2. bacterial infections: endocarditis,
osteomyelitis, and bacteremia
Tuberculosis
3. Connective tissue diseases SLE Mixed
connective tissue Temporal arteritis RA
Sarcoid
4. Liver diseases: alcohol Cirrhosis
hepatitis biliary cirrhosis Primary
sclerosing cholangitis

10. Indications
Suspected multiple myeloma, Waldenström’s macroglobulinemia,
primary amyloidosis, or related disorder
Unexplained peripheral neuropathy (not attributed to longstanding
diabetes mellitus, toxin exposure, chemotherapy, etc.)
New-onset anemia associated with renal failure or insufficiency and bone
pain
Back pain in which multiple myeloma is suspected
Hypercalcemia attributed to possible malignancy (e.g., associated weight
loss, fatigue, bone pain, abnormal bleeding)
Rouleaux formations noted on peripheral blood smear
Renal insufficiency with associated serum protein elevation
Unexplained pathologic fracture or lytic lesion identified on radiograph
Bence Jones proteinuria

12. Myeloma
Paving the
Way

13. 1.8% of all cancers
17% of all haematological malignancies
median age at diagnosis of 69 years
Diagnosed among people 65-74y

14. Diagnostic Criteria
2014 IMWG criteria
 Clonal bone marrow plasma cells ≥ 10% or biopsy-proven
bone or extramedullary plasmacytoma
 Any one or more of the following myeloma-defining events
 Hypercalcemia (greater than upper limit of normal)
 Renal insufficiency: serum creatinine >2 g/dL or creatinine
clearance <40 mL/min
 Anemia: hemoglobin <10 g/dL or 2 g/dL below lower limit of
normal
 Bone lesions: one or more osteolytic lesions (as demonstrated
on imaging studies)
New criteria
 Involved/uninvolved serum free light chains ratio ≥ 100, and
the involved serum free light chain level ≥ 100 mg/dL
 Clonal bone marrow plasma cells ≥ 60%
 ≥ 2 focal lesions based on MRI studies of the skeleton

15. Work up
 Serum and/or urine protein electrophoresis
(24h urine collection) : M band
 Quantification of IgG, IgA, IgM
immunoglobulins;
 Immunofixation; and serum-free light chain
(FLC) measurement.
 Bone marrow :plasma cell infiltration ,
cytogenetics, flowcytometry
 CBC: rouleaux formation
 serum creatinine, creatinine clearance and
calcium
 LDH , B2M, albumin

16. Lytic bone lesions: whole-body low-
dose computed tomography (WBLD-
CT). Conventional radiography if
WBLD-CT is not available
MRI used in selected situations (eg, risk
stratifying smoldering myeloma, for
monitoring response of nonsecretory
and oligosecretory myeloma, and if CT
or skeletal survey is inconclusive)

17. Cytogenetics
 17p del
 T(4,14), t(14,16), t(14,20)
 13q del
 1p del, 1q amplification

18. Staging

19. Treatment
 Transplant eligible or not ??
 eligibility criteria for ASCT?
 Chronologic age and renal function
should not be the sole criteria used to
determine eligibility for SCT

20. What are the options for initial
therapy before transplant?
 at least three to four cycles of
induction therapy including an
immunomodulatory drug, proteasome
inhibitor (PI), and steroids
 achieving at least very good partial
response (VGPR)
 Up-front transplant should be offered
to all transplant-eligible patients.
improved PFS

21. TRANSPLANT-INELIGIBLE
POPULATION
 Multiple factors should be considered;
disease-specific factors such as stage and
cytogenetic abnormalities, and patient-
specific factors including age, comorbidities,
functional status, frailty status, and patient
preferences
 should include at minimum a novel agent
(immunomodulatory drugs or PI) and a
steroid if possible
 The combination of thalidomide, melphalan,
and prednisone, combination of bortezomib,
melphalan, and prednisone
 Daratumumab plus bortezomib plus
melphalan plus prednisone may also be

22. Drugs Used in the Treatment of
Patients With Multiple Myeloma

25. Mechanism of imid

26. Mechanism of PI
 PIs suppress the production of
cytokines (IL-6), (IGF-1), (TNFα), which
can affect MSC and myeloma cell
interactions.
 PIs suppress angiogenesis by
decreasing VEGF secretion.
 PIs allow for the accumulation of
misfolded and unfolded proteins,
resulting in endoplasmic reticulum (ER)
stress, reactive oxygen species (ROS)-
induced oxidative stress, and the

27.  PIs inhibit NF-κB signaling, a major
growth and survival signaling pathway in
MM
 PIs upregulate p53, a tumor
suppressor to induce cell cycle arrest.
 PIs can induce apoptosis through
extrinsic caspase-8 cascade ,
and via caspase-9 cleavage.
 PIs suppress adhesion molecule and
growth factor receptor expression (e.g.,
IL-6R) and inhibit cellular mechanisms
for repairing double-strand DNA breaks

30.  increasing use of immunomodulatory
drugs, lenalidomide in particular,
(beyond four to six cycles) may also
compromise stem-cell yield.

31. Tandem or not tandem ?
 A single ASCT is considered the
standard of care based upon the
randomized BMT Clinical Trial
 Tandem ASCT should not be routinely
recommended
 High-dose melphalan is the
recommended conditioning regimen
for ASCT

32. Role of Allo
 not routinely recommended but may
be considered in select high-risk
patients or in the context of a clinical
trial

33. Consolidation and Maintaince
 Consolidation therapy is not routinely
recommended
 For patients ineligible or unwilling to consider
maintenance therapy, consolidation therapy
for at least two cycles may be considered.
 Lenalidomide maintenance therapy should be
routinely offered to standard-risk patients
starting at approximately day 90 to 110 at 10
to 15 mg daily until progression.
 A minimum of 2 years of maintenance
therapy is associated with improved survival

34.  For patients intolerant of or unable to
receive lenalidomide, bortezomib
maintenance every 2 weeks may be
considered
 For high-risk patients, maintenance
therapy with a PI with or without
lenalidomide may be considered

36. RELAPSED DISEASE
 should be treated immediately
 A triplet regimen with two novel agents
(PI, immunomodulatory drug, or
monoclonal antibody) in combination
with a steroid
 A monoclonal antibody–based regimen
in combination with an
immunomodulatory drug and/or PI
should be considered.
 Treatment of relapsed multiple myeloma
may be continued until disease

39. Transplant post relapse
 ASCT, if not received after primary
induction therapy, should be offered to
transplant eligible
 Repeat SCT may be considered in
relapsed multiple myeloma if PFS
after first transplant is ≥ 18 months
 Allogeneic hematopoietic cell
transplantation has the potential of
producing cure (TRM, GVHD)

41. Bone disease 80%
Pamidronate is administered at a
monthly dose of 90mg via a 2 h i.v.
infusion.
Zoledronic acid at a monthly dose of
4mg administered via a 15 min infusion.
In patients with creatinine clearance 30–
60 mL/min,
the dose of zoledronic acid must be
reduced to a maximum of 3mg
Patients with hypercalcaemia should
also receive zoledronic acid
osteonecrosis of the jaw.

42. IMWG and the ASCO do not
recommend the initial use of
bisphosphonates for more than 2 years.
In relapsed patients, treatment with
bisphosphonates can be restarted and
administered concomitantly with active
therapy.

43. spinal cord compression
 emergency that requires treatment
with high-dose dexamethasone and
simultaneous local radiotherapy
should be started as soon as possible;

44. Anaemia, BM failure and
infections
 Recombinant human erythropoietin
and darbepoetin alfa can be used for
the treatment of myeloma-associated
anaemia (haemoglobin level < 10
g/dL), once other causes of anaemia
have been excluded .
 The target is to maintain haemoglobin
around12 g/dL (below 14 g/dL to avoid
thromboembolic complications and
hypertension)

45.  G-CSF may be required to treat
chemotherapy-induced severe
granulocytopaenia.
 Infectious episodes require immediate
therapy with broad spectrum antibiotics.
 Prophylaxis of infection controversial
,first 2–3 months of initiation of
lenalidomide or pomalidomide, or in
patients at high risk of infection

46.  IVIG for recurrent life threatening
infection
 Influenza and pneumococcal
vaccinations are recommended
 Acyclovir or valacyclovir for herpes-
zoster virus prophylaxis is
recommended for patients receiving
proteasome inhibitor-based therapies

47. Renal impairment 33%
 Bortezomib-based therapies (in
combination with dexamethasone
 thalidomide or doxorubicin or
cyclophosphamide is the treatment of
choice in patients with renal failure

48. Venous thromboembolism.
 Increased risk of thrombosis 3%–4%
 High-dose dexamethasone, cytotoxic
chemotherapy such as doxorubicin and
IMiDs (thalidomide and lenalidomide)
increase this risk
 The current recommendations for
patients with MM who are due to start
IMiD therapy are to use aspirin (81-325
mg) in the absence of risk factors for
thrombosis and to use full dose
anticoagulants for those at higher risk

49. Hypercalcemia
 Hydration
 Bisphosphonate
 Denosumab
 Steroids

50. Non-Secretory Myeloma: Ready
for a new Definition?
 monoclonal plasma cells ≥10% in the
bone marrow and by negative results
on serum and urine electrophoresis
and immunofixation studies.
 evidence of end-organ damage
 Either non producer or non secretors

51. Oligo-secretory “free light only”
myeloma light chain myeloma
 serum protein of < 1.0 g/dL, urine
protein of < 200 mg/24 hrs, and free
light chain values of < 100 mg/L

52. Solitary Plasmacytoma
 existence of a histologically confirmed
solitary plasma cell tumour either
osseous or extraosseous in the
absence of BM infiltration and CRAB
symptoms
 Local radiotherapy is the preferred
treatment of choice 30-60 Gy, but
about two-thirds of patients develop
MM at 10 years’ follow-up
 Follow up 3-6 m

53. Plasma cell leukaemia
 Poor outcomes OS≈ 1y
 >20% clonal plasma cells in peripheral
blood or >2 × 109 /l
 no specific treatment approaches for
PCL.
 The use of multidrug combinations
(including both a proteasome inhibitor
and an IMiD) followed by HDT in
eligible patients, followed by
prolonged maintenance until
progression

54. POEMS syndrome