MM Flashcards

1
Q

Define Smoldering multiple myeloma

A

Both criteria must be met:

  • Serum monoclonal protein (IgG or IgA) ≥30 g/L or urinary monoclonal protein ≥500 mg per 24 h and/OR clonal bone marrow plasma cells 10% to 60%
  • Absence of myeloma-defining events or amyloidosis
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2
Q

Define Non-IgM monoclonal gammopathy of undetermined significance (MGUS)

A

Serum monoclonal protein <30 g/L
Clonal bone marrow plasma cells <10%
Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder

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3
Q

Define IgM MGUS

A
  • Serum IgM monoclonal protein <30 g/L
  • BM clonal PC <10%
  • No evidence of anemia, constitutional symptoms, hyperviscosity, lymphadenopathy, HSM, or other end-organ damage that can be attributed to the plasma cell proliferative disorder
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4
Q

Define Light-chain MGUS

A
  1. Abnormal FLC ratio (<0.26 or >1.65)
  2. Increased level of the appropriate free light chain (increased kappa sFLC in patients with ratio >1.65 and increased lambda sFLC in patients with ratio <0.26)
  3. No immunoglobulin heavy chain expression on immunofixation
  4. Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
  5. Clonal bone marrow plasma cells <10%
  6. Urinary monoclonal protein <500 mg/24 h
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5
Q

Define Solitary plasmacytoma

A
  • Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
  • Normal bone marrow with no evidence of clonal plasma cells
  • Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
  • Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
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6
Q

Define Solitary plasmacytoma with minimal marrow involvement

A
  1. Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
  2. Clonal bone marrow plasma cells <10%
  3. Normal skeletal survey and MRI (or CT) of spine and pelvis (except for the primary solitary lesion)
  4. Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions (CRAB) or amyloidosis that can be attributed to the plasma cell proliferative disorder
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7
Q

Define POEMS syndrome

A
  • Polyneuropathy
  • Monoclonal plasma cell proliferative disorder

-Any one of the 3 other major criteria: sclerotic bone lesions, Castleman disease, elevated levels of VEGF

-Any one of the following 6 minor criteria:
Organomegaly (HSM or LAD)
Extravascular volume overload (edema, pleural effusion, or ascites)
Endocrinopathy (adrenal, thyroid, pituitary, gonadal, parathyroid, pancreatic)
Skin changes (hyperpigmentation, hypertrichosis, glomeruloid hemangiomata, plethora, acrocyanosis, flushing, white nails)
-Papilledema
-Thrombocytosis/polycythemia

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8
Q

Define Systemic AL amyloidosis

A
  1. Presence of an amyloid-related systemic syndrome* (eg, renal, liver, heart, gastrointestinal tract, or peripheral nerve involvement)
    2.Positive amyloid staining by Congo red in any tissue (eg, fat aspirate, bone marrow, or organ biopsy)
  2. Evidence that amyloid is light-chain-related established by direct examination of the amyloid using mass spectrometry-based proteomic analysis or immunoelectron microscopy
    4.Evidence of a monoclonal plasma cell proliferative disorder (serum monoclonal protein, abnormal
    free light chain ratio, or clonal plasma cells in the bone marrow)
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9
Q

Risk factors for progression of MGUS to MM

A
  1. Higher M-protein levels at diagnosis*
  2. Non-IgG monoclonal protein*
  3. Extreme abnormalities of the FLC ratio* <0.26 or >1.65)
  4. Percentage of PCs in bone marrow
  5. Suppression of uninvolved immunoglobulins
  6. Presence of circulating PCs or clonal B-cells
  7. Bone density abnormalities
  8. Advanced age
  9. Bence Jones proteinuria
  10. Increasing M protein concentration
  11. Imaging evidence of neoplastic deposits by MRI or PET
  12. High risk genetic markers
  13. High number of abnormal plasma cells

*=MAYO risk score

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10
Q

Factors associated with increased risk of progression of SMM to MM. Ie 20/20/20

A

FLC ratio>20
M protein >20g/L
PC in BM >20 %

Low-risk group (0)- 5% risk of disease progression at 2 years
Intermediate-risk group (1-2)- 17% risk;
High-risk group (>2)- 46% risk.

Others:

  1. Suppression of uninvolved immunoglobulins
  2. Presence of circulating PCs
  3. A high predominance of abnormal PCs (≥95%) (defined by phenotype and flow-based assessment) from the total PCs in the marrow
  4. Presence of FISH abnormalities (t(4;14), deletion 17p, gain 1q21, and hyperdiploidy)
  5. IgA isotype
  6. Evolving M-component
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11
Q

Dosing changes to Bortezomib based on toxicity.

A

1.3 mg/m2: Full dose
1.0 mg/m2: Dose reduced to this if peripheral neuropathy, Plt < 30 or if ANC < 1
0.7 mg/m2: if persistent

We do weekly dosing and SC at baseline rather than IV and twice weekly to attempt to limit toxicity.

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12
Q

Autoimmune conditions associated with IgM MGUS

A
  1. Cryglobulinemia
  2. Cold agglutinin
  3. Schnitzler Syndrome (autoimmune with fever, bone/joint pain, chronic hives)
  4. CANOMAD Chronic ataxic neuropathy, ophthalmoplegia, IgM-MGUS, cold agglutinin, and disialosyl antibodies
  5. Sensorimotor neuropathy (against myelin-associated protein: ANTI-MAG)
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13
Q

Name 3 causes of renal disease in myeloma

A

Glomerular
GN
AL Amyloidosis (Amyloid light-chain (AL) amyloidosis)
light/heavy chain deposition

Tubular
ATN
Cast nephropathy
Proximal tubular dysfunction – acquired Fanconi
 distal tubular dysfunction	

Interstitial
AIN secondary to plasma cell infiltration

Other
Hypercalcemia
Dehydration
Medications: NSAIDS, zoledronic acid
Pyelonephritis
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14
Q

What genes are dysregulated in t(4;14) myeloma

A

first example of an IgH translocation that simultaneously dysregulated two genes with oncogenic potential:

FGFR3 on chrom(14) and MMSET on chrom(4)

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15
Q

Drawbacks of using Lenolidamide

A

Cytopenias (especially Neutropenia and thrombocytopenia)
VTE
Infection
Diarrhea
Rash
secondary malignancies
Affects ability to be able to mobilize stem cells for auto-SCT

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16
Q

Drawbacks of using Bortezomib based protocol

A

Peripheral Neuropathy
Herpes zoster reactivation
Thrombocytopenia
GI symptoms (constipation/diarrhea)

Benefit: good in renal failure

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17
Q

Name 2 drawbacks of maintenance therapy in myeloma with lenalidomide

A
Increased rates of second malignancy in all three lenalidomide maintenance trials
From UTD: severe myelosuppression
Thrombosis
Patients D/C due to adverse events
\$\$$
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18
Q

Explain the difference between stringent CR vs CR in MM

A

CR:
Normal SPEP/UPEP and Immunofixation
Disappearance of any soft tissue plasmacytoma
BM plasma cells < 5%

Stringent Complete Response
Complete response plus:
Normal free light chain ratio
Absence of clonal cells in the bone marrow by immunohistochemistry (confirmation with repeat bone marrow biopsy not needed). (κ/λ ratio ≤ 4:1 or ≥ 1:2 for κ and λ patients, respectively, after counting ≥ 100 plasma cells.

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19
Q

Why are you able to use a bortezomib based regime in the upfront and relapsed setting in MM? What principle of myeloma allows this?

A

Clonal tiding

Upfront regimen kills off majority of myeloma cells, but with 1st relapse, another population of mutated myeloma cells takes over, which must be targeted with a different regimen. At 2nd relapse, another population of cells will have developed which will be resistant to current regimen, but not necessarily previous regimens.

