multiple myeloma Flashcards
1
Q
RVD is…
A
Rvd = lenalidomide (Revlimid), Bortezomib (Velcade) and dexamethasone (VRd) (1 g q month).
2
Q
newly approved agents for MM
A
monoclonal antibodies
CAR T-cell
ADC’s
BiTES
3
Q
bortezomib MOA
A
proteasome inhibitor, protein production halts, leading to apoptosis
4
Q
prognosis in general/progress in treatment
A
people are living longer but they are still dying (MM can’t be cured yet)
5
Q
IMiDs means
A
immunomodulatory drugs
6
Q
new monoclonal antibody added to RvD
A
darzalex
7
Q
primary problems with CAR T cell therapy
A
cost + *access (not available most places)
8
Q
sequential vs combined therapy in MM
A
combined therapy better (multiple populations of cells), so 3 drug regimens are standard of care (triplet therapy)
9
Q
response assessment
A
M-protein level + BMB
10
Q
How is CR defined?
A
- NO evidence of disease in marrow or serum.
- NO monoclonal (M) protein in serum or urine by immunofixation with no current evidence of soft tissue plasmacytoma.
- Less than 5 percent clonal plasma cells on bone marrow aspirate
11
Q
What is concept of MRD testing?
A
minimal residual disease
- response criteria for MM, prognostic marker but we don’t know how it influences management yet
- use NGS or next generation flow
12
Q
most impt prognosticator
A
not CR, but durability of CR
13
Q
MGUS risk of progression
A
1%
14
Q
smoldering myeloma risk of progression
A
10%
15
Q
Mm can progress to what?
A
Plasma cell leukemia
16
Q
Branching concept in oncology
A
there are clonal populations of cells and subclonal
In remission in myeloma you may just be suppressing one population while another progresses
17
Q
most common presentation of multiple myeloma
A
fatigue from anemia, bone pain, fractures
18
Q
What are the high risk FISH markers?
A
del17p
t(4;14)
1q gain
Also (t(14:16), t(14;20)??)
19
Q
darzalex generic name
A
daratumumab
20
Q
what are the plasma cell dyscrasias?
A
- Plasma cell myeloma, AKA multiple myeloma
- MGUS
- Solitary plasmacytoma
- Primary amyloidosis
- POEMS
- Light and heavy chain deposition diseases
21
Q
diagnostic criteria for MGUS
A
1) serum M protein >3 g/dL
2) Clonal plasma cells >10% of bone marrow
3) Absence of end-organ damage
22
Q
diagnostic criteria for smoldering MM
A
1) serum M protein >3
2) clonal plasma cells 10-59% of bone marrow
3) no end-organ damage or other myeloma defining event
23
Q
How is solitary plasmacytoma defined?
A
Clonal plasma cell mass + NO bone marrow involvement or end organ damage from monoclonal plasma cells. (less than 10% of clonal marrow plasma cells)
- plasmacytoma if patient has MM, is just a plasmacytoma
24
Q
POEMS stands for
A
Polyneuropathy, organomegaly, endocrinopathy, monoclonal gammopathy, skin changes
25
pathophys of AL amyloidosis
systemic deposition of amyloid protein composed of immunoglobulin light chains
26
How is MM risk stratified?
Primarily based on chromosomal translocations and LDH level
27
Risk stratification scoring system
Revised-International Scoring System (RISS)
28
Variables used for staging in R-ISS?
