MM Flashcards
Define Smoldering multiple myeloma
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
Define Non-IgM monoclonal gammopathy of undetermined significance (MGUS)
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
Define IgM MGUS
- 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
Define Light-chain MGUS
- Abnormal FLC ratio (<0.26 or >1.65)
- 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)
- No immunoglobulin heavy chain expression on immunofixation
- 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
- Clonal bone marrow plasma cells <10%
- Urinary monoclonal protein <500 mg/24 h
Define Solitary plasmacytoma
- 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
Define Solitary plasmacytoma with minimal marrow involvement
- Biopsy-proven solitary lesion of bone or soft tissue with evidence of clonal plasma cells
- Clonal bone marrow plasma cells <10%
- 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
Define POEMS syndrome
- 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
Define Systemic AL amyloidosis
- 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) - 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)
Risk factors for progression of MGUS to MM
- Higher M-protein levels at diagnosis*
- Non-IgG monoclonal protein*
- Extreme abnormalities of the FLC ratio* <0.26 or >1.65)
- Percentage of PCs in bone marrow
- Suppression of uninvolved immunoglobulins
- Presence of circulating PCs or clonal B-cells
- Bone density abnormalities
- Advanced age
- Bence Jones proteinuria
- Increasing M protein concentration
- Imaging evidence of neoplastic deposits by MRI or PET
- High risk genetic markers
- High number of abnormal plasma cells
*=MAYO risk score
Factors associated with increased risk of progression of SMM to MM. Ie 20/20/20
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:
- Suppression of uninvolved immunoglobulins
- Presence of circulating PCs
- A high predominance of abnormal PCs (≥95%) (defined by phenotype and flow-based assessment) from the total PCs in the marrow
- Presence of FISH abnormalities (t(4;14), deletion 17p, gain 1q21, and hyperdiploidy)
- IgA isotype
- Evolving M-component
Dosing changes to Bortezomib based on toxicity.
- 3 mg/m2: Full dose
- 0 mg/m2: Dose reduced to this if peripheral neuropathy, Plt < 30 or if ANC < 1
- 7 mg/m2: if persistent
We do weekly dosing and SC at baseline rather than IV and twice weekly to attempt to limit toxicity.
Autoimmune conditions associated with IgM MGUS
- Cryglobulinemia
- Cold agglutinin
- Schnitzler Syndrome (autoimmune with fever, bone/joint pain, chronic hives)
- CANOMAD Chronic ataxic neuropathy, ophthalmoplegia, IgM-MGUS, cold agglutinin, and disialosyl antibodies
- Sensorimotor neuropathy (against myelin-associated protein: ANTI-MAG)
Name 3 causes of renal disease in myeloma
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
What genes are dysregulated in t(4;14) myeloma
first example of an IgH translocation that simultaneously dysregulated two genes with oncogenic potential:
FGFR3 on chrom(14) and MMSET on chrom(4)
Drawbacks of using Lenolidamide
Cytopenias (especially Neutropenia and thrombocytopenia)
VTE
Infection
Diarrhea
Rash
secondary malignancies
Affects ability to be able to mobilize stem cells for auto-SCT
Drawbacks of using Bortezomib based protocol
Peripheral Neuropathy
Herpes zoster reactivation
Thrombocytopenia
GI symptoms (constipation/diarrhea)
Benefit: good in renal failure
Name 2 drawbacks of maintenance therapy in myeloma with lenalidomide
Increased rates of second malignancy in all three lenalidomide maintenance trials From UTD: severe myelosuppression Thrombosis Patients D/C due to adverse events \$\$$
Explain the difference between stringent CR vs CR in MM
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.
Why are you able to use a bortezomib based regime in the upfront and relapsed setting in MM? What principle of myeloma allows this?
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.
Mayo Risk factors for progression of MGUS to MM, rates of progression based on points.
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%
Define SLiM
- FLC >100
- BMPC >60%
- > 1 MRI focal bone lesions > 5mm
What are 3 advantages to using low dose dex compared to high dose when combined with lenalidomide?