20
Q

Mayo Risk factors for progression of MGUS to MM, rates of progression based on points.

A

M protein ≥15 g/L
Non-IgG MGUS (ie, IgA, IgM, IgD MGUS)
Abnormal SFLC ( <0.26 or >1.65)

The absolute risk of disease progression over 20 years for patients with various combinations of risk factors is:

3 risk factors (high-risk MGUS) — 58%
2 risk factors (high-intermediate risk MGUS) — 37%
1 risk factor (low-intermediate risk MGUS) — 21%
no risk factors (low-risk MGUS) — 5%

21
Q

Define SLiM

A
  1. FLC >100
  2. BMPC >60%
  3. > 1 MRI focal bone lesions > 5mm
22
Q

What are 3 advantages to using low dose dex compared to high dose when combined with lenalidomide?

A
  • OS improved
  • Decreased DVT
  • Lower risk of infection/PNA
  • Lower Fatigue
23
Q

What two drug types act through Cereblon in hematologic malignancies?

A

ImIDS bind through Cereblon →modulate CRBN gene
leads to ubiquination of transcription factors → leading to proteolysis and alteration of B and T cell function → cytotoxicity

Drugs:
Pomalidomide
Lenalidomide
Thalidomide
CelMoDs  (in clinical trials)
24
Q

How do the mechanisms of Bortezomib and Carfilzomib differ – name TWO ways?

A

Both are proteasome inhibitors:

  1. Bortezomib- inhibits 26S proteasome (a protein complex that degrades ubiquitinated proteins)—> cell death/apoptosis during the G2-M phase of the cell cycle.
  2. REVERSIBLE INHIBITION
  3. Less specific (more off target effect)
  4. Carfilzomib- inhibition of the 20S core of the 26S proteasome
  5. IRREVERSIBLE INHIBITION (more sustained inhibition)
  6. More SPECIFIC/SELECTIVE for chymotrypsin
25
Q

Name THREE molecular targets under investigation for monoclonal antibody therapy in myeloma.

A

CD38- isatuximab + Dara
SLAMF7- Elotuzumab
CD138
B cell maturation antigen (BCMA)-belantamab Mafodotin

26
Q

Woman wants to wait to proceed with SCT she has failed several lines of therapy. 2 recommendations for successful collection later?

A

o Avoid stem cell toxic agents (lenalidomide, melphalan)
o Use plerixafor or chemotherapy for mobilization
o Avoid radiation

27
Q

MOA of Romidepsin

A

HDAC inhibitor

28
Q

3 causes for IgG monoclonal protein that aren’t MGUS or MM.

A
  1. Plamsa cell related- POEMS, AL amyloidosis
  2. LPDs-CLL, NHL
  3. MG of significance-MGRS, MGNS (neurological)
  4. Acquired vWD
  5. Random: TEMPI, Clarkson/Capillary leak.
29
Q

3 things that increase your risk for osteonecrosis of the jaw with bisphosphonates

A
Recent dental work
Poor baseline dentition
Longer duration
Type of bisphonate: zolendronate higher risk than pamidronate. 
Dental trauma
30
Q

8 symptoms of hyperviscosity in WM, why can’t you use Rituximab upfront?

A

Headaches, visions changes, dizziness, altered LOC, stroke, ataxia, nystagmus, vertigo, tinnitus, deafness, diplopia.

Can not use rituximab with high IgM, flair of hyperviscosity and need plasmapheresis first!

31
Q

What are the components of the ISS-R including specific cytogenetic aberrations?

A

Stage I-B2MCG <3.5, albumin >35, N LDH, N cytogenetics (5 yr OS 82%)

Stage II- Not stage I or stage III (5 OS 62%)

Stage III- B2MCG >5.5mg/L AND, bad cyto OR highLDH (5 OS 40%)

Bad cyto
t(4;14)
t(14;16)
Del17p

32
Q
Which of the following does not require herpes zoster prophylaxis? 
A. Bortezomib
B. Daratumumab
C. Elotuzumab
D. Ixazomib
A

Elotuzumab

33
Q

What genes are dysregulated in t(11;14) myeloma?

