Updates in the Management of Side Effects
in Multiple Myeloma:
A Case-Based Approach to Care
Accredited by Medical Education Resources
Supported by The International Myeloma Foundation
Grant Funding provided by
Celgene Corporation and Millennium The Takeda Oncology
Company
Beth Faiman MSN, APRN, BC, AOCN®
Pre-Doctoral Research Fellow,
Francis Payne Bolton School of Nursing at Case Western Reserve
Nurse Practitioner, Taussig Cancer Institute
Cleveland Clinic Foundation
Cleveland , Ohio
Learning Objectives:
A Case­Based Approach to Care
­ Describe important management
strategies for renal failure in MM
­ Identify the appropriate nursing
interventions for hypercalcemia in MM
­ Describe side effects of steroids in MM
­ Discuss management of steroid ­
associated effects
What is Multiple Myeloma?
· Cancer of plasma cells
· Healthy plasma cells produce antibodies
or immunoglobulins
· Part of our humoral immunity, they are released in
response to foreign body invasion
· Myeloma cells produce abnormal
immunoglobulin
· Overproduce monoclonal protein or paraprotein
· Ineffective immunoglobulins
· Leads to decreased bone marrow function
· Destruction of bone tissue
San Miguel JF, et al. Pathogenesis of Multiple Myeloma: Rationale for New and Novel Therapies. Clinical Care Options: Accessed 22 February, 2007.
http://clinicaloptions.com/Oncology/Treatment%20Updates/Myeloma/Modules/Pathophysiology/Pages/Page%203.aspx.
Clinical Manifestations of
Multiple Myeloma
· Overproliferation of plasma cells can cause
­ Risk of infection
­ Osteolytic bone lesions
­ Hypercalcemia
­ Bone marrow suppression (pancytopenia)
­ Renal complication risk
· Production of monoclonal M proteins
causes
­
Decreased levels of normal immunoglobulins
­ Hyperviscosity
http://myeloma.org/pdfs/ph07-eng_f2.pdf
Criteria for Diagnosis of
Multiple Myeloma
Monoclonal plasma cells present in the bone
marrow 10%, and/or presence of a documented
plasmacytoma
+
Presence of M component in serum and/or urine*
+
One or more of the following (CRAB criteria)
· Calcium elevation (serum calcium >11.5 mg/dL)
· Renal insufficiency (serum creatinine >2 mg/dL)
· Anemia (hemoglobin <10 g/dL or 2 g/dL <normal)
· Bone disease (lytic lesions or osteopenia)
*Monoclonal M spike on electrophoresis IgG>3.5g/dL, IgA>2g/dL, light chain >1g/dL in 24-hr urine sample
Durie et al for the International Myeloma Working Group. Leukemia. 2006:1-7.
Challenges in MM Management
· Currently incurable in most patients
· Long-term complete responses are rare
· Median survival with standard therapy is about 3
years
· Autologous stem cell transplant may prolong
progression free survival, but not curative
· Treatment of relapse
­ No standard therapy
­ Existing options inadequate
· New treatment options needed
NCCN Practice Guidelines. Rajkumar SV, et al. Mayo Clin Proc. 2002;77:813-822.
MM Treatment Options
Conventional chemotherapy:
·
Melphalan
·
Doxorubicin
·
Cyclophosphamide
Maintenance in MM
Steroid therapy:
·After transplant
· Dexamethasone
·Conventional therapy
· Prednisone
Novel therapeutics:
·
Thalidomide
·
Lenalidomide
·
Bortezomib
Stem cell transplantation:
·
Autologous
·
Allogeneic
Radiation therapy
Thalomid ® Prescribing Information, Revlimid ® Prescribing
Information; Velcade® Prescribing Information
Effective Nursing Tools Improve Patient
Care and Treatment Outcomes
· Nurses play an essential role in managing
patient care
· Nurses are key in efficiently and optimally
managing emergent side effects
· Managing emergent side effects is an
important endeavor for improving MM
patient care and treatment outcome
· Improving nursing assessment contributes
to positive outcomes
IMF-NLB `Consensus Statements' supplement In Press, CJON June 2008
Case Study
46-year-old male
Lower back pain rated 8/10.