Serum B2M, albumin, LDH, and genetics (translocations)
29
general treatment approach for MM
Induction therapy --> collect stem cells if candidate -->
| HCT or continuation on therapy if not HCT candidate
30
Stem cell transplant method used for MM
autologous
31
age cutoff for HSCT
65
32
Contraindications to HSCT at most centers in the US
1) Age >77 years
2) Frank cirrhosis of the liver
3) Eastern Cooperative Oncology Group (ECOG) performance status 3 or 4 unless due to bone pain (table 4)
4) New York Heart Association functional status Class III or IV
33
renal function and eligibility for HCT
Autologous HCT may be safely performed among patients with all stages of kidney disease, even among patients on dialysis. Renal impairment appears to have no adverse effect on either the quality of stem cell collection or engraftment following autologous HCT
34
bortezomib side effects
peripheral neuropathy, thrombocytopenia, herpes zoster reactivation (viral prophylaxis with acyclovir required)
35
bortezomib metabolism
- hepatic, dose adjustment for liver dysfunction required
36
thalidomide SE profile
peripheral neuropathy, constipation, fatigue, edema, somnolence, VTE
37
lenalidomide SE's
Fatigue + myelosuppression + constipation/diarrhea + peripheral edema + fever + VTE
38
lenalidomide metabolism
renal
39
why are bisphosphonates used in MM?
- decrease risk of skeletal fractures and improve bone-related pain
40
formulation and dosing of bisphosphonates
Once monthly IV infusion
41
bisphosphonates SE profile
hypocalcemia, renal insufficiency, osteonecrosis of the jaw
42
evidence for autologous HCT in MM
- Improved PFS, mixed evidence for OS
43
when are autologous hematopoietic stem cells collected after induction therapy for MM patients?
Usually after 2-4 months of herapy and cytoreduction by 50% (partial remission)
44
can someone undergo a second HCT?
Yes, usually enough stem cells are collected to perform two autologous HCTs
45
Treatment modification for MM patient who is candidate for autologous HCT?
Avoid prolonged therapy with alkylating agents (cyclophosphamide or melphalan) or lenalidomide, which can interfere with stem cell collection
46
what are the alkylating agents?
cyclophosphamide or melphalan
47
what does early and late stem cell transplant refer to?
```
early = immediate transplant following induction therapy
late = transplant after relapse
```
48
most commonly used induction regimen for standard-risk myeloma
RvD (bortezomib, lenalidomide, dexamethasone)
49
management of frail patient with MM
Usually 2 drug regimen like bortezomib or lenalidomide with dexamethasone (VD or RD)
50
Maintenance therapy after induction and HCT
- Lenalidomide-based
| - consider adding Bortezomib
51
How is disease progression defined?
- new serum calcium >11.5
- increase in size of a preexisting bony lesion or plasmacytoma
- appearance of new bony lesions or plasmacytomas
- 25% increase in serum or urine monoclonal immunoglobulin, bone marrow clonal plasma cell percentage, change in kappa/lambda serum FLC ratio.
52
management of VTE risk with lenalidomide
IF average risk = aspirin daily
| IF elevated risk = warfarin
53
Diagnosis of patient with isolated bone mass + biopsy showing 5% monoclonal plasma cells without other end-organ involvement
solitary plasmacytoma
54
High risk MM defined as
1) t(14;20)
2) t(14;16)
3) del17p
4) LDH>upper limit of normal
5) evidence of plasma cell leukemia
55
type of stem cell transplant typically used in MM
autologous
56
R-ISS incorporates
Beta2 + LDH + albumin + FISH
57
Factors influencing early vs delayed HCT
Patient preference, risk stratification (early HCT is preferred for high-risk MM), patient age (as age approaches 70, early HCT is preferred), response and tolerability to the initial chemotherapy regimen, insurance approval (some insurers do not cover stem cell harvest and cryopreservation without immediate transplantation), and whether centers have the facilities and resources for long-term storage of stem cells
58
why there is a limit to number of cycles with MM before stem cells
bortezomib will eventually knock out stem cells
59
revlimid regulation
Highly regulated because it causes a lot of birth defects. You have to fill out a form after each month. This can occasionally cause delays.
60
Revlimid formulation
Pill
61
Bortezomib formulation
Sub q injection
62
Initial workup if concern for myeloma
SPEP/UPEP + Serum free light chain (FLC) assay
63
what is M protein
Monoclonal Immunoglobulin produced by clonal population of plasma cells
64
diagnosis
```
Clonal bone marrow plasma cells ≥10% or biopsy-proven bony or extramedullary plasmacytoma* and any one or more of the following myeloma-defining events:
Hypercalcemia (greater than 11)
Renal insufficiency (Cr>2)
Anemia (Hgb <10)
One or more osteolytic lesions
```
65
Imaging for lytic lesions
Whole body noncon CT (just looking at bone)
PET/CT
OR MRI
66
What is CyBorD regimen?