A

CCND1 + IGH

34
Q

What genes are dysregulated in t(14;16) myeloma?

A

t(14;16): IGH + MAF

35
Q

What are 2 standard risk cytogenetic abnormalities in MM?

A

t(11;14), t(6;14)

gain(5q) and hyperdiploid do not confer poor prognosis.

36
Q

What are 4 high risk cytogenetic abnormalities in MM?

A
t(4;14), t(14:16), t(14:20)
gain 1q
tp53
Non-hyperdipliody 
Del 13
37
Q

Prognosis for solitary bone plasmacytoma?

A
SBP: 
   Median overall survival 10 years
10% develop into MM in 3 years
~10% locally recur
~50-70% ultimately progress to overt MM after radiation

Prognosis for extra-osseous plasmacytoma (SEP):
25% recur
15% develop myeloma

38
Q

Predictors of plasmacytoma coverting to overt MM?

A

Older patients > 60
Axial skeletal lesions
Persistent serum M-protein level ≥ 5 g/L 1-2 yrs after dx
Abnormal FLC at the time of diagnosis
Large solitary lesion
Osteopenia
Reduction in uninvolved immunoglobulin levels (eg, low levels of IgA and/or IgM in a patient with an IgG plasmacytoma),
High-grade angiogenesis in the tumor sample

Patients younger than 60 years and with tumors <5 cm have a better overall survival rate.

39
Q

MM pt refractory to bortezomib who lives out of town. Requested an all oral regime for next therapy. What do you prescribe?

A
  1. Ixazomib, len, dex

2. Len/Dex (triplets are always preferred unless frail)

40
Q

MM pt with t(11:14), what agent may they have a superior response to? Is there any other MM targets this drug shows benefit form other than t(11:14)

A
  1. Venetoclax

2. High BCL2

41
Q

What is belantamab mafodotin?

A

Antibody drug conjugate used in MM
Anti-BCMA linked to aurostatin immunotoxin
ORR= 60% in heavily pre-treated pts, PFS 14 months.

42
Q

Define VGPR in MM.

A

Serum and urine M-protein detectable by immunofixation but not on electrophoresis or > 90% reduction in serum M-protein plus urine M-protein level < 100 mg/24 h

43
Q

How do you treat transplant eligible and ineligible AL amyloidosis?

A

Tx: Dara +CyBorD or just CyBorD, followed by high dose melphalan and auto-SCT

Non tx: Dara +CyBorD or just CyBorD

44
Q

4 contraindications to autoSCT in AL amyloidosis.

A
  1. sBP<=90
  2. ECOG>2
  3. GI bleeding
  4. NT-ProBNP>1000
  5. eGFR<40
45
Q

4 mechanisms of action of Daratumumab

A
  1. Direct induction of apoptosis
  2. Antibody mediated cellular toxicity
  3. Complement mediated cell lysis
  4. Down regulation of lymphoid and myeloid suppressor cells
46
Q

Peripheral neuropathy or neuropathic pain grading for pts on bortezomib.

A
Grade 1 (asymptomatic, loss of deep tendon reflexes or paresthesia without pain or loss of function): No action required.
Grade 1 (with pain) or Grade 2 (interfering function but not activities of daily living): Reduce by one level (from 1.5 mg/m2 to 1.3 mg/m2; or from 1.3 mg/m2 to 1 mg/m2; or from 1 mg/m2 to 0.7 mg/m2).
Grade 2 (with pain) or Grade 3 (interfering with activities of daily living): Hold until resolution, may reinitiate at 0.7 mg/m2 once weekly.
Grade 4 (life-threatening, disabling, eg, paralysis): Discontinue.