Download Mul Ma ltiple M anagin Myelo g Rela oma: C apse an Current nd Ref

 Mulltiple M
Myelo
oma: C
Currentt Apprroachees to Maanaging Relaapse an
nd Reffractory Diseease
Pressented ass a Live W
Webinar Tuesday, A
August 20
0, 2013 and W
Wednesd
day, Septeember 18
8, 2013 Planned
d and conducte
ed by ASHP Advvantage and su
upported by ed
ducational grants from
Millennium
m: The Takeda O
Oncology Company and Onyxx Pharmaceuticals, Inc. Multiple Myeloma: Current Approaches to
Managing Relapse and Refractory Disease
WEBINAR INFORMATION
How do I register?
Go to www.ashpadvantage.com/myeloma/relapse and click on the Register Now button. After you submit your
information, you will be e-mailed computer and audio information.
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program. You listen to the speaker presentation in “real time” as you watch the slides on the screen. You will
have the opportunity to ask the speaker questions at the end of the program. Please join the conference at least
5 minutes before the scheduled start time for important announcements.
How do I process my Continuing Education (CE) credit?
Continuing pharmacy education for this activity will be processed on ASHP’s eLearning system and reported
directly to CPE Monitor. After completion of the live webinar, you can process your CPE credit and print your
statement of credit online at http://elearning.ashp.org/my-activities. To process your CPE credit, you will need
the enrollment code that will be announced at the end of the webinar. Full CE processing instructions can be
found on the last page of this handout as well as at http://www.ashp.org/claimce.
What if I would like to arrange for my colleagues to participate in this webinar as a group?
One person serving as the group coordinator should register for the webinar. That group coordinator will receive
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individual continuing education statement online.
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1. Computer with internet access and basic system requirements. When you register, the webinar system will
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[VoIP] via your computer).
Webinar System Requirements
Be sure to view the webinar system requirements for Windows, Mac, iOS, and Android prior to the activity.
1
Multiple Myeloma: Current Approaches to
Managing Relapse and Refractory Disease
ACTIVITY FACULTY
Christopher A. Fausel, Pharm.D., M.H.A., BCOP
Clinical Manager of Oncology Pharmacy
Indiana University Simon Cancer Center
Indiana University Health
Indianapolis, Indiana
Christopher A. Fausel, Pharm.D., M.H.A, BCOP, is Clinical Manager of Oncology Pharmacy at Indiana University
Simon Cancer Center (IUSCC) in Indianapolis, Indiana. He oversees the clinical and dispensing pharmacy services
at the IUSCC ambulatory infusion center and six satellite infusion clinics. Dr. Fausel holds academic
appointments at the Department of Medicine at Indiana University School of Medicine, Purdue University
School of Pharmacy and Pharmaceutical Sciences, and Butler University College of Pharmacy. He is the founding
Residency Program Director for the postgraduate year two (PGY-2) oncology pharmacy residency at Indiana
University Health. He serves on the Indiana University Purdue University at Indianapolis Institutional Review
Board and Indiana University Simon Cancer Center Scientific Review Committee.
Dr. Fausel received his Bachelor of Science degree in pharmacy and Doctor of Pharmacy degree from Albany
College of Pharmacy in Albany, New York. He completed a pharmacy practice residency accredited by the
American Society of Health-System Pharmacists (ASHP) at the Samuel S. Stratton VA Medical Center in Albany,
New York. More recently, he earned a Master of Health Administration degree from Simmons College in Boston,
Massachusetts.
Dr. Fausel is a board-certified oncology pharmacist (BCOP), and he is certified in basic life support by the
American Red Cross. He is a member of the Hoosier Oncology Group Board of Directors and a long-standing
member of ASHP, American Society of Clinical Oncology, and Hematology/Oncology Pharmacy Association.
2
Multiple Myeloma: Current Approaches to
Managing Relapse and Refractory Disease
DISCLOSURE STATEMENT
In accordance with the Accreditation Council for Continuing Medical Education’s Standards for Commercial
Support and the Accreditation Council for Pharmacy Education’s Guidelines for Standards for Commercial
Support, ASHP Advantage requires that all individuals involved in the development of activity content disclose
their relevant financial relationships. A person has a relevant financial relationship if the individual or his or her
spouse/partner has a financial relationship (e.g., employee, consultant, research grant recipient, speakers
bureau, or stockholder) in any amount occurring in the last 12 months with a commercial interest whose
products or services may be discussed in the educational activity content over which the individual has control.
The existence of these relationships is provided for the information of participants and should not be assumed
to have an adverse impact on presentations.
All faculty and planners for ASHP Advantage education activities are qualified and selected by ASHP Advantage
and required to disclose any relevant financial relationships with commercial interests. ASHP Advantage
identifies and resolves conflicts of interest prior to an individual’s participation in development of content for an
educational activity.
The following faculty and planners report no relationships pertinent to this activity:
-
Christopher A. Fausel, Pharm.D., M.H.A., BCOP
Tippu Khan, Pharm.D., BCOP, CPP
Gerald M. Higa, Pharm.D.
James Aubrey Waddell, Pharm.D., BCOP, FAPhA
Jill A. Sellers, Pharm.D.
Carla J. Brink, M.S., B.S.Pharm.
ASHP staff has no relevant financial relationships to disclose.
3
Multiple Myeloma: Current Approaches to
Managing Relapse and Refractory Disease
ACTIVITY OVERVIEW
Among the many challenges of managing patients with multiple myeloma is the fact that most patients
eventually develop resistance to therapy. Several new treatment options have emerged over the past few years
for managing relapse and refractory disease. This educational activity will review current options to address this
challenge.
Time for questions and answers from the webinar audience will be provided at the end of the presentation.
LEARNING OBJECTIVES
At the conclusion of this application-based educational activity, participants should be able to
• Review current and emerging treatment strategies for the management of patients with relapsed and
refractory multiple myeloma.
• Apply evidence-based approaches to managing the challenges in treating relapsed and refractory
multiple myeloma.
• Describe appropriate supportive care measures for patients receiving active treatment for multiple
myeloma.
LIST
OF
ABBREVIATIONS
For a list of abbreviations used in this activity, please see page 18.
CONTINUING EDUCATION ACCREDITATION
The American Society of Health-System Pharmacists is accredited by the Accreditation Council for
Pharmacy Education as a provider of continuing pharmacy education. This activity provides 1 hour
(0.1 CEU) of continuing pharmacy education credit (ACPE activity # 0204-0000-13-460-L01-P).
Attendees must complete a Continuing Pharmacy Education Request online and may print their
official ASHP statements of continuing pharmacy education credit at the ASHP eLearning site
(elearning.ashp.org) immediately following this activity.
Complete instructions for processing CE can be found on the last page of this handout.
4
Which of these represents true
progressive disease in multiple
myeloma (MM)?
Multiple Myeloma:
Current Approaches to
Managing Relapse and
Refractory Disease
A. Less than 50% reduction in serum
M-component
B. Less than 25% reduction in serum
M-component
C. Incomplete resolution of plasmacytoma
D. New-onset hypercalcemia that may be
secondary to MM
Christopher A. Fausel, Pharm.D., M.H.A., BCOP
Indiana University Health
Indianapolis, Indiana
Enlarged version on page 13
Enlarged version on page 13
Salvage Therapy Options
Definition of Progression
Progression
Increase in 25% or more from lowest response value in any one or more of the
following:
Serum M-component (absolute increase must be ≥ 0.5 g/dL)
Urine M-component (absolute increase must be ≥ 200 mg per 24 hours)
Only in patients without measureable serum and urine M-protein levels: the
difference between involved and uninvolved free light chains levels (absolute
increase must be > 10 mg/L)
Bone marrow plasma cell percentage (absolute percentage must be ≥ 10%)
Definite development of new bone lesions or soft tissue plasmacytomas or
definite increase in the size of existing bone lesions or soft tissue
plasmacytomas
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) that
can be attributed solely to the plasma cell proliferative disorder
Preferred regimens
Other regimens
Repeat primary induction (if relapse at > 6 months)
Bortezomib
Bortezomib, dexamethasone
Bortezomib, lenalidomide, dexamethasone
Bortezomib, liposomal doxorubicin
Bortezomib, thalidomide, dexamethasone
Carfilzomib
Cyclophosphamide, bortezomib, dexamethasone
Dexamethasone, cyclophosphamide, etoposide,
cisplatin
Dexamethasone, thalidomide, cisplatin,
doxorubicin, cyclophosphamide, etoposide ±
bortezomib
High-dose cyclophosphamide
Lenalidomide, dexamethasone
Pomalidomide, dexamethasone
Thalidomide, dexamethasone
Bendamustine
Bortezomib, vorinostat
Lenalidomide, bendamustine,
dexamethasone
NCCN Guidelines Version 2.2013 Multiple Myeloma. www.nccn.org
Durie BGM et al. Leukemia. 2006; 20:1467-73.
Which of these is an appropriate
supportive care measure with patients
receiving treatment with bortezomib?
?
Bortezomib vs. Dexamethasone:
Phase III in Refractory Disease
?
A. Pre-emptive therapy with gabapentin
B. Pre-emptive therapy with romiplostim
C. Pre-medication with palonosetron,
dexamethasone, aprepitant
D. Prophylaxis with acyclovir
Response
rate
Median time
to
progression
Median
overall
survival
Bortezomib
(n = 313)
43%
6 months
29.8 months
Dexamethasone
(n = 312)
19%
3.5 months
23.7 months
P value
<0.001
<0.001
0.027
Richardson PG et al. N Engl J Med. 2005; 352:2487-92.
Richardson PG et al. Blood. 2007; 110:3557-60.
5
Grade III/IV Toxicity
Toxicity
Bortezomib Retreatment
Bortezomib Dexamethasone
(n = 313)
(n = 312)
Anemia
10%
11%
Constipation
2%
1%
Diarrhea
7%
2%
Dyspepsia
6%
4%
Fatigue
6%
4%
Nausea/vomiting
5%
1%
Neutropenia
14%
1%
Peripheral
neuropathy
8%
1%
Pyrexia
2%
2%
Thrombocytopenia
30%
6%
• Phase II study of 130 patients with a
median of two lines of prior treatment
• Regimen
– Bortezomib 1 or 1.3 mg/m2 (last tolerated
dose with first treatment) IV on days 1, 4, 8,
11 in a 21-day cycle
• Primary endpoint: best confirmed
response at retreatment
Richardson PG et al. N Engl J Med. 2005; 352:2487-92.
Richardson PG et al. Blood. 2007; 110:3557-60.
Petrucci MT et al. Br J Haematol. 2013; 160:649-59.
Results
Efficacy
Prior exposure to bortezomib
N = 130 (total)
Patients receiving ≥ 4 treatment
cycles
90%
Single-agent bortezomib
37%
Bortezomib with another agent
63%
Last tolerated dose – 1.3 mg/m2
Last tolerated dose – 1 mg/m2
29%
62%
Median duration of therapy
Median time from prior bortezomib
treatment
Response parameter
N = 126
Overall response
40%
Complete response
1%
39%
4.9 months
Very good partial
response/partial response
Median response duration
6.5 months
13.9 months
Progression free survival
8.4 months
Petrucci MT et al. Br J Haematol. 2013; 160:649-59.
Petrucci MT et al. Br J Haematol. 2013; 160:649-59.
Bortezomib + Liposomal
Doxorubicin: Phase III Results
Grade III/IV Toxicity
Toxicity
N = 130
Thrombocytopenia
35%
Diarrhea
7%
Neutropenia
7%
Pneumonia
6%
Bortezomib 41
2
Progression Overall
free survival survival
at 15
(months)
months
(%)
6.5
65
5%
Bortezomib 44
+ liposomal
doxorubicin
4
9.3
Anemia
Neuropathy
0%
Any Grade III/IV
60%
Regimen
Response Complete
rate (%)
response
(%)
*p = 0.03
Orlowski RZ et al. J Clin Oncol. 2007; 25:3892-901.
Petrucci MT et al. Br J Haematol. 2013; 160:649-59.
6
76*
Cyclophosphamide, Bortezomib,
Dexamethasone
Efficacy
Parameter
• Phase II trial with 54 patients receiving
– Bortezomib 1.3 mg/m2 IV on days 1, 4, 8, 11
– Dexamethasone 20 mg PO on days 1, 2, 4, 5,
8, 9, 11, 12
– Cyclophosphamide 50 mg PO daily
– Cycle repeated every 21 days
• Primary endpoint
– Response rate
Kropff M et al. Br J Haematol. 2007; 138:330-7.
Overall response
Evaluable patients
(n = 50)
82%
Complete response
16%
Partial response
66%
Minor response
8%
Median event free
survival
Overall survival
12 months
22 months
Kropff M et al. Br J Haematol. 2007; 138:330-7.
Which of these represents the most
reasonable therapy choice for a patient
with refractory MM and cirrhosis?
Grade III/IV Toxicity
Toxicity
Grade III/IV (n = 53)
Anemia
Bleeding
9%
2%
Dyspnea
4%
Fatigue
15%
Herpes zoster
15%
Infection
23%
Leukocytopenia
20%
Neuropathy
Thrombocytopenia
21%
53%
?
A. Bortezomib and dexamethasone
B. Bortezomib, cyclophosphamide,
dexamethasone
C. Dexamethasone, cyclophosphamide,
etoposide, cisplatin
D. Lenalidomide and dexamethasone
Kropff M et al. Br J Haematol. 2007; 138:330-7.
Lenalidomide + Dexamethasone:
Phase III results (combined)
Regimen
Response Complete
rate (%)
response
(%)
Time to
progression
(months)
Overall
survival
(months)
Dexamethasone 19
(n = 352)
1-3.4
4.7
20.1
Lenalidomide + 61
dexamethasone
(n = 352)
14-16
11.2
29.6
Carfilzomib: Phase II Trial
• Phase II study evaluated 266 patients with
relapsed/refractory MM previously treated
with bortezomib
• Regimen
– Carfilzomib 20 mg/m2 IV on days 1, 2, 8, 9, 15, 16
repeated every 28 days x cycle 1
– Then carfilzomib 27 mg/m2 IV on days 1, 2, 8, 9,
15, 16 repeated every 28 days
– Plus dexamethasone 4 mg PO or IV prior to each
carfilzomib dose
• Primary endpoint
– Response rate
Dimopoulos M et al. N Engl J Med. 2007; 357:2123-32.
Weber DM et al. N Engl J Med. 2007; 357:2133-42.
Siegel DS et al. Blood. 2012; 120:2817-25.
7
Grade III/IV Toxicity
Efficacy
Parameter
N = 257
Thrombocytopenia
29%
Parameter
N = 257
Response rate
24%
Anemia
24%
Complete response
0.4%
Lymphopenia
20%
Very good partial response
5%
Neutropenia
11%
Pneumonia
9%
Time to progression
7.8 months
Overall survival
15.6 months
All patients had received prior bortezomib (except one).
Fatigue
8%
Hyponatremia
8%
Leukopenia
7%
Hypophosphatemia
6%
Upper respiratory infection
5%
Siegel DS et al. Blood. 2012; 120:2817-25.
Siegel DS et al. Blood. 2012; 120:2817-25.
Results
Pomalidomide
• Phase II study evaluated 84 patients with
relapsed/refractory myeloma previously
treated with bortezomib and lenalidomide
with two dosing regimens for pomalidomide
• Dosing
– Pomalidomide 4 mg PO daily on days 1 through
21 of a 28-day cycle or continuously for a 28-day
cycle with dexamethasone 40 mg PO once
weekly
• Primary endpoint
– Response rate
Parameter
21 of 28-day P 28 of 28-day P
dosing (n = 43) dosing (n = 41)
Response rate (%)
35
34
Complete response (%)
2
5
Very good partial
response (%)
2
2
Time to progression
(months)
5.5
4.6
Overall survival at 18
months (%)
49
39
P = Pomalidomide
Leleu X et al. Blood. 2013; 121:1968-75.
Leleu X et al. Blood. 2013; 121:1968-75.
Carfilzomib, Lenalidomide,
Dexamethasone (CLD) – Refractory MM
Grade III/IV Toxicity
Toxicity
N = 84
Neutropenia
62%
Anemia
36%
Thrombocytopenia
General disorders
27%
24%
Musculoskeletal and connective tissue
disorders
20%
Pneumonia
13%
Dyspnea
12%
Bone pain
11%
Renal failure
11%
• Phase I trial to establish maximum tolerated
dose (MTD) of CLD in a refractory cohort of
40 patients
– Prior treatments – 75% bortezomib, 70%
lenalidomide, 75% transplant
• MTD
–
–
–
–
Carfilzomib 27 mg/m2 IV days 1, 2, 8, 9, 15, 16
Lenalidomide 25 mg PO daily days 1 through 21
Dexamethasone 40 mg PO weekly
Repeat cycle every 28 days
Niesvizky R et al. Clin Cancer Res. 2013; 19:2248-56.
Leleu X et al. Blood. 2013; 121:1968-75.
8
Efficacy
Toxicity – Grade III/IV
Parameter
Outcome (n = 40)
Toxicity Event
Grade III/IV (n = 40)
Overall response rate
62.5%
Neutropenia
43%
Stringent complete response
2.5%
Thrombocytopenia
Lymphopenia
33%
28%
Hyperglycemia
23%
Very good partial response
32.5%
Partial response
27.5%
Median duration of response
11.8 months
Median progression free
survival
10.2 months
Anemia
20%
Hypophosphatemia
20%
Leukopenia
18%
Hyponatremia
15%
Hypokalemia
10%
Niesvizky R et al. Clin Cancer Res. 2013; 19:2248-56.
Niesvizky R et al. Clin Cancer Res. 2013; 19:2248-56.
Future Drug Targets in MM
Monoclonal Antibody Therapy
Cell surface
targets
Cytokines
CD40
FGFR3
CS1
BAFF-R
VEGF-R
IL-6
VEGF
IGF-1
SDF-1α
BAFF
APRIL
BSF-3
1. Induction of apoptosis
Monoclonal
antibody
Intact C1
Plasma cell
Target antigen
Fc receptor
2. Activation of
complement
Bone
marrow
stroma
NF-κB
Smad
ERK
Killer cell
Anderson KC. J Clin Oncol. 2012; 30:445-52.
3. ADCC
Investigational Agents (MoAb)
Agent
BHQ880
Dacetuzumab
Daratumumab
Elotuzumab
huN901-DM1
RAP-011
1339
Target
DKK1
CD40
CD38
CS1
CD56
Activin A
IL-6
Supportive Care
Anderson KC. J Natl Compr Canc Netw. 2013; 11(5 Suppl):676-9.
9
Adhesion
molecules
ICAM-1
VCAM-1
Fibronectin
LFA-1
MUC-1
VLA-4
Which of the following would be the
most likely cause of mortality in a
patient with MM?
Adjunctive Therapy for MM
?
• Bone disease
– All patients receiving primary MM therapy
should be given bisphosphonates
– Use of bisphosphonates in smoldering or
stage I disease should preferably be in the
context of a clinical trial
A. Lytic lesions of bone
B. Hypercalcemia of malignancy
C. Anemia
D. Infection
• Conduct bone surveys annually and if symptomatic
– Monitor for renal dysfunction with use of
bisphosphonates
– Monitor for osteonecrosis of the jaw
NCCN Guidelines Version 2.2013 Multiple Myeloma. www.nccn.org
Adjunctive Therapy for MM
Adjunctive Therapy for MM
• Radiation therapy
• Hypercalcemia
– Low-dose radiation (10-30Gy) can be used as palliative
treatment for uncontrolled pain, impending pathologic
fracture, or impending cord compression
– Limited involved fields should be used to limit the impact
of irradiation on stem-cell harvest or impact on potential
future treatments
– Hydration/furosemide, bisphosphonates,
(zoledronic acid preferred), steroids +/- calcitonin
• Hyperviscosity
– Plasmapheresis should be used for symptomatic
hyperviscosity
• Surgery
• Anemia
– Orthopedic consultation for long bone fractures, spinal
cord compression, or vertebral column instability
– Vertebroplasty or kyphoplasty for symptomatic vertebral
compression fractures
– Consider erythropoietin for anemic patients
(guideline-based prescribing)
NCCN Guidelines Version 2.2013 Multiple Myeloma. www.nccn.org
NCCN Guidelines Version 2.2013 Multiple Myeloma. www.nccn.org
Adjunctive Therapy for MM
Adjunctive Therapy for MM
• Infection
• Renal dysfunction
– Intravenous immunoglobulin consideration in
the setting of recurrent life-threatening
infections
– Consider pneumococcal and influenza
vaccines
– Pneumocystis, herpes, and antifungal
prophylaxis if high-dose dexamethasone
therapy
– Herpes zoster prophylaxis for patient treated
with bortezomib
– Maintain hydration to avoid renal failure
– Avoid use of NSAIDs
– Avoid IV contrast
– Plasmapheresis
– Not a contraindication to transplant
– Monitor for renal dysfunction with chronic use
of bisphosphonates
NCCN Guidelines Version 2.2013 Multiple Myeloma. www.nccn.org
NCCN Guidelines Version 2.2013 Multiple Myeloma. www.nccn.org
10
Adjunctive Therapy for MM
Phase III Thromboprophylaxis
• Thromboembolism
– Prophylactic anticoagulation recommended for
patients receiving thalidomide-based or
lenalidomide with dexamethasone therapy
• MM patients receiving a
thalidomide-based
regimen (n=667)
• Regimen-specific risk
• Primary endpoint: Rate
of thromboembolic/
acute cardiac events or
sudden death in first 6
months of treatment
– Thalidomide 200 mg/day with Dex 40 mg daily
days 1-4, 9-12, 17-20 (high dose Dex) – 17%
– Lenalidomide 25 mg/day days 1-21 of 28 with
high dose Dex – 26%
– Lenalidomide 25 mg/day days 1-21 of 28 with
Dex 40 mg PO weekly – 12%
Rajukumar SV et al. J Clin Oncol. 2006; 24:431-6.
Rajukumar SV et al. Lancet Oncol. 2010; 11:29-37.
NCCN Guidelines Version 2.2013 Multiple Myeloma. www.nccn.org
Aspirin 100 mg/day
Warfarin 1.25 mg/day
Enoxaparin 40 mg/day
Palumbo A et al. J Clin Oncol. 2011; 29:986-93.
Efficacy
First 6
months
Entire
follow-up
R
A
N
D
O
M
I
Z
E
Skeletal-related Events
Aspirin
(n = 220)
Warfarin
(n = 220)
Enoxaparin
(n = 219)
6.4%
8.2%
5%
8.6%
10%
7.8%
•
•
•
•
•
•
Differences were not statistically different.
Median follow up was 24.9 months
Palumbo A et al. J Clin Oncol. 2011; 29:986-93.
Which of these is most appropriate for a
patient with MM taking monthly
bisphosphonates who requires a tooth
extraction?
Hypercalcemia of malignancy
Pathologic fracture
Bone pain
Spinal cord compression
Radiation therapy to the bone
Bone surgery
Body JJ. Support Care Cancer. 2006; 14:408-18.
Osteonecrosis of the Jaw
?
• Resembles “osteoradionecrosis”
• Consistent with localized vascular
insufficiency
• Associated with use of higher-potency
bisphosphonates
A. Continue monthly bisphosphonate
uninterrupted
B. Discontinue bisphosphonate permanently
C. Switch to alternate bisphosphonate
D. Hold bisphosphonate for several months
– Especially zoledronic acid
Woo SB et al. Ann Intern Med. 2006; 144:753-61.
11
Osteonecrosis of the Jaw:
Risk Factors
Associated
comorbidities
Cancer
Corticosteroid use
Hypercoagulability
Diabetes
Osteonecrosis of the Jaw:
Treatment
• Dental care before or during
bisphosphonate therapy
• Antibiotics
• Surgical debridement
• Pain control
• Discontinuation of bisphosphonate
Common risk factors
Bisphosphonate type
Bisphosphonate total dose
Dental disease
Dunstan CR et al. Nat Clin Pract Oncol. 2007; 4:42-55.
Woo SB et al. Ann Intern Med. 2006; 144:753-61.
Migliorati CA et al. Cancer. 2005; 104:83-93.
Enlarged version on page 14
Enlarged version on page 14
Adjusting Therapy for End-organ
Dysfunction
Secondary Primary Malignancies
2nd
Study
N
% with second
malignancy
Median time to
malignancy
Retrospective single site
589
3
35 months
Randomized, phase III,
lenalidomide vs. placebo
maintenance post HSCT
614
5.5 - L
1 - placebo
44 months
Randomized, phase III,
lenalidomide vs. placebo
maintenance post HSCT
460
6.5 - L
2 - placebo
17.5 months post HSCT
Randomized, phase III,
lenalidomide vs. placebo
maintenance post MPL
459
3.9 - L
1.3 - placebo
25 months
Retrospective single site
279
3.5
354 days (Imid)
415 days (no Imid)
Hasskarl et al. Leuk Lymphoma. 2011; 52:247-59; Attal M et al. Blood. 2010; 116:310;
McCarthy PL et al. Blood. 2010; 116:37; Palumbo A et al. Blood. 2010; 116:310;
Ormerod A et al. Clin Lymphoma Myeloma Leuk. 2012; 12:113-7.
Conclusion
• Acceptable treatment options are available
for patients with refractory MM
• Factors such as response with prior
therapy and medical comorbidities should
be weighed when selecting a salvage
regimen for MM
• Patients with MM require supportive care
during active treatment that can be
managed by experienced pharmacists
12
Drug
Primary route of
metabolism
Recommendations for
dosage modification
Melphalan
Hydrolysis
Yes – reduce dose in HSCT
conditioning to 140 mg/m2
Thalidomide
Renal
None
Lenalidomide
Renal
Adjust dose with CrCl < 60
mL/min
Pomalidomide
Hepatic
None (not well studied in
hepatic and renal dysfunction)
Bortezomib
Hepatic
Yes – reduce for elevated
bilirubin
Carfilzomib
Peptidase cleavage
None
and epoxide hydrolysis
Bisphosphonates
Renal
Yes - renal
Definition of Progression
Progression
Increase in 25% or more from lowest response value in any one or more of the
following:
Serum M-component (absolute increase must be ≥ 0.5 g/dL)
Urine M-component (absolute increase must be ≥ 200 mg per 24 hours)
Only in patients without measureable serum and urine M-protein levels: the
difference between involved and uninvolved free light chains levels (absolute
increase must be > 10 mg/L)
Bone marrow plasma cell percentage (absolute percentage must be ≥ 10%)
Definite development of new bone lesions or soft tissue plasmacytomas or
definite increase in the size of existing bone lesions or soft tissue
plasmacytomas
Development of hypercalcemia (corrected serum calcium > 11.5 mg/dL) that
can be attributed solely to the plasma cell proliferative disorder
Durie BGM et al. Leukemia. 2006; 20:1467-73.
Salvage Therapy Options
Preferred regimens
Other regimens
Repeat primary induction (if relapse at > 6 months)
Bortezomib
Bortezomib, dexamethasone
Bortezomib, lenalidomide, dexamethasone
Bortezomib, liposomal doxorubicin
Bortezomib, thalidomide, dexamethasone
Carfilzomib
Cyclophosphamide, bortezomib, dexamethasone
Dexamethasone, cyclophosphamide, etoposide,
cisplatin
Dexamethasone, thalidomide, cisplatin,
doxorubicin, cyclophosphamide, etoposide ±
bortezomib
High-dose cyclophosphamide
Lenalidomