SET1 Flashcards
True of False: Bortezomib does NOT require dose adjustments in renal failure
True; lenalidomide does but Bortezomib does not
What immunoconjugate carries maytansine and targets CD138 on MM cells?
Indatuximab
What is the main cause of Pure Red Cell Aplasia in Sickle Cell? What test is most helpful?
Parvovirus B19; IgM antibody
What did the TAPS study show in Sickle Cell?
That patients who had simple transfusions prior to general anesthesia with a goal of Hgb of 10 had decreased complications
When should Pure Red Cell Aplasia be considered in a sickle cell patient?
Whenever their hemoglobin is below their baseline it should be considered, also if the reticulocyte count is <1%; generally due to Parvo B19
Bortezomib and dexamethasone is the preferred induction regimen for MM in what situation in particular?
MM patients presenting in renal failure as Revlamid (lenalidomide) requires dose adjustments
What is better in MM, hyperdiploidy or hypodiploidy?
Hyperdiploidy (standard risk) and hypodiploidy is intermediate risk
What are 3 indications for Hydroxyurea in Sickle Cell and what is the dose?
Acute Chest syndrome, Recurrent painful crises, frequent hospitalizations; 35 mg/kg
What kind of anemia may result from Waldenstoms macroglobulinemia?
Cold Agglutinin Hemolytic Anemia (recall, this is more intravascular and warm is more extravascular so you only see microspheroctyes in warm)
What is the main side effect of Bortezomib? How can it be alleviated?
Peripheral neuropathy; Occurs less commonly with SubQ than IV or you can switch to Carfilzomib
Can Pomalidomide be given if someones MM has relapsed after lenalidomide?
Yes, this is actually when it is used
What is standard dose Bortezomib?
1.3 mg/m2 SQ or IV (SQ has less neuropathy than IV)
What other immunomodulator can be given in relapsed myeloma after patient already exposed to lenalidomide?
Pomalidomide
What is the dose of zoledronic acid to give if patient has a normal GFR?
4 mg
What is the best management of Acute Stroke in sickle cell?
Exchange or regular RBC transfusions to reduce HbS to less than 30%
What are three ways that Hydroxyurea is helpful in Sickle Cell?
1) Inhibits RNA reductase leading to cell death 2) Increases production of NO to dilate blood vessels to alleviate sickling/pulm HTN and 3) activates guanylate cyclase which increases HbF
What is the ISS staging of MM?
Stage 1 B2M <3.5 and albumin >3.5, Stage 2 is neither I nor III, Stage III is albumin <3.5 or B2M >5.5
What is a potential blood bank issue with Daratumumab?
It can interfere with certain tests done at the blood bank i.e. for a transfusion
What is the MOA of Afuresertib?
AKT inhibitor as AKT is activated by proteasome inhibition
Where do the sickle cells sludge leading to renal papillary necrosis?
In the vasa recta of the renal medulla because it is more hypoxic
What is the mechanism of action of Daratumumab?
Anti-CD38 antibody (CD38 expressed on plasma cells)
Why are Sickle Cell patients at increased risk of Pulmonary HTN?
Due to increased breakdown of cells in pulmonary blood vessels = inflammation with decreased NO and inability to vasodilate
What is Pabinostat and when can it be used in MM?
It is an HDAC inhibitor and can be used in relapsed MM
In general what is a common motif of the genetic abnormalies of Multiple Myeloma?
Commonly, there is a translocation that leads to juxtaposition of an oncogene next to the Ig heavy chain locus on chromosome 14 (oncogenes on 11q, 6p, 16q, 20q, and 4p)
How should you treat Plasma Cell Leukemia? What is the OS?
Aggressively i.e. with DT-PACE or VD-PACE followed by high dose melphalan (200 mg/m2) + prednisone followed by autologous xplant; < 12 months
Why do you need to do plasmapheresis in patients with IgM > 5000 prior to giving Rituximab, EVEN IF serum viscosity is normal?
Because there is concern for Rituximab-Related IgM flare
Explain the hemoglobin electrophoresis results of a Sickle Cell patient that has a Delayed Hemolytic Transfusion Reaction
You can see that they have almost all HbS because all of the donor cells have been lysed and those would be HbA
What are three indications for LMWH ppx in a patient on lenalidomide or thalidomide?
High Dose dexamethasone, Doxorubicin (i.e. DT-PACE), or multiagent chemo
What are the two criteria to make a diagnosis of Multiple Myeloma?
BM plasma cells >10%, M spike > 3g/dl
What is the standard first line therapy for newly diagnosed TRANSPLANT INELEGIBLE MM?
Lenalidomide + Dexamethasone (obviously have to watch for renal dysfunction)
What is the main molecule, present on the basolateral side of enteric cells, that is responsible for iron absorption?
Ferroportin
What does SLAMF7 stand for? What drug targets
Signaling Lymphocyte Activation Molecule Family 7 (Elotuzumab is an inhibitor); expressed on myeloma and NK cells
What is one way AL amyloidosis can be treated?
Melphalan + Prednisone
When is Daratumumab used in MM?
It is an anti-CD38 ab that is used in patients who have failed at least 3 lines of Tx
What translocation leads to a particularly bad outcome in MM?
t(4;14)
What is Indatuximab?
An anti-CD138 immunoconjugate that carries maytansine as CD138 is expressed on MM cells
What is the most common cause of renal failure in MM?
Cast nephropathy i.e. the light chains form casts that lead to deposition in the DCT
If a person was treated with Bortezomib contaning regimen and relapses is it okay to give Bortezomib again?
Only if the relapse was greater than 6 months after induction then it is okay to use a Bortezomib retreatment strategy (Phase II RETRIEVE study)
Although sickle cell trait is mostly a benign condition what are some issues it can cause?
Isothenuria and hematuria due to medullary ischemia (vasa recta sickling, medulla is hypoxic) main concern is for Renal Papillary Necrosis as it can occur in both the Dz and in trait
What sorts of drugs should not be given in Myeloma if considering an autologous transplant?
Would not give any myelotoxic agents prior to harvesting stem cells (i.e. alkylating agents, melphalan) this will lead to inadequate stem cell harvest
How do you manage neuropathy in a patient on Bortezomib?
Stop the drug and if the neuropathy goes away you can restart it at a lower dose (i.e. decrease from 1.3 mg/m2 to 0.7 mg/m2)
At what GFR should zoledronic acid not be given?
When the CrCl is <30; prior to this you can dose reduce
If a sickle cell pt has had a stroke can the be optimally managed with just Hydrea afterwards?
No they should also get chronic transfusions to prevent secondary strokes
What is the worst cytogenetic MM?
17p deletion (lose TP53 tumor suppressor gene); t(4;14) is also bad but Bortezomib shown to be active here
What are the side effects of zoledronic acid and when should it be avoided?
Myalgias, hypocalcemia, osteonecrosis of jaw, kidney issues; do not give if CrCl <30
What translocation in systemic amyloidosis is associated with inferior hematologic EFS and OS when Bortezomib regimens are used?
t(11;14)
What 3 cytogenetic mutations make up standard risk MM?
Hyperdiploidy, t(11;14), and t(6;14)
What is the mechanism of action of Elotuzumab?
Anti-SLAMF7 used best in combo with lenalidomide (SLAMF7 expressed on NK cells and MM)
Why are Salmonella infections common in Sickle Cell patients?
Because of intravascular sickling and necrosis in the enteric system leading to gut translocation of Salmonella; not to mention it compromises splenic and reticuloendothelial fxn
What are the two really bad cytogenetic classes of Multiple Myeloma?
t(4;14) and 17p deletion (TP53)
What 5 cytogenetic mutations make up Poor Risk Group MM?
t(4;14) 17p deletion, t(14;20), t(14;16), amplification of 1q21
What mutation in MM is a poor risk factor when detected by cytogenetics but is NOT a poor risk factor when detected by FISH?
13q deletion
Why can B12 deficiency lead to hemolytic anemia?
Due to ineffective hematopoiesis; you will see a LOW reticulocyte count
If a patient with Sickle Cell dz has a R heart cath showing pulmonary HTN what is the mgmt?
Lifelong anticoagulation
When is Pomalidomide used in MM?
It is used for relapsed myeloma that has failed at least two prior therapies INCLUDING lenalidomide and bortezomib
What is the MOA of Filanesib?
Kinesin Spindle Protein inhibitor
How is Hyperhemolysis different from a Delayed Hemolytic Transfusion reaction in Sickle Cell?
In DHTR the DAT is positive and only the donor RBC are lysed so Hb electro will show all HbS; in Hyperhemolysis BOTH donor AND host RBC are lysed so Hb electro has both HbA and HbS
Elotuzumab is directed against SLAMF7 on what two types of cells?
Myeloma cells and Natural Killer cells
What is the treatment of a Solitary Plasmacytoma of Bone?
45 Gy radiation to the site, and this can be curative though some may progress to frank MM (by definition a SPB has no marrow plasmacytosis)
Name 2 anti-CD38 abs?
Daratumumab and SAR650984
What is the deal with preoperative simple transfusions in Sickle Cell patients?
They are associated with decreased complication rate (TAPS study); the goal is Hgb of 10 in patients undergoing general anesthesia
What is the management for Waldenstroms and Lymphoplasmacytic lymphomas that are asymptomatic?
Observation
What are the units of serum viscosity?
cP (Centipoise, named after Poiselle)
What is Darzelex?
Daratumumab (Anti-CD38 used in relapsed myeloma who have failed 3 tx)
What are some (2) poor prognostic features of Smoldering Myeloma (i.e. High Risk Smoldering Myeloma)?
Marked BM plasmacytosis, i.e. >60%, Very skewed serum free light chain ratio either >8 or <0.125 (Kappa:Lambda)
What is meperidine out of favor for Sickle Cell pain crises?
It lowers the seizure threshold
When is aspirin okay for DVT prophylaxis in pts on lenalidomide or thalidomide? When do you need LMWH?
If the patient is healthy; If the lenalidomide is given with high dose dex, doxorubicin (i.e. DT-PACE), or any multiagent chemo
What can you say about maintenance lenalidomide (Revlamid) AFTER autologous transplant?
No role for continuing it as it increases the risk of secondary malignancy
What are some precipitants of acute chest syndrome?
lung infection, in-situ thrombosis, and fat embolism; all increase inflammation deoxygenation which increases sickling
What molecule leads to proteolysis of ferroportin in anemia of chronic disease?
Hepcidin
What is Ixazomib and when is it used?
It is an oral proteasome inhibitor that can be used in MM who have failed at least 1 line of therapy
If there is hemolytic anemia, what may tip you off that it is actually due to B12 deficiency?
A hemolytic anemia with LOW reticulocytes can suggest B12 def as a possible cause
What antigen does Parvovirus B19 bind to in order to cause aplastic crisis?
P antigen
Explain the strangeness of 13q deletion on prognosis in MM
13q deletion detected by cytogenetics is a bad risk factor but 13q detected by FISH is NOT!
In general, what is the HbS and overal hemoglobin goal in an exchange transfusion in Sickle Cell?
HbS less than 30%; Hgb no more than 10
What molecule causes retention of iron in the reticuloendothelial macrophages in anemia of chronic disease?
Hepcidin
What percentage of MM patients have co-occuring amyloidosis?
>10%
Why should Aminocaproic acid not be used in hematuria?
It can thrombose and occlude the ureters necessitating nephrostomy tube placement due to obstructive renal failure
Explain the role of Hepcidin in Anemia of Chronic Disease
It causes retention of iron in the reticuloendothelial system; it causes proteolysis of ferroportin on the basolateral membrane of intestinal cells causing decreased absorption from the enteric system
What two cells express SLAMF7? What drug targets SLAMF7?
All myeloma and NK cells; Elotuzumab
Dose adjustments of Lenalidomide are made on what basis?
Renal function; there are various dose adjustments that are made based on renal fxn (GFR)
True or False: CyBorD is okay to give in renal failure
True
How is Lenalidomide often given in MM?
25 mg daily on days 1-14 q3 weeks
What is the preferred treatment of Myeloma patients who present in renal failure?
Bortezomib + Dexamethasone (CyBorD, VCD); the reason for this is that so much dose adjustment is needed for lenalidomide (Revlamid) and early and aggressive tx necessary to prevent permanent dialysis needs
What are 5 potential causes of renal failure in MM?
Cast nephropathy w/ Bence-Jones lodged in DCT, Amyloidosis, light chain deposition disease, hypercalcemia, and acquired Adult Fanconi Anemia
If a person has MM but no bony lesions should they be on a bisphosphonate?
Yes they should all be on bisphosphonates
What do you need to have Plasma Cell Leukemia? Treatment?
>2000 circulating plasma cells; Aggressive multiagent chemo like DT-PACE/VD-PACE followed by high dose melphalan and auto-HSCT
What is Hyperhemolysis in Sickle Cell and what is the treatment?
It occurs after a transfusion and there is a negative DAT test and lysis of BOTH donor and host RBC so Hb electrophoresis shows BOTH HbS and HbA. Tx = avoid xfusion, IVIG, Steroids
What are indications to Tx Waldenstroms?
Disease related Hgb <10 or Plt <100,000; Bulky adenopathy or HSM, Hyperviscosity syndrome; Neuropathy, amyloidosis, cryoglobulinemia, or cold-agglutinin dz
What two cytogenetic groups make up intermediate risk MM?
Del13q, hypodiploidy
What prophylaxis do patients receiving lenalidomide need? Bortezomib?
DVT ppx (if healthy, aspirin is okay); viral prophylaxis with valacylovir
What are the two MANDATORY criteria to have POEMS
M spike and Polyneuropathy, the organomegaly, endocrinopathy, and skin changes less important
How can you use neutrophils on a blood smear to help make a dx of B12 def?
5 neutrophils with nuclei with 5 lobes or one neutrophil with 6 lobes
At what serum viscosity does hyperviscosity syndrome appear?
> 4 cp, requires urgent plasmapheresis
In a sickle cell patient who has suffered a stroke, what is the long term management?
Chronic Simple Transfusions have been shown to help prevent secondary strokes; indefinite xfusion recommended as DC leads to recurrent strokes even with Hydrea
Definition of MGUS and annual transformation risk per year
BM plasma cells <10% and M spike < 3 g/dl; 1% risk per year
What is the best induction regimen of MM pt who is transplant eligible? Transplant inegilible?
Bortezomib containing regimen like CyBorD, VCD; transplant ineligible then lenalidomide dex (RD) is standard
What is POEMS syndrome
Polyneuropathy, Organomegaly, Endocrinopathy, M-Spike and Skin Changes
What kind of drug is Ricolinostat?
HDAC inhibitor
Why does amyloidosis cause coagulopathy?
Amyloid fibers lead to adsorption of Factor X to the light chain fibrils (check PT, aPTT, and factor X level)
What is the effect of Bortezomib on Myeloma patients harboring 17 p deletion? T(4;14)?
No effect on 17p deletion it’s really bad; there is increased survival in patients with t(4;14)
Name 6 indications for Simple Transfusion in Sickle Cell
Symptomatic anemia, Aplastic Crisis, Splenic/Hepatic sequestration, Acute chest, Acute MODS, preop xfusion for major surgery (TAPS study)
The Mayo Risk Model considers what serum free light chain ratios to be high risk features for Smoldering Myeloma?
K:L >8 or <0.125
What drug would be the backbone of therapy in the poor cytogenetic class of t(4;14) Multiple Myeloma?
Bortezomib increases survival in this class, it does not affect 17 p deletion
What test is often helpful in identifying a Delayed Hemolytic Transfusion Reaction?
Direct Coombs; as it will detect the alloimmunization that occurs about 5-10 days after transfusion
True or false: you should use Sildenafil in sickle cell pts with pulmonary HTN
False the FDA halted a trial because it increased pain crises
Are all lymphoplasmacytic lymphomas IgM producing?
No there are IgA, IgG and even non-secretory forms but all are less likely to cause hyperviscosity symptoms than Waldenstroms bc IgM is a pentamer
Why do patients with amylodosis have orthostatic hypotension?
Amyloid fibers damage autonomic nervous system leading to autonomic neuropathy
Intravascular sickling in the enteric capillaries predisposes to what enteric infection in Sickle Cell disease?
Salmonella enteriditis
True or false: Renal Papillary Necrosis occurs only in sickle cell disease
False it can occur in both sickle cell disease and sickle cell trait
What are the drugs of choice for sickle cell pain crisis?
Morphine or Hydromorphone; meperidine out of favor bc causes seizures