Cyclophosphamide + Bortezomib + Dexamethasone
67
Use of CyBorD
Induction therapy for patients with previously untreated multiple myeloma, prior to autologous stem cell transplantation (ASCT).
68
Initial Management of patient eligible for HCT
Induction therapy with a triplet regimen for three to four months to reduce the number of tumor cells in the bone marrow and peripheral blood, lessen symptoms, and mitigate end-organ damage --> stem cell collection.
69
Initial management of patient ineligible for HCT
8 to 12 cycles of initial therapy with a triplet regimen --> maintenance therapy until disease progression or unacceptable toxicity
70
Management of frail, old patient not thought to be candidate for triplet therapy
doublet therapy - hold bortezomib, given lenalidomide and low dose dexamethasone until progression
71
Why is acyclovir given?
Prophylaxis for herpes zoster due to bortezomib
72
Indication for PPI
GI ppx if receiving decadron
73
Preferred induction therapy regimens per NCCN for transplant candidates
RvD firstline
| CyBorD if renal failure
74
prophylaxis recommendations with high dose decadron
1) PCP prophylaxis
2) zoster prophylaxis
3) antifungal ppx (don't see people do this)
75
What is an SPEP and relevance to MM
- Serum proteins are separated by an electrical currents into five major fractions by size and electrical charge
- MM appears as a spike in the gamma globulin region
76
Relation of AL amyloidosis to MM
MM can lead to amyloidosis
77
Revlimid trade name
Lenalidomide
78
Bortezomib trade name
Velcade
79
How to test for minimum residual disease
NGS or next generation flow
80
Induction regimen typically used for patients with renal failure
CyBorD
81
Demographic RF's for MM
More common in men
| More common in African Americans
82
RF's for developing MM
BMI
| ?
83
Presentation
Usually asymptomatic
- fatigue/weakness from anemia
- bone pain
- weight loss
84
Relation of M protein to total serum protein
*total serum protein level may be normal in patients with MM (eg in light chain MM because free light chains seldom rises to a level that affects the total protein)
85
anemia features in MM
normocytic, normochromic (bone marrow replacement, epo deficiency, or dilutional effect)
86
Typical location of bone pain and why
Central skeleton (vertebral bodies, skull/neck, ribs, shoulders, pelvis, hip) rather than the extremities (these are areas with active hematopoesis
87
2 major causes of renal insufficiency in patients with MM
1) Light chain cast nephropathy
2) hypercalcemia
* thus patients who don't secrete light chains aren't at risk for kidney injury
88
etiology of hypercalcemia in MM
Bone demineralization
89
Range for K/L ratio
0.26-1.65
90
Most common myeloma subtypes
IgG most common (half)
IgA -- 20%
Kappa or lambda -- 16%
91
What is plasma cell leukemia in general?
Rare but aggressive form of MM characterized by high levels of plasma cells in peripheral blood
92
Preferred imaging modalities for bone involvement and performance
MRI most sensitive
low dose CT second best
Plain film/skeletal survey worst
93
When you need UPEP as part of the initial workup
- if plasma cell proliferative disorder is identified (need to quantify M protein and total urine protein concentration)
94
Indications for measuring serum viscosity?
M protein greater than 5 or symptoms of hyperviscosity
95
Diagnostic criteria
1) clonal plasma cells greater than or equal to 10% or biopsy proven soft tissue plasmacytoma
AND
2) organ or tissue impairment
OR 3) presence of a biomarker associated with "near inevitable progression to end-organ damage"
96
Definitions of organ impairment for MM diagnosis
Hgb less than 10
Serum calcium greater than 11
EGFR less than 40 or Creatinine greater than 2
Bone lesions
97
Bone lesions criteria for MM diagnosis
One or more lesions 5 mm or greater
98
What are the SLiM criteria? What does this define
SLiM
Sixty (60 percent clonal plasma cells in the bone marrow)
L(ight chain ratio -- FLC of 100 or more)
M(RI w/ 1 or more focal lesions)
***New additional criteria defining MM (in addition to CRAB)
99
What's the most important aspect of establishing MM diagnosis?
Make sure end organ damage is definitively related to MM
100
Natural course of MM without treatment
Without therapy, symptomatic patients die within a median of 6 months
101
Criteria defining high-risk myeloma
1) High risk fish translocations
2) LDH 2 or greater upper limit of normal
3) Features of primary plasma cell leukemia (either 2000 or greater plasma cells of peripheral blood or 20% or greater on a manual diff count)
102
High risk myeloma fish translocations
4;14
14;16
14;20
del17p13
103
Optimal time for collecting stem cells
Early in treatment course
104
Contraindications to transplant for MM
Age -- *over 77
Liver cirrhosis
*Functional status -- ECOG status 3 or 4 unless due to bone pain
NYHA Class III or IV
105
Renal failure and transplant eligibility
Still eligible but associated with relatively high transplant-related mortality
106
Preferred induction therapy regimens
*no standard, experts use different regimens
107
Difference in induction therapy duration between patients eligible and patients ineligble for HCT
IF eligible --> 3-4 months
| IF ineligible --> 8-12 cycles then maintenance therapy
108
Efficacy of early vs. delayed transplant strategies
Comparable results in studies in MM
109
Why allogeneic HCT is not done
You can be cured, but its use is limited by high early mortality rates and morbidity
110
Factors influencing early vs delayed HCT
- patient preference
- risk (early preferred for high-risk MM)
- age (early preferred for older)
- insurance (some insurers don't cover cryopreservation)
111
Maintenance therapy for patients who aren't transplant eligible
High-risk = bortezomib
Standard-risk = lenalidomide
Frail patients = lenalidomide + dexamethasone (len dex)
112
When patients are typically evaluated for response
Before each treatment cycle
113
clinical relapse means
Patient develops CRAB symptoms
114
Lab definitions of relapse
1) Doubling of M protein over 2 months
2) Increase in absolute levels of M protein of greater than 1 in serum or of greater than 500 mg per 24 hours in the urine, confirmed by 2 measurements
115
Treatment options for patients with relapsed or refractory MM
1) HCT
2) Rechallenge previous chemo regimen
3) Trial new chemo regimen
116
IFE is
immunofixation (SPEP, UPEP)
117
RRMM means
relapsed and refractory multiple myeloma
118
Differential for M Spike
- cryoglobulinemia
- hemolysis
- elevated fibrinogen
- elevated CRP
119
D-VrD is
daratumumab-VrD
120
what is CyBorD
Cyclophosphamide + bortezomib + dexamethasone
121
High risk cytogenetics
```
17p13
t(4;14)
t(14;16)
t(14;20)
Gain 1q
LDH>2x upper level of normal
Features of primary plasma cell leukemia
```
122
Initial therapy depends on...
- Risk stratification
| - Transplant eligibility
123
Initial therapy for frail patients with standard risk MM
Rd
124
Standard of care for eligible in patients in general
High dose chemo followed by autologous HCT
125
Lenalidomide mechanism in general
immunomodulatory
126
Variables used for risk stratification
1) Cytogenetics
2) LDH
3) beta-2 microglobulin
127
Initial treatment for standard-risk MM patients who are transplant candidates
Induction chemotherapy with VRd
128
Initial treatment for standard-risk MM patients who are NOT transplant candidates
D-Rd (avoid bortezomib)
129
Mayo Risk categories
Standard risk
Intermediate risk
High risk
130
General response to treatment of high-risk myeloma patients
These patients respond poorly to conventional therapies
131
other immunoglobulin levels are
typically suppressed
132
HIgh risk chromosomal abnormalities
```
del 17p
t(4;14) (controversial)
t(14;16)
gain 1q
p53 mutation
```
133
double-hit MM means
2 or more high-risk abnormalities
134
Preferred induction regimen for patient with peripheral neuropathy before induction
KRD (kyprolis is a proteasome inhibitor that doesn't cause peripheral neuropathy)
135
KRD vs. RVD
there is data that KRD is better than RVD in high risk patients
136
1) Revlimid vs. thalidomide
| 2) Most potent IMID
revlimid is more potent (but pomalidomide is most potent)
137
KRD is
Kyprolis, revlimid, dex
138
why is CyBoRd used for patients
Found o be efficacious in patients with light-chain cast nephropathy
139
Regimen used for patients with extramedullary disease
VDT-PACE
140
Caveat about CyBoRd
Always switch to RVD when renal function improves
141
goal of maintenance therapy
prolong PFS and deepen response to induction therapy
142
how is MRD assessed
NGS + PET/CT (but better tools are needed because 25% still relapse at 3 years)
143
Role for darzalex
Transplant ineligible (though may become standard of care for transplant eligible)
144
zoledronic acid mechanism
bisphosphonates
145
standard-of-care duration of bisphosphonates for MM
2 years
146
When you use denosumab
renal impairment
147
how much of the cortex needs to be involved to be called lytic lesion
50%
148
First line imaging modality for skeletal lesions per the International Myeloma Working Group
whole body MRI
149
Definition of skeletal lesions per the International Myeloma Working Group
More than one lesion greater than 5 mm
150
Management of equivocal small skeletal lesion on MRI
Repeat MRI in 3 months
151
Management of lytic bone lesions
dental referral + check vitamin D level and correct before starting
zoledronic acid 4 mg IV over 15 minutes q1 month indefinitely
152
Drug class of zoledronic acid
Bisphosphonate
153
Duration of bisphosphonate therapy in MM
Typically indefinite, unless in remission
154
Etiology of AKI in multiple myeloma patients
Broad array of etiologies:
- light chain cast nephropathy (most commonly)
- hypercalcemia
- volume depletion
- nephrotoxic agents (eg, radiocontrast, nonsteroidal antiinflammatory drugs [NSAIDs])
- less frequently, hyperuricemia or rarely hyperviscosity.
155
is myeloma curative?
no
156
why is melphalan not used in transplant eligible?
compromises ability to collect stem cells
157
what is early transplant strategy
- proceed with autologous HCT directly after recovery from stem cell collection
158
what is delayed transplant strategy
continued therapy usually with same regimen as used for induction, go to transplant once first relapse occurs
159
drug used as maintenance
IF standard risk -- lenalidomide
| IF high risk -- proteasome-inhibitor
160
preferred approach for high-risk MM
early HCT
161
lenalidomide dosing on dialysis
5 mg once dialysis (on dialysis days, give after dialysis)
162
lenalidomide dosing options
1) 25 mg daily, days 1-14, q 3 weeks
| 2) 25 mg, days 1-21, q 4 weeks
163
additional creatures beyond CRAB that classify someone as having multiple myeloma
- bone marrow plasmacytosis greater than 60%
| - K to L greater than 100
164
Features of high risk smoldering myeloma
- 20/2/20
- presence of 20% or more bone marrow plasma cells
- serum M protein spike of 2 or greater
- FLC ratio greater than 20
165
what is a high beta-2 microglobulin per ISS staging
greater than 5.4
166
variables involved in ISS staging system for multiple myeloma
LDH -- normal vs. greater than ULN
beta2
serum albumin (less than or greater than 3.5)
cytogenetics by fish
167
other term for light chain cast nephropathy
"myeloma kidney"
168
other etiologies of renal failure in myeloma patients
- amyloidosis
- light chain deposition disease
- acquired adult Fanconi syndrome
169
Creatinine threshold defining end organ damage from myeloma
greater than 2
170
Scoring systems for thromboprophylaxis for revlimid
SAVED, IMPEDE
171
clinical significance of hyperdiploidy
favorable risk feature
172
Drug class to avoid in induction therapy
alkylating agents (melphalan), which can compromise stem-cell reserve, preventing one from acquiring an adequate stem-cell harvest
173
intermediate risk features
- hypodiploidy
| - 13q deletion
174
what is KRd regimen
- carfilzomib (kyprolis)
- lenalidomide (revlimid)
- dexamethasone
175
induction therapy options for myeloma patients with baseline neuropathy
1) KRD
| 2) SQ bortezomib
176
pomalidomide mechanism
- derivative of thalidomide that acts as an immunomodulator
| - directly inhibits angiogenesis and myeloma cell growth
177
VGPR means
very good partial response
178
G3 neuropathy management with bortezomib
1) Hold until resolution
| IF improved to G1, rechallenge with dose reduced SQ formulation OR give every other week
179
G3 neuropathy menas
interfering with ADLs
180
Daratumumab target
CD38
181
Belantamab mafotodin (blenrep) mechanism
BCMA (conjugated with a cytotoxic agent, maleimidocaproyl monomethyl auristatin F)
182
panobinostat mechanism
HDAC inhibitor
183
selinexor mechanism
selective inhibitor of nuclear export
184
afuresertib mechanism
AKT inhibitor
185
indatuximab ravtansine mechanism
immunoconjugate CD138 with maytansine
186
indication for bisphosphonates in multiple myeloma
Bisphosphonate regardless of presence of bone lesions for up to 2 years
187
name for diagnostic criteria for MM
International Myeloma Working Group (IMWG)
188
Size of lesion on MRI that defines MM
Greater than or equal to 5 mm
189
panobinostat mechanism
HDAC inhibitor (histone deacetylase inhibitor)
190
panobinostat toxicity
- diarrhea + severe and fatal cardiac arrhythmias and EKG changes
191
daratumumab mechanism
targets CD38
192
elotuzumab mechanism
targets signaling lymphocytic activation molecule F7 (SLAMF7)
193
what are the IMIDs?
- lenalidomide
- thalidomide
- pomalidomide
194
FLC ratio defining smoldering myeloma features
- M protein >3
- Serum free light chain ratio >20
195
Management approach of patients with myeloma kidney (in general)
Early and aggressive treatment is necessary to avoid dialysis
196
What is standard risk
No high-risk chromosomal abnormality
197
R-ISS stage II is
NOT R-ISS stage I or III
198
R-ISS stage I is
- standard risk cytogenetics + LDH and beta-2 upper limit of normal
199
Creatinine that defines myeloma in CRAB criteria
Creatinine greater than 2
200
Thromboprophylaxis with lenalidome
IF no VTE RF’s → Aspirin 81 mg daily
| IF high VTE risk --> prophylactic dose LMWH
201
labs for plasma cell leukemia
Greater than 20% plasma cells in the blood
202
Drugs you shouldn't use for transplant candidates
alkylating agents (melphalan, which compromise stem-cell reserve)
203
NCCN first line regimens for transplant candidates
VRD
Carfilzomib + lenalidomide + dexamethasone
D-VRD
Ixazomib, lenalidomide, dex (category 2B)
204
Management of patient with G3 neuropathy who improves to G1 neuropathy after stopping bortezomib
- reinitiate at dose reduced and consider giving every other week
205
What is a Bence Jones protein?
Just monoclonal protein in the urine.
206
how does standard vs high risk influence treatment?
Standard risk = three-drug regimens are preferred over two-drug regimens because randomized trials suggest that they improve OS
High-risk = encourage participation in clinical trials since they do less well with conventional treatment
207
Car-T's approved for myeloma
Cilta-cel (better response rates)
| Ide-cel
208
bortezomib formulation
Always given subcue now due to reduced peripheral neuropathy
209
Preferred second line at UMass for myeloma
DKd (Dara-Carfilzomib/dexamethasone) (Preferred at UMass)
210
Contraindications to transplant in myeloma
1) EF below 40%
2) Uncontrolled arrhythmias (AF not rate controlled)
3) uncontrolled CAD
211
Relapsed-refractory management of patient who is frail with extensive comorbidities
belantamab mafodotin