- OS improved
- Decreased DVT
- Lower risk of infection/PNA
- Lower Fatigue
What two drug types act through Cereblon in hematologic malignancies?
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)
How do the mechanisms of Bortezomib and Carfilzomib differ – name TWO ways?
Both are proteasome inhibitors:
- Bortezomib- inhibits 26S proteasome (a protein complex that degrades ubiquitinated proteins)—> cell death/apoptosis during the G2-M phase of the cell cycle.
- REVERSIBLE INHIBITION
- Less specific (more off target effect)
- Carfilzomib- inhibition of the 20S core of the 26S proteasome
- IRREVERSIBLE INHIBITION (more sustained inhibition)
- More SPECIFIC/SELECTIVE for chymotrypsin
Name THREE molecular targets under investigation for monoclonal antibody therapy in myeloma.
CD38- isatuximab + Dara
SLAMF7- Elotuzumab
CD138
B cell maturation antigen (BCMA)-belantamab Mafodotin
Woman wants to wait to proceed with SCT she has failed several lines of therapy. 2 recommendations for successful collection later?
o Avoid stem cell toxic agents (lenalidomide, melphalan)
o Use plerixafor or chemotherapy for mobilization
o Avoid radiation
MOA of Romidepsin
HDAC inhibitor
3 causes for IgG monoclonal protein that aren’t MGUS or MM.
- Plamsa cell related- POEMS, AL amyloidosis
- LPDs-CLL, NHL
- MG of significance-MGRS, MGNS (neurological)
- Acquired vWD
- Random: TEMPI, Clarkson/Capillary leak.
3 things that increase your risk for osteonecrosis of the jaw with bisphosphonates
Recent dental work Poor baseline dentition Longer duration Type of bisphonate: zolendronate higher risk than pamidronate. Dental trauma
8 symptoms of hyperviscosity in WM, why can’t you use Rituximab upfront?
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!
What are the components of the ISS-R including specific cytogenetic aberrations?
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
Which of the following does not require herpes zoster prophylaxis? A. Bortezomib B. Daratumumab C. Elotuzumab D. Ixazomib
Elotuzumab
What genes are dysregulated in t(11;14) myeloma?
CCND1 + IGH
What genes are dysregulated in t(14;16) myeloma?
t(14;16): IGH + MAF
What are 2 standard risk cytogenetic abnormalities in MM?
t(11;14), t(6;14)
gain(5q) and hyperdiploid do not confer poor prognosis.
What are 4 high risk cytogenetic abnormalities in MM?
t(4;14), t(14:16), t(14:20) gain 1q tp53 Non-hyperdipliody Del 13
Prognosis for solitary bone plasmacytoma?
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
Predictors of plasmacytoma coverting to overt MM?
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.
MM pt refractory to bortezomib who lives out of town. Requested an all oral regime for next therapy. What do you prescribe?
- Ixazomib, len, dex
2. Len/Dex (triplets are always preferred unless frail)
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)
- Venetoclax
2. High BCL2
What is belantamab mafodotin?
Antibody drug conjugate used in MM
Anti-BCMA linked to aurostatin immunotoxin
ORR= 60% in heavily pre-treated pts, PFS 14 months.
Define VGPR in MM.
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
How do you treat transplant eligible and ineligible AL amyloidosis?
Tx: Dara +CyBorD or just CyBorD, followed by high dose melphalan and auto-SCT
Non tx: Dara +CyBorD or just CyBorD
4 contraindications to autoSCT in AL amyloidosis.
- sBP<=90
- ECOG>2
- GI bleeding
- NT-ProBNP>1000
- eGFR<40
4 mechanisms of action of Daratumumab
- Direct induction of apoptosis
- Antibody mediated cellular toxicity
- Complement mediated cell lysis
- Down regulation of lymphoid and myeloid suppressor cells
Peripheral neuropathy or neuropathic pain grading for pts on bortezomib.
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.