· Ibuprofen 4x/day
· Urgent care visit
History of mild high blood pressure and "blood sugar
problems", was told "if I lose weight my blood sugar
would be ok"
ROS:
· Lower than normal urine output
· Fatigue and shortness of breath when walking
Case Study
Lab/ Normal Reference
Value
Lab/ Normal Reference
Value
Range
Range
WBC 3.0-11.0 k/uL
11.55 (H)
BUN 8-25 mg/dL
53
Plt Ct 150-400 k/Ul
140(L)
Creatinine 0.7-1.4
3.9 (H)
Hgb 13.0-17.0 g/dL
8.3 (L)
mg/dL
Hct 39.0-51.0 %
24.4 (L)
Calcium 8.5-10.5 mg/dL
13.2(H)
MCV 80-100 fL
110.6 (H)
Albumin 3.5-5.0 g/dL
2.9 (L)
RDW-CV 11.5-15.0 %
14.7
Alk Phos 40-150 U/L
192 (H)
Neut% 38.5-75.0 %
76.2
Abs Neut 1.00-7.50 k/uL
5.07
B2M
20.8 (H)
Glucose
208 H
Total protein
6.4
Case Study
UPEP: Lab/ Normal
Value
Lab/
Value
Reference Range
Normal Reference Range
Urine Albumin
20.9%
MPA Serum IgG
338 (!)
717-1411 mg/dL
MPA Serum IgA
<7 (!)
Alpha 1
3.6
78-391 mg/dL
MPA Serum IgM
8 (!)
Alpha 2 Globulin
4.1
53-334 mg/dL
Beta G 0.50-1.00 gm/dL
69.1
MPA Serum Kappa
382
534-1267 mg/dL
Gamma Glob
2.3
MPA Serum Lambda 253-
0.65 (!)
653 mg/dL
Urine M spike g/dL)
4.10
Case Study
Component
Ref Range
Result
KAPPA, FREE, SERUM
3.3-19.4 mg/L
<3.0 (L)
LAMBDA, FREE, SERUM 5.7-26.3 mg/L
11150.4 (H)
K/L RATIO, SERUM
0.26-1.65
0.00 (L)
Case 1
Bone marrow biopsy: 60% plasma cells, lambda
restricted
· Cytogenetics: Normal male chromosome
· FISH is negative for 17p, del 13 and t(4:14)
Skeletal Survey:
· Widespread osteopenia, scattered lytic lesions femurs,
pelvis and calvarium.
­ T10 compression fracture and large lesion in his
humerus
Diagnosis:
· Lambda Light chain Multiple Myeloma, Stage III (ISS)
ARS Question
What would you consider to be part of the treatment plan?
1)
Start lenalidomide, melphalan + dexamethasone today (dose
adjust for renal failure), increase oral fluid intake
2)
Add him on the outpatient schedule for bortezomib and
dexamethasone first thing in the morning
3)
Admit for hydration, IV bisphosphonates, MM treatment and
pain control
4)
Clinical trial
ARS Question
What would you consider to be part of the treatment plan?
1)
Start lenalidomide, melphalan + dexamethasone today ­
Lenalidomide would be ok but avoid melphalan (stem cell)
2)
Add him on the schedule for bortezomib and dexamethasone
first thing in the morning ­ Urgent - we cannot wait!
3)
Admit for hydration, IV bisphosphonates, MM treatment and
pain control ­ Correct!
4)
Clinical trial ­ possibly, once the hypercalcemia and renal
failure are reversed or improved
Renal Failure
Myeloma kidney: proximal and distal tubules obstructed by
protein casts*
Myeloma cells in the kidney
Hypercalcemia
Hyperuricemia
Tumor lysis rare
· Bortezomib,Carfilzomib?
NSAIDs, ACE inhibitors
Infection
Amyloidosis
IV contrast dye
*Iggo N, et al. QJM. 1997;90:653-656.
Renal Failure
Survival depends on
· Response to chemotherapy
· Severity of renal failure
Factors associated with renal function recovery
· Degree of renal failure
· Presence of hypercalcemia
· Amount of proteinuria
· NSAIDs
· Creatinine <3.5
TREAT UNDERLYING CAUSE
Management of Renal Failure and Hypercalcemia
Supportive therapy
· Hydration
­ Hypovolemia, transfuse for anemia
· Correct underlying cause
­ Hypercalcemia, NSAIDS, MM
· Pamidronate or zoledronic acid IV for hypercalcemia of
malignancy
­ No dose reduction for pamidronate is necessary
· Avoid IV contrast and nephrotoxic agents
· Plasmapheresis ­
­ questionable benefit
· Dialysis-
­ May reverse renal failure in combination with newer agents
Durie et al, 2003; Chanan-Khan et al, 2007; Clark et al, 2005; Hutchinson et al, 2007; Rajkumar et al, 2005.
Treatment Options in Renal Insufficiency
Thalidomide
· metabolism of thalidomide in patients with renal failure similar to
that in normal renal function
· No dose modification in dialysis
Lenalidomide ­careful dose adjustment and observation required
· Substantially excreted by the kidney
· Myelosuppression
Bortezomib ­ no need to dose adjust even in ESRD
· Viable treatment option regardless of degree of renal impairment,
including dialysis dependence
· Since dialysis may reduce bortezomib concentrations, the drug
should be administered after dialysis
· Reversal of renal failure
Dialysis for severe renal failure ­ HD filters vs plasmapheresis??
Mulkerin D, et al. Blood (ASH Annual Meeting Abstracts) 2007;110:3477.
Dose Modifications for Renal Insufficiency -
Lenalidomide
Celgene Package Insert
Case Study ­ Care Plan
1-Treat hypovolemia/anemia:
·
Hydration: NS 1000ml IV over 4 hrs, then reduce the rate
to 125ml/hr
·
Transfuse 2 units PRBCs over 2 hours each
2- Treat hypercalcemia: Pamidronate 90mg IV over 4 hrs
3- Treat Disease: Dexamethasone 40mg po days 1-4
5- Supportive care: Blood glucose readings 4 times daily
with sliding scale insulin coverage
6- Pain Management: Morphine 2mg IV every 2-4 hours as
needed for pain
Case Study Follow Up
Your patient was admitted. He received IV hydration, pamidronate,
dexamethasone, pain medications and his renal function has
improved. He has a vertebral compression fracture T10 and a
large lesion in his humerus. Which is true?
1.
Bisphosphonates are contraindicated in patients with
myeloma once hypercalcemia resolved
2.
Bone marrow transplant is not recommended for patients
with kidney failure at presentation
3.
Radiation therapy cannot be given to patients with spinal
lesions
4.
Orthopedics consult + radiation consult are necessary for
possible surgical evaluation, radiation
Case Study Follow Up
Your patient was admitted. He received IV hydration, pamidronate,
dexamethasone, pain medications and his renal function has
improved. He has a vertebral compression fracture T10 and a
large lesion in his humerus. Which is true?
1.
Bisphosphonates are contraindicated in patients with
myeloma once hypercalcemia resolved
2.
Bone marrow transplant is not recommended for patients
with kidney failure at presentation
3.
Radiation therapy cannot be given to patients with spinal
lesions
4.
Orthopedics consult + radiation consult are necessary for
possible surgical evaluation, radiation ­ Correct!
Bone Remodeling
Continuous throughout life
· Osteoblasts: cells that build bone
· Osteoclasts: cells that break down bone
Osteoblastic and osteoclastic activity is tightly
coupled and balanced
· Resorption = growth
Ensures skeletal integrity
Maintains mineral homeostasis
Bone Disease in MM
The Central Role of the Osteoclast in
Osteolytic Bone Destruction
Tumor cells
Osteoclast differentiation
Growth
Direct effects on
factors
osteoclast differentiation
Active
osteoclast
Osteolysis
Bone loss
Adapted from Roodman GD. N Engl J Med. 2004;350:1655-1664.
Clinical Consequences of Myeloma
Bone Disease
Pathological fractures
· Non-vertebral
· Vertebral compression
Spinal cord
compression/collapse
Radiation therapy
Surgery
· Minimally invasive
· Fixation or Fracture
prevention
Pain, QOL ,Survival
Supportive Care: Vertebroplasty
Source: Fourney DR, et al. J Neurosurg (Spine 1). 2003;98:21-30.
Supportive Care:
Balloon Kyphoplasty
KyphX Introducer Tool Kit:
KyphX IBT inflation:
KyphX IBT Removal:
· Allows precise, minimally
· Reduces the fracture
· Leaves a defined cavity
invasive access to the
· Compacts the bone
and trabecular dam that
vertebral body
· May elevate endplates
can be filled with an
· Provides working channel
approved bone void filler
of the physician's choice
Mechanism of Bisphosphonate Inhibition of
Osteoclast Activity
Bisphosphonates may modulate
signaling from osteoblasts
to osteoclasts
Bisphosphonates
inhibit osteoclast
X
Increased OPG production2
activity, and promote
Decreased RANKL expression3
osteoclast apoptosis1
New bone
Bone
Bisphosphonates
Bisphosphonates are
are released locally
concentrated under
during bone resorption1
osteoclasts1
1. Reszka AA, Rodan GA. Curr Rheumatol Rep. 2003;5:65-74. 2. Viereck V et al. Biochem Biophys Res Commun.
2002;291:680-686. 3. Pan B et al. J Bone Miner Res. 2004;19:147-154.
Bisphosphonates and
Renal Dysfunction
Potent inhibitors bone resorption
· Pamidronate1 ­ Glomerular
· Zoledronic acid2 ­ Tubular
· Both effective to decrease SRE's
BASELINE DENTAL EXAM!
· Acute Phase Reactions, albuminuria, creatinine
Dialysis (irreversibly), may use either zoledronic acid or
pamidronate at same dose, infusion time and interval
Poor renal function at diagnosis
· No dose reduction recommended
· Most wait until kidneys improve; treat Hyperca++
with fluids
1Berenson JR, et al. J Clin Pharmacol. 1997;37:285-290. 2Novartis, data on file. 3Major P, et al. J
Clin Oncol. 2001;19:558-567.
Receptor Activator of Nuclear Factor B Ligand (RANKL)
and Osteoprotegerin (OPG)
Stromal cell/Osteoblast
Parathyroid hormone/
Parathyroid hormone­related protein
1,25D
RANKL
3
OPG
PGE
RANK
2
Interleukin-11
Osteoclast Precursor
Osteoclast
Derived from Roodman GD. N Engl J Med. 2004;350:1655-1664.
Novel Agents in Bone Disease
Phase I denosumab in MM
· Denosumab SC at 0.1, 0.3, 1.0, or 3.0 mg/kg
· Pamidronate IV 90 mg
Assess bone resorption markers
· Urine and serum N-telopeptide levels for 84
days following dose
Effective for MM plateau phase (Vij 2007)
Bortezomib may stimulate osteoblasts
Lenalidomide and thalidomide NF-KB inhibitors,
block signaling
Body JJ, et al. Clin Cancer Res. 2006;12:1221-1228; Vij R, et al. Blood. 2007;118:1054A. Ma MH, et al. Clin Cancer Res. 2003;9:1136-1144. Zangari
M, et al. Br J Haematol. 2005;131:71-73. Shimazaki C, et al. Leukemia. 2005;19:1102-1103. Oyajobi. et al. Br J Haematol. 2007;139:434-438.
Case Study Follow up
Your patient received radiation to his humerus and is being
evaluated for kyphoplasty. Pain and energy is much better 48
hrs after being admitted but is complaining of excessive
thirst, mood swings, insomnia ("I'm very depressed"), and
excessive urination.
Labs:
Calcium 8.5 (normal)
Hemoglobin 9.0 (mild anemia)
Creatinine 1.8 (still a little elevated)
Blood sugar 309 (normal <150)
Of these readings, what would be the most concerning?
Steroids ­
The Nursing Management Challenge
· Steroids affect multiple physiological systems
· Can negatively impact QOL
­ Physical
­Social
­ Psychological
· Impact can lead to decreased compliance with
treatment
· Increase awareness of side effects and interventions
· Address steroid effects in a timely manner
Steroid Therapy in Multiple Myeloma
· Steroids are one of the most helpful group of drugs
for the treatment of multiple myeloma
· Steroids can increase the ability of chemotherapeutic
and immunomodulatory agents to destroy myeloma
cells
· Steroids appear to cause apoptosis, thus can trigger
the destruction of myeloma cells
· Treatment can sometimes bring remission
· Dexamethasone and Prednisone are two commonly
used steroids for Multiple Myeloma
Adapted from NLB Consensus Recommendations. Faiman et al, 2008.
Steroid Therapy in Multiple Myeloma (Con't)
· Steroids have the following advantages:
· Shrink plasmacytomas
· Reduce neurologic pressure
· Reduce hypercalcemia
· Achieve overall control of the disease
· Best agents for maintenance therapy
· In patients with renal failure, they can be used without dose
adjustment.
· In patients who have low blood counts, they can be used
without fear of further reduction in counts.
Adapted from NLB Consensus Recommendations. Faiman et al, 2008.
Steroid Side Effects Associated
With Multiple Myeloma Therapy
· Steroidal use can cause multiple system side effects,
such as:
­ Constitutional
­ Ophthalmic
­ Psychiatric
­ Gastrointestinal
­ Immune system
­ Endocrine
­ Musculoskeletal
­ Cardiovascular
­ Bone loss
­ Dermatologic
­ Body image
Faiman et al, 2008.
Management of Constitutional Symptoms : Insomnia
·Insomnia is the prolonged and abnormal inability to
obtain adequate sleep
Insomnia (CTCAE v3.0 Grading)
Grade 1 ­ difficulty sleeping, not interfering with function
Grade 2 ­ difficulty sleeping, interfering with function but not ADL
Grade 3 ­ frequent difficulty sleeping, interfering with ADL
Grade 4 ­ disabling
· Nonpharmacological interventions
­ Evaluate sleep habits
­ Educate paient requarding sleep preparatio
· Pharmacololgical interventions
­ Hypnotic/sedatives
­ Drug class determined by type of insomnia
Faiman et al, 2008
Management of Psychiatric Symptoms: Personality
changes/mood alterations
·Personality changes generally lead to chronic, inflexible,
maladaptive pattern of perceiving, thinking, and behaving that
seriously impairs an individual's ability to function in social or other
settings.
Personality Changes (CTCAE v3.0 Grading)
Grade 1 ­ change, but not adversely affecting patient or family
Grade 2 ­ change, adversely affecting patient or family
Grade 3 ­ mental health intervention indicated
Grade 4 ­ change harmful to others or self; hospitalization indicated
Faiman et al, 2008
Management of Psychiatric Symptoms: Mood
alterations
·Mood disorder defines alterations leading to severe depression or
depression alternating with mania.
Mood Alteration (CTCAE v3.0 Grading)
Grade 1 ­ mild mood alteration not interfering with function
Grade 2 ­ moderate mood alteration interfering with function, but not
interfering with activities of daily living (ADL); medication indicated
Grade 3 ­ severe mood alteration interfering with ADL
Grade 4 ­ suicidal ideation; danger to self or others
Faiman et al, 2008
Management of Psychiatric Symptoms: Personality
changes/mood alterations
· Nonpharmacological interventions
­ Patient education and support
­ Referral to support groups
­ Referral to pyschosocial services
· Pharmacololgical interventions
­ Dose reduction or discontinuation of steroids
­ Dose in am
­ SSRIs or mood stabilizers (Lexapro, Celexa or Zyprexa)
Faiman et al, 2008
Management of Endocrine Effects:
Hyperglycemia
·Hyperglycemia is an elevated level of the sugar glucose in the blood
·Can lead to the disease of diabetes
Hyperglycemia Grading CTCAE v3.0
Grade 1- >ULN-160mg/dL
Grade 2- >160-250mg/dL
Grade 3- >250-500mg/dL
Grade 4- >500mg/dL
Faiman et al, 2008
Management of Endocrine Effects:
Hyperglycemia
· Nonpharmacological recommendations (mild blood
glucose, no prior history of diabetes)
­ Nutrition counseling to avoid simple carbohydrates and sugar
­ Weight loss if overweight
­ Increase physical activity
· Pharmacological recommendations
­ If serum glucose >200mg/dL
­ glucose monitoring with possible oral hypoglycemics
­ Diabetic Education (signs/symptoms of hyper/hypoglycemia
­ Refer to PCP or Endocrinology for baseline assessment
­ If serum glucose >300mg/dL
­ All of the above
­ May require insulin therapy
Faiman et al, 2008
Steroid Therapy in Multiple Myeloma
· Constitutional Symptoms
­ Tapered doses or dose reduction
­ Urology consult/hormone supplementation for sexual
dysfunction
­ Hypnotics/sedatives
· Psychiatric symptoms
­ Referral to psychosocial services
­ Dose reduction
­ SSRIS or mood stabilizers
­ Benzodiazepines
Faiman et al, 2008
Steroid Therapy in Multiple Myeloma
· Gastrointestinal
­ Diet changes, decrease greasy, fried or acidic foods
­ Over the counter antacids for GERD-like symptoms
· Maalox, Priosec, Prevacid, Tagamet
· Simethicone OTC or Pepto-Bismal for gas
· Endocrine
­ Nutrition counseling
­ Weight loss
­ Increase physical activity
­ Temporary insulin in needed for hyperglycemia
­ Tapering of steroids
­ Endocrinology referral
Faiman et al, 2008
Steroid Therapy in Multiple Myeloma
· Cardiovascular symptoms
­ Diet changes
­ Diuretics,
­ Physical activity
· Dermatologic
­ Good hygiene
­ Exfoliant use
­ Tripleantibiotic treatment
·
Faiman et al, 2008
Patient and Caregiver Education
It is important to educate the patient and caregiver on
the following:
· Patients should be advised regarding steroids related side effects
and measurement, especially short and long term toxicities
· The importance of non-pharmacological and pharmacological
management of steroid related side effects
· Indications for contacting medical personnel based on institution
policy
· Emergency contact numbers
Faiman et al, 2008
Case Study- Outcome
-Was discharged with normal creatinine, calcium and
anemia improved
-Started on a clinical trial with lenalidomide, bortezomib
and dexamethasone
- Steroids were reduced to the day of and after
bortezomib
- Started on glipizide to help with blood sugars
- Took steroids at night helped side effects
- Started on an anti-depressant to help with mood
- Back pain improved as a result of kyphoplasty,
bisphosphonates
Key Takeaways
· It is important to be aware of common side effects of
MM and nursing management
· Nurses are integral to the treatmen team
· Renal failure and hypercalcemia are often reversible if
prompt intervention
· Support the side effects to adhere to treatment
· Be aware of patient resources!
Educational Resources
·
American Cancer Society
·
National Cancer Institute
·
International Myeloma Foundation
- IMF Myeloma Today Newsletter
- 1 800-452-CURE
-IMF Website
www.myeloma.org