CCO Myeloma Nursing TU13 Slides

Nursing Care for a Patient With
Multiple Myeloma
Sandra E. Kurtin, RN, MS, AOCN,
ANP-C
Hematology/Oncology Nurse Practitioner
Clinical Assistant Professor of Nursing
Clinical Assistant Professor of Medicine
Arizona Cancer Center
University of Arizona
Tucson, Arizona
This program is supported by educational grants from
Nursing Care for a Patient With Multiple Myeloma
clinicaloptions.com/oncology
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Faculty
Sandra E. Kurtin, RN, MS, AOCN, ANP-C
Hematology/Oncology Nurse Practitioner
Clinical Assistant Professor of Nursing
Clinical Assistant Professor of Medicine
Arizona Cancer Center
University of Arizona
Tucson, Arizona
Disclosure
Sandra E. Kurtin, RN, MS, AOCN, ANP-C, has disclosed
that she has received fees for non-CME/CE services from
Celgene, Millennium, and Onyx.
Introduction:
Overview of MM
Overproduction of Abnormal Plasma Cells

and Associated Serum Proteins in MM
Renal impairment
Cytopenias
MM bone marrow
Myeloid
progenitor cell Invasion of
bone
Hematopoietic
stem cell T lymphocytes
marrow
Lymphoid
Genetic progenitor
cell
and
molecular
defects
NK cells B lymphocytes
Invasion of bone
circulating abnormal
Lytic lesions serum proteins
hypercalcemia Immunodeficiency
Abnormal plasma cells neurological disease
NIH. Stem cell basics. 2009.
Image created by Sandy Kurtin, The University of Arizona Cancer Center.
MM Diagnostic Evaluation
History and physical Establish diagnosis of MM
CBC, differential and platelet count MGUS
Smoldering
Additional laboratory tests Bone marrow biopsy and
aspiration Active
Serum immunoglobulins
Hematopathology Determine subtype
Quantitative (IgG, IgM, IgA, IgD)
Heavy chain/light chain
Presence of plasma
SPEP Nonsecretory
cells, %
SFLC assay (kappa, lambda) Solitary plasmacytoma
Cellularity
24-hr urine Determine stage
Ploidy
BUN, creatinine, electrolytes ISS
Cytogenetics
Serum calcium (corrected) Salmon-Durie staging system
FISH Estimate prognosis
Serum albumin
Cytogenetics
2-microglobulin
Albumin
LDH 2-microglobulin
Additional testing based on Ploidy
preliminary analysis
Identify need for immediate
intervention
Radiology
Severe hypercalcemia
Skeletal survey Acute renal failure
MRI if vertebral compression fractures suspected Cord compression
PET/CT Severe pain or impending fracture
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2013. Kurtin S. JAdPrO. 2010;1:19-29.
MM Disease Trajectory
Nonmalignant Aggressive and
Accumulation Malignant Transformation Stromal Independent
Plasma
Stroma and IL-6
angiogenesis dependent cell
leukemia
MGUS Smoldering Myeloma Multiple Myeloma

< 3 g M protein 30 g/L M protein 10% clonal BMPC
< 10% clonal BMPC 10% clonal BMPC M protein in serum and/or urine
No MM-related No MM-related 1 CRAB features of disease related to
end-organ damage end-organ damage organ damage
1%/yr risk of 10%/yr risk of C: Calcium elevation > 11.5 mg/L or ULN
progression to MM progression to MM in
the first 5 yrs R: Renal dysfunction (serum creatinine
> 2 mg/dL)
A: Anemia (Hb <10 g/dL or 2 g < normal)
B: Bone disease (lytic lesions or
osteoporosis)
Kuehl WM, et al. Nat Rev Cancer. 2002;2:175-187. Vacca A, et al. Leukemia. 2006;20:193-199. Agarwal A, et al. Clin Cancer
Res. 2013,19:985-994. Durie BG, et al. Hematol J. 2003;4:379-398. Adapted with permission from Kurtin SE. J Adv Pract
Oncol. 2010;1:19-29.
MM Staging Systems
Stage Durie-Salmon Staging System[1] International Staging System[2]
I Hemoglobin > 10 g/dL 2M < 3.5 g/dL and albumin
3.5 g/dL
Calcium normal or 12 mg/dL
Normal skeletal survey or solitary plasmacytoma
Low M protein production
IgG < 5 g/dL
IgA < 3 g/dL
Bence Jones protein < 4 g/24 h
II Neither stage I nor stage III
III 1 or more of the following 2M 5.5 g/dL
Hb < 8.5 g/dL
Calcium > 12 mg/dL
Multiple lytic bone lesions
High M protein component
IgG > 7 g/dL
IgA > 5 g/dL
Bence Jones protein > 12 g/24 hrs
1. Durie BG, et al. Cancer. 1975;36:842-854. 2. Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420.
International Staging System

Stage Characteristic Median Survival, Mos
I 2M < 3.5 mg/L 62
Albumin 3.5 g/dL
II 2M 3.5 to 5.4 mg/L 44
Albumin < 3.5 g/dL
III 2M 5.5 mg/L 29
Greipp PR, et al. J Clin Oncol. 2005;23:3412-3420. Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110.
Risk-Adapted Treatment for MM
Treatment of Multiple Myeloma

Confirmed Diagnosis of Multiple MyelomaCRAB Criteria
Determination of Immediate interventions for
transplantation eligibility serious adverse events
Individualized Treatment Selection for Induction Therapy

Transplantation Eligible Transplantation Ineligible
Works rapidly (CR, nCR, VGPR) Achieving a CR or nCR
Well tolerated Level of evidence 1 or 2A
Spares stem cells Tolerability and QoL
Level of evidence 1 or 2A PS and comorbidities
Continued Treatment
Salvage therapy Maintenance therapy
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2013.
Treatment Options Have Greatly Increased

in the Past Decade
MM Therapies Introduction FDA Approved in MM
1950 1960 1970 1980 1990 2000 2010
1958 1983 2003

Melphalan Autologous Bortezomib 3rd line 2013
transplantation Pomalidomide
3rd line
1962 2005
Prednisone Bortezomib 2nd line
1986
2012
1969 High-dose
2006 Carfilzomib
Melphalan + dexamethasone
Lenalidomide + dex 3rd line
prednisone 2nd line
2012
Bortezomib SC
2006
Thalidomide + dex 2008
1st line Bortezomib frontline
2007
Doxorubicin + bortezomib
2nd line
MM Survival Is Improving With Novel

Agents
1.0
Proportion of Pts Surviving
Median 7.3 yrs

0.9
0.8
0.7 5-Yr Survival by Age, %
0.6 2006-2010
65 Yrs > 65 Yrs
0.5
0.4 2006-2010 73 56
0.3 2001-2005 63 31
0.2 2001-2005
0.1
0
0 1 2 3 4 5 6 7 8 9 10
Follow-up From Diagnosis (Yrs)
Kumar SK, et al. ASH 2012. Abstract 3972.

Changing Treatment Paradigm: Combinations

Common Myeloma Regimens*
Combination Abbreviation(s)
Bortezomib/dexamethasone VD or Vd
Bortezomib/cyclophosphamide/dexamethasone CyBorD Rationale: combination
Transplant
Bortezomib/doxorubicin/dexamethasone therapies demonstrated

Primary Induction
Bortezomib/lenalidomide/dexamethasone VRD or VRd improved response rates,

Bortezomib/thalidomide/dexamethasone VTD or VTd
PFS, and/or OS compared
Lenalidomide/dexamethasone RD or Rd
Carfilzomib/lenalidomide/dexamethasone
with single agents
Bortezomib/dexamethasone VD or Vd
Nursing considerations
transplant
Non-
Melphalan/ prednisone/bortezomib VMP or MPB AE management

Melphalan/prednisone/lenalidomide MPR or MPL
Melphalan/prednisone/thalidomide MPT Patient adherence
Repeat primary induction (if relapse > 6 mos)
Performance status
Pomalidomide + dexamethasone (most preferred)
Bortezomib dexamethasone lenalidomide V, VD, Vd, VRD, VRd Frailty
Bortezomib/liposomal doxorubicin
Salvage Regimens
Bortezomib/thalidomide/dexamethasone VTD or VTd Renal function

Other comorbidities
Carfilzomib
Cyclophosphamide/lenalidomide/dexamethasone Patient preference
Dexamethasone/cyclophosphamide/etoposide/cisplatin DCEP
Dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophos DT-PACE See
phamide/etoposide bortezomib VTD-PACE
clinicaloptions.com/OncTools
High-dose cyclophosphamide
Thalidomide/dexamethasone TD or Td
for treatment tool
*Preferred regimens according to NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2013.
Common Dosing Regimens for Novel

Therapies
Agent/Class Dosing and Route of Administration
Bortezomib[1]/ 1.3 mg/m2 IV or SC on Days 1, 4, 8, 11, every 21 days x 2 cycles,
proteasome inhibitor then weekly dosing 3 wks on/1 wk off
Variable dosing in combination regimens
Dose modification for neuropathy, cytopenias
Carfilzomib[2]/ 20 mg/m2 IV (cycle 1), 27 mg/m2 (cycles 2-12) on Days 1, 2, 8, 9, 15,
proteasome inhibitor 16, every 28 days
Dose modifications for cytopenias, cardiopulmonary symptoms
Lenalidomide[3]/ 25 mg/day by mouth for induction
immunomodulatory agent Variable dosing in combination regimens
Dose modification based on renal function, cytopenias
Pomalidomide[4]/ 4 mg/day on Days 1-21 using a 28 day cycle
immunomodulatory agent Dose modifications for cytopenias
Thalidomide[5]/ 200 mg/day by mouth at bedtime
immunomodulatory agent Variable dosing in combination regimens
Dose modification for neuropathy, cytopenias
1. Bortezomib [package insert]. 2. Carfilzomib [package insert]. 3. Lenalidomide [package insert].

4. Pomalidomide [package insert]. 5. Thalidomide [package insert].
Risk-Stratification Based on Tumor

Biology
High Risk* Intermediate Risk Standard Risk
17p deletion t(4;14) (FGFR3/MMSET) All others including
t(14;16) (C-MAF) Hyperdiploidy
t(14;20) (MAF-B) t(11;14) (CCND1)
High-risk GEP t(6;14) (CCND3)
signature
*Presence of trisomies ameliorates high risk.
Complete Response Bortezomib Excellent

appears critical critical outcome with
novel agents
Rajkumar SV. Am J Hematol. 2012;87:78-88. Moreaux J, et al. Hematologica. 2011;96:574-582.

Common Disease-Related and Treatment-

Emergent Adverse Events
Myelosuppression*; all agents
Anemia, neutropenia, thrombocytopenia
Renal toxicities*
Hepatic toxicities
Neurotoxicity*
Nausea and vomiting
Constipation or diarrhea
Pain
Infection
Drug-specific treatment-emergent adverse events
*May also be disease related.
Kurtin SE, et al. J Adv Pract Oncol. 2013. In press.

PIs: Common Adverse Events in MM Trials

Adverse Events > 5% to 10%,
Bortezomib Carfilzomib Relapsed/Refractory
All Grades (Grade 3/4), %
Thrombocytopenia and Thrombocytopenia (cyclic): 36 (29) Thrombocytopenia: (cyclic): 36.3 (23.4)
neutropenia Neutropenia: 17; (12) Neutropenia: 20.7 (10.3)
Twice weekly IV: 53 (16)
Peripheral neuropathy Weekly IV: 41 (16) Overall: 14 (1% grade 3, no grade 4)
Weekly SC: 24 (6)
Fatigue Overall: 64 (16) Overall: 55.5 (7.6)
Diarrhea: Constipation: 20.9 (0.2)
Gastrointestinal Overall: 52 (8) Diarrhea: 32.7 (1.0)
Nausea: 57 (8) Nausea: 44.9 (1.3 )
Dyspnea: 11, (3)
Dyspnea: 34.6 (5.1)
Hypotension: 13
Cardiopulmonary Hypertension: 14.3 (3.3)
Congestive heart failure: 5
Peripheral edema: 24.0 (0.6)
Peripheral edema: 11
Varicella zoster: 2
Infectious complications Varicella zoster: 13-20
Pneumonia: 12.7 (10.5)
Renal dose adjustment recommended for
Renal dose modification No renal dose adjustment required
creatinine 2 x baseline
Thromboembolic events Not reported* Not reported*
Rash Not reported* Not reported*
*Data not available or incidence was below threshold for reporting.
Bortezomib [package insert]. Carfilzomib [package insert]. Palumbo A, et al. N Engl J Med. 2011;364:1046-
1060. Kurtin SE, et al. J Adv Pract Oncol. 2013. In press.
IMiDs: Common Adverse Events in MM Trials

Adverse Events > 5% to Lenalidomide (With Thalidomide (With Pomalidomide 4 mg* (With
10%, All Grades (Grade Dexamethasone) Dexamethasone) Dexamethasone)
3/4), % Relapsed/Refractory
Thrombocytopenia and Thrombocytopenia: 21 (12) Thrombocytopenia: 23 Thrombocytopenia: 23 (19 )
neutropenia Neutropenia: 42 (33) Neutropenia: 31 Neutropenia: 47 (38)
Not significant All grades: 54 (3-5) Overall: 7 (0)
Peripheral neuropathy with higher doses and
prolonged therapy
Fatigue Overall: 43 (6) Overall: 81 (17) Overall: 63 (13)
Constipation: 40 (3) Constipation: 56 (8) Diarrhea: 33 (0)
Gastrointestinal Diarrhea: 38.5 (2) Nausea: 29 (5) Anorexia: 35 (0)
Nausea: 26 (1) Nausea: 22 (0)
Dyspnea: 23 (not reported) Dyspnea: 41 (13) Dyspnea: 45 (13)
Cardiopulmonary Hypotension: 7 (not Peripheral edema: 57 (6) Peripheral edema: 16 (0)
reported) Bradycardia reported
Infectious complications Pneumonia: 14 Pneumonia: 35 Pneumonia: 29 (23)
Requires renal dose No dose modification Dose modification should be
adjustment required considered if creatinine > 3.0;
Renal dose modification
clinical trial in renal impairment
under way
Thromboembolic events Overall: 9.3 Overall: 23 Not reported*
Rash Overall: 21 Overall: 30 Overall: 16
*Data not available or incidence was below threshold for reporting.
Lenalidomide [package insert]. Thalidomide [package insert]. Pomalidomide [package insert]. Palumbo A, et al. N Engl J Med.
2011;364:1046-1060. Kurtin SE, et al. J Adv Pract Oncol. 2013. In press.
How to Select Therapy for the Older

Adult?
Goals of therapy
Early and sustained CR with an acceptable level of toxicity
and improved QoL
Risk stratification including transplantation eligibility and
individual patient factors
Disease-Related Factors Patient-Related Factors
High tumor burden Fit vs frail/vulnerability
Renal failure Comorbidities: controlled vs uncontrolled
Hypercalcemia Clotting or bleeding history
Fractures Preexisting neuropathy
Patient wishes
Availability of a caregiver
Niesvizky R, et al. Oncology. 2010;24:14-21. NCCN. Clinical practice guidelines in oncology: multiple
myeloma. v.2.2013. Stadtmauer EA. Oncology. 2010;24:7-13.
Functional Status, Comorbidities, Frailty,

and Vulnerability
Functional status: measured by ECOG and Karnofsky PS
ADLs: ability to bathe, dress, toilet and maintain continence,
transfer, and eat independently
IADLs: finances, shopping, housekeeping, transportation,
and self-medication
Comorbidities
Cardiovascular, renal, hepatic, pulmonary, endocrine,
rheumatologic disease, and other cancers
Number, severity, controlled or uncontrolled
Palumbo A, et al. Blood. 2011;118:4519-4529. Kumar S, et al. CA Cancer J Clin. 2010;60:120-132.

Balducci L, et al. Oncologist. 2000;5:224-237.
Functional Status, Comorbidities, Frailty,

and Vulnerability
Frailty
Weight loss, weakness, poor nutritional intake, cognitive
impairment, and poor endurance
Cardiovascular Health Study (n = 5317): frailty associated
with hospitalization, falls, declining ADLs including
diminished mobility, and death (P < .0001)
Vulnerability
A complex of comorbidity (presence of chronic diseases or
conditions), disability (physical or mental impairment), and
frailty (fatigue, low activity) that could prevent adequate
therapy
Palumbo A, et al. Blood. 2011;118:4519-4529. Kumar S, et al. CA Cancer J Clin. 2010;60:120-132. Balducci
L, et al. Oncologist. 2000;5:224-237.
Dose Adjustments for Age/Frailty

Drug No Risk Factors* At Least 1 Risk Factor* At Least 1 Risk Factor*
+ Grade 3-4
Nonhematological AE
1.3 mg/m2 biweekly 1.3 mg/m2/wk 1.0 mg/m2/wk
Bortezomib
Days 1, 4, 8,11 q3w Days 1, 8, 15, 22 q5w Days 1, 8, 15, 22 q5w
25 mg/day
15 mg/day 10 mg/day
Lenalidomide Days 1-21 of 28-day
Days 1-21 of 28-day cycle Days 1-21 of 28-day cycle
cycle
40 mg/day 20 mg/day 10 mg/day
Dexamethasone
Days 1, 8, 15, 22 q4w Days 1, 8, 15, 22 q4w Days 1, 8, 15, 22 q4w
0.25 mg/kg or 9 mg/m2 0.18 mg/kg or 7.5 mg/m2 0.13 mg/kg or 5 mg/m2
Melphalan
Days 1-4 q4-6w Days 1-4 q4-6w Days 1-4 q4-6w
Thalidomide 100 mg/day 50 mg/day 50 mg QOD
*Dosing based on risk factors including age, comorbidities, controlled vs uncontrolled. Patients grouped
from very fit to severely frail, depending on need for help and level of activity.
Palumbo A, et al. Blood. 2011;118:4519-4529.

Recommendations for Adjunctive

Treatment
Bone disease* Hypercalcemia
Bisphosphonates Hydration, steroids, furosemide
Monitor for osteonecrosis Zoledronic acid preferred
Renal dosing required bisphosphonate
Treat for 2 yrs Anemia
Radiation therapy Consider erythropoietin
Orthopedic consultation Caution in patients at high risk
for thrombosis
Vertebroplasty or kyphoplasty
Transfusion
Hyperviscosity
Coagulation/thrombosis
Plasmapheresis
Prophylactic anticoagulation if
treated with IMiDs
*Included in the International Myeloma Foundation Nursing Leadership Board Survivorship Plan for MM
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2013. Miceli TS, et al. Clin J Oncol
Nurs. 2011;15:9-23. Faiman BM, et al. Clin J Oncol Nurs. 2011;15:66-76.
Recommendations for Adjunctive

Treatment
Infection Renal dysfunction*
IVIG for recurrent infections Dose modifications for selected
regimens
Pneumococcus and influenza
vaccines Avoid aggravating factors:
contrast, NSAIDs, dehydration
PCP, herpes, and antifungal
prophylaxis for high-dose or Not a contraindication to HSCT
long-term steroids
Monitor bisphosphonates
Herpes zoster prophylaxis for
bortezomib-treated patients Neuropathy
No live zoster vaccine Requires dose adjustment for
selected agents
Bortezomib SC vs IV
Baseline, ongoing monitoring
*Included in the International Myeloma Foundation Nursing Leadership Board Survivorship Plan for MM
NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.2.2013. Miceli TS, et al. Clin J Oncol
Nurs. 2011;15:9-23. Faiman BM, et al. Clin J Oncol Nurs. 2011;15:66-76.
Bortezomib: SC vs IV Administration
Subcutaneous (SC) Intravenous (IV)
FDA approved SC in 2012 FDA approved IV in 2003
Equivalent efficacy as IV (numerous Highly effective myeloma therapy
studies)
Neuropathy a notable AE
Reduced neuropathy, GI AEs
67.8% of patients prefer SC over IV
54 min less chair time on average
46 min less clinic time on average
For SC administration, Reconstituting For IV administration,

add 1.4 mL bortezomib add 35 mL
0.9% sodium chloride (3.5 mg vial) 0.9% sodium chloride
Hydration: a key nursing consideration, especially

in patients with renal compromise
Shah GL, et al. ASH 2012. Abstract 2968. Barbee MS, et al. ASCO 2012. Abstract E18553. Moreau P, et al.
ASH 2011. Abstract 1863. Moreau P, et al. Lancet Oncol. 2011;12:431-440. Bortezomib [package insert].
Phase III Study: Subcutaneous vs

Intravenous Bortezomib
Route and ORR, % CR, % Median Median PN PN
Administration Time to TTP, Mos All Grade
Response, Grades, 3/4, %
Mos %
IV (n = 73) 42 8 1.4 9.4 53 16
SC (n = 145) 42 6 1.4 10.4 38 6
P value .387 .044 .026
SC administration of bortezomib noninferior to IV

(P = .002)
Improved safety profile with bortezomib SC vs IV
Moreau P, et al. Lancet Oncol. 2011;12:431-440. Bortezomib [package insert].

SC Bortezomib: Site Selection
SC Injection-Site Selection
Front Back
Adequate adipose tissue: pinch an inch
using index finger and thumb
Rotate sites, minimum of 1 cm apart
Avoid: 2-cm region surrounding the

umbilicus, areas prone to friction (eg,
belt-line, seatbelt region, etc), injecting
into areas with scarring, birthmarks,
Sites for SC bortezomib inflammation, hair follicles, or impaired
Not studied for SC bortezomib skin integrity
SC Thickness in Adults, mm
Male Female ~ 6% patients had injection
Upper arm* 9 15 site reactions (itching, swelling,
Abdomen 14 (2-30) 23 (6-58)
pain, and/or redness); median 6
Thigh 7 (2-22) 14 (5-34)
days to resolve
*Not included in pharmacokinetic studies for SC bortezomib.
Kurtin S, et al. J Adv Pract Oncol. 2012;3:406-410. Bortezomib [package insert].
SC Bortezomib: Air Sandwich Technique

Air Sandwich Technique
Attach fresh needle (4-6 mm) to syringe with
prepared medication
Do not purge needle (air in needle)
Maximum volume for SC injection is 2 mL
per site
Pull 0.5-1.0 mL air into syringe
Use index finger and thumb to pinch an
inchavoid pinching the underlying muscle
Invert syringe and inject, including air behind
the drug
90 angle for 4- to 6-mm needles
45 angle for 8-mm needle Use air sandwich technique
Remove needle promptly to avoid seeding of irritating
Apply gentle pressure to site medication in the injection track
Kurtin S, et al. J Adv Pract Oncol. 2012;3:406-410.

Thromboembolic Events
Cancer patients are at increased risk of TEE (4- to 5-fold)
Risk of mortality from a TEE is 2-fold higher in cancer
patients
Individuals with advanced disease are at higher risk of
TEE
Myeloma patients at highest risk at time of initial diagnosis
Kristinsson SY. Hematology Am Soc Hematol Educ Program. 2010;2010:437-444.

Boyle EM. Expert Rev Hematol. 2012;5:617-626.
Thromboprophylaxis: Thalidomide,
Lenalidomide, and Pomalidomide
Individual Risk Factors Actions
Obesity LMWH (enoxaparin 40 mg/day or equivalent)
Previous VTE Warfarin (target INR: 2-3)
Central venous catheter, pacemaker
Associated diseases In general:
Cardiac
Chronic renal disease Low risk (1 risk factor): patient should receive
Diabetes ASA 81-325 mg/day
Acute infection High risk: patient should receive therapeutic
Immobilization prophylactic anticoagulation with LMWH,
Blood clotting disorders warfarin
Surgery, anesthesia, or trauma
Medications MYELOMA IS A RISK FACTOR
ESAs
Myeloma-Related Risk Factors
Diagnosis LMWH (enoxaparin 40 mg/day or equivalent)
Hyperviscosity Warfarin (target INR: 2-3)
Myeloma therapy
High-dose dexamethasone
Doxorubicin
Multiagent chemotherapy
Trujillo Santos AJ. Med Clin. 2012;139:31-35. Boyle EM, et al. Expert Rev Hematol. 2012;5:617-626.
Larocca A, et al. Blood. 2012;119:933-999.
Nursing Considerations for
the Patient With Relapsed or
Relapsed/Refractory MM
MM as a Chronic Disease
MM patients are living longer
Patients will be exposed to multiple therapies over the
course of their disease
AHSCT remains an important treatment option but is not
curative in the majority of patients
Relapse or progression is inevitable for most patients
Patients who fail first-line novel agents have a poor
prognosis (~ 9 mos from time of relapse)
Response to salvage therapy for relapsed and refractory
MM may be as short as 6 mos
Kumar SK, et al. Leukemia. 2012.26:149-157. Richardson PG, et al. Oncology. 2010;24:22-29.
Natural History of Multiple Myeloma

Asymptomatic Symptomatic
100
Active 2. Relapse
M Protein (g/L)
myeloma
Refractory
50 1. Relapse relapse
MGUS or
smoldering
myeloma Plateau
20 remission
First-line therapy Second-line Third-line

therapy therapy
Kuehl WM, et al. Nat Rev Cancer. 2002;2:175-187. Vacca A, et al. Leukemia. 2006;20:193-199. Siegel DS, et al. Community Oncol.
2009;6:12:22-29. Durie BG, et al. Hematol J. 2003;4:379-398. Adapted with permission from Durie B at www.myeloma.org.
Clonal Evolution and Clonal Competition

31% Multiple clones may be present at
64% 21%
9% the time of diagnosis
64%
Remission
~ 2N
Relapse 1
The predominant clone may
~ 2N change over time, especially after
treatment rounds
Clone 1.1 Hypothesis: effective treatment
Clone 1.2 Relapse 2
10%
11% Diagnosis
~ 2N
19%
58%
reduces or eliminates the dominant
~ 2N Clone 2.1
72%
Clone 2.2
clone; however, other clones can
Misc still exist
Relapse 3
17%
~ 2N
clg-high
Relapse can occur when:
71%
66% clg-high
37%
Existing clone no longer has to
95% 78%
compete for space with the
Plasma cell leukemia ~ 3N Relapse 4 formerly dominant clone
clg-low ~ 3N
34% clg-low Acquires additional mutation(s)
96%
96%
63% providing a growth and/or survival
advantage
Keats JJ, et al. Blood. 2012;120:1067-1076.
Relapsed and Relapsed/Refractory MM

Relapse: development of clinically measurable disease or
secondary organ effects after achieving a CR
Progression: development of clinically measurable signs of
increased disease activity after achieving a PR or disease
plateau
Progression of disease is implied in the term relapsed
Relapsed and refractory: defined as a lack of response or

disease progression on or within 60 days of the last therapy
The therapy in use at the time of progression is what the patient is
refractory to based on the dominant clone
Primary refractory: failure to achieve any response to specific

MM treatments, often 2 or 3 novel agent combination regimens
Salvage Therapy
MM Salvage Therapy: Clinical Guidelines

Proteosome InhibitorContaining Regimens
Bortezomib Bortezomib (category 1)
Bortezomib/liposomal doxorubicin (category 1)
Lenalidomide/bortezomib/dexamethasone
Bortezomib/dexamethasone
Cyclophosphamide/bortezomib/dexamethasone
Dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide/
bortezomib
Carfilzomib Single-agent carfilzomib*
IMiD-Containing Regimens
Lenalidomide Lenalidomide/bortezomib/dexamethasone
Lenalidomide/dexamethasone (category 1)
Pomalidomide Pomalidomide*/dexamethasone
Thalidomide Thalidomide/dexamethasone
Other Dexamethasone/cyclophosphamide/etoposide/cisplatin
regimens Dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide
*Indicated for patients with MM who have received 2 previous therapies (including bortezomib and an IMiD)
and have progressed on/within 60 days of completing last therapy.
Kurtin SE, et al. J Adv Pract Oncol. 2013. In press. NCCN. Clinical practice guidelines in oncology:
multiple myeloma. v.2.2013.
Considerations in Selecting Salvage

Therapy
Time from previous therapy to > 6 mos may use similar agents
relapse or progression < 6 mos: consider alternative agents in combination
Refractory disease Clinical trial enrollment
Newly FDA-approved agents pomalidomide or carfilzomib
Reassess transplantation Previous ASCT: second ASCT if TTP > 2 yrs
options, including alloSCT on Agents based on
clinical trial Time from previous therapy to relapse/progression
Any residual clinical conditions (neuropathy, renal function, etc)
Previous thalidomide Bortezomib or bortezomib/PLD
Len/dex
High-dose dexamethasone/carfilzomib/pomalidomide
Previous bortezomib Thalidomide
Lenalidomide
Bortezomib/carfilzomib/pomalidomide
Previous lenalidomide Bortezomib
Bortezomib/PLD
Carfilzomib/pomalidomide
Richardson PG, et al. Oncology. 2010;24:22-29. NCCN. Clinical practice guidelines in oncology:
multiple myeloma. v.2.2013.
Treatment Paradigm Shift:

Maintenance vs Continuous Therapy
IMWG Consensus on Maintenance Therapy
Drug Common Dose Duration Tolerance Comments
or Regimen
Lenalidomide 10* (5-15) Until PD or Few Unprecedented extension of
mg/day intolerance discontinuations PFS, increased OS in 1 of 3
continuously or due to AEs studies; generally well
on Days 1-21, tolerated, but risk of second
every 28 days malignancies increased
Bortezomib 1.3 mg 2 yrs or until Grade 3/4 PNP: Only comparison between
biweekly PD or 16% (IV PADASCT bortezomib and
intolerance administration) VADASCT thalidomide
available
Thalidomide 50* (100) Up to 1 year; PNP, fatigue, and Poor tolerance in some patients
mg/day no correlation other limiting dose (notably in elderly); no benefit
between and duration of in patients with FISH-defined
duration and therapy high-risk profile
outcome
*Recommended
Adapted from Ludwig H, et al. Blood. 2012; 119:3003-3015.
Natural History of Multiple Myeloma

Asymptomatic Symptomatic
100
Active 2. Relapse
M Protein (g/L)
myeloma
Refractory
50 1. Relapse relapse
MGUS or
smoldering
myeloma Plateau
20 remission
First-line therapy Second-line Third-line

therapy therapy
Kuehl WM, et al. Nat Rev Cancer. 2002;2:175-187. Vacca A, et al. Leukemia. 2006;20:193-199. Siegel DS, et al. Community Oncol.
2009;6:12:22-29. Durie BG, et al. Hematol J. 2003;4:379-398. Adapted with permission from Durie B at www.myeloma.org.
Relapsed and Refractory MM: General

Principles
Treatment of patients with relapsed and refractory MM is
complicated by the heterogeneity of the disease as well as
adverse events of MM treatments
As proteasome inhibitors and IMiDs are now used more
frequently in the upfront setting, novel salvage therapies
are needed that are efficacious and well tolerated
2 novel agents have recently been approved
Pomalidomide
Carfilzomib
Newly Approved Agents: Pomalidomide

FDA approved: February 8, 2013 Pomalidomide Common AEs (in > 30%) Patients, %
Class: IMiD Fatigue and asthenia 55
Administration: oral Neutropenia 52
Constipation 36
REMS program Nausea 36
Discuss administration with Diarrhea 34

patient : 4 mg once daily on Dyspnea 34
Days 1-21 of 28-day cycle Upper resp. tract infection 32
Back pain 32
Take without food Pyrexia (pom + dex) 30
At least 2 hrs before/after
meals
Educate patients on
Do not break, chew, or open
the capsules DVT prophylaxis
Infection risk/blood counts
Adherence: consistent
Fatigue
schedule (AM or PM)
Should not cause PN
Pomalidomide [package insert]. FDA.gov. 2013.
Newly Approved Agents: Carfilzomib

FDA approved: July 20, 2012 Carfilzomib AEs (All Grades)
Class: proteasome inhibitor Patients, %
> 30%
Administration Fatigue 56
Premedicate: 4-mg dexamethasone Anemia 47
before carfilzomib Nausea 45
All doses cycle 1; 1st dose cycle 2 Thrombocytopenia 36
Additional doses/cycles if infusion Dyspnea 35
reactions
Diarrhea 33
Hydrate: 250-500 mL IV saline Pyrexia 30
Before carfilzomib; after (optional)
Monitor for over hydration Monitor AEs, which may include
Administer carfilzomib IV cardiopulmonary
20 mg/m2 over 2-10 mins The drug may require dose
Rinse IV with saline before and after adjustment for toxicities, diuretics,
inhalers, minimal PN
Carfilzomib [package insert]. FDA.gov. 2012.
Selected Problems Faced by Patients With

MM and Their Caregivers
Information
Provide detailed information about AEs of medication
Adherence
Provide calendar with treatment regimen and dates of
administration to improve adherence
Inform patient and caregiver of symptoms
DVT/PE, peripheral neuropathy, infection, bleeding, and
neutropenia
Reinforce precautions
Wulff-Burchfield, et al. Bone Marrow Transplant. 2013;48:469-473. Fife BL, et al. Bone Marrow Transplant.
2009;43:959-966. Stenberg U, et al. Psychooncology. 2010;19:1013-1025.
Communication With Team Members

Communication with nursing staff
Improves quality of life
Reduces distress
Encourages active participation
Financial and social support

Treatment should NOT be compromised if patients lack financial or
social support
Multidisciplinary cancer treatment team (social worker, dietary, etc)
Emphasize the importance of local and national support groups
(transportation assistance, reimbursement)
Bensing J, et al. Patient Educ Couns. 2013;90:287-290. Thorne S, et al. Patient Educ Couns. 2013;90:291-
296. McMullen L. Semin Oncol Nurs. 2013;29:105-117.
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About These Slides

Overproduction of Abnormal Plasma Cells

MGUS Smoldering Myeloma Multiple Myeloma

International Staging System

Treatment of Multiple Myeloma

Individualized Treatment Selection for Induction Therapy

Treatment Options Have Greatly Increased

1950 1960 1970 1980 1990 2000 2010

1958 1983 2003

MM Survival Is Improving With Novel

Median 7.3 yrs

Kumar SK, et al. ASH 2012. Abstract 3972.

Changing Treatment Paradigm: Combinations

Bortezomib/doxorubicin/dexamethasone therapies demonstrated

Bortezomib/lenalidomide/dexamethasone VRD or VRd improved response rates,

Melphalan/ prednisone/bortezomib VMP or MPB AE management

Bortezomib/thalidomide/dexamethasone VTD or VTd Renal function

Common Dosing Regimens for Novel

1. Bortezomib [package insert]. 2. Carfilzomib [package insert]. 3. Lenalidomide [package insert].

Risk-Stratification Based on Tumor

Complete Response Bortezomib Excellent

Rajkumar SV. Am J Hematol. 2012;87:78-88. Moreaux J, et al. Hematologica. 2011;96:574-582.

Common Disease-Related and Treatment-

Kurtin SE, et al. J Adv Pract Oncol. 2013. In press.

PIs: Common Adverse Events in MM Trials

IMiDs: Common Adverse Events in MM Trials

How to Select Therapy for the Older

Functional Status, Comorbidities, Frailty,

Palumbo A, et al. Blood. 2011;118:4519-4529. Kumar S, et al. CA Cancer J Clin. 2010;60:120-132.

Functional Status, Comorbidities, Frailty,

Dose Adjustments for Age/Frailty

Palumbo A, et al. Blood. 2011;118:4519-4529.

Recommendations for Adjunctive

Recommendations for Adjunctive

For SC administration, Reconstituting For IV administration,

Hydration: a key nursing consideration, especially

Phase III Study: Subcutaneous vs

SC administration of bortezomib noninferior to IV

Moreau P, et al. Lancet Oncol. 2011;12:431-440. Bortezomib [package insert].

SC Bortezomib: Site Selection

Rotate sites, minimum of 1 cm apart

Avoid: 2-cm region surrounding the

SC Bortezomib: Air Sandwich Technique

Kurtin S, et al. J Adv Pract Oncol. 2012;3:406-410.

Kristinsson SY. Hematology Am Soc Hematol Educ Program. 2010;2010:437-444.

Natural History of Multiple Myeloma

First-line therapy Second-line Third-line

Clonal Evolution and Clonal Competition

Relapsed and Relapsed/Refractory MM

Relapsed and refractory: defined as a lack of response or

Primary refractory: failure to achieve any response to specific

MM Salvage Therapy: Clinical Guidelines

Considerations in Selecting Salvage

Treatment Paradigm Shift:

Natural History of Multiple Myeloma

First-line therapy Second-line Third-line

Relapsed and Refractory MM: General

Newly Approved Agents: Pomalidomide

Discuss administration with Diarrhea 34

Newly Approved Agents: Carfilzomib

Selected Problems Faced by Patients With

Communication With Team Members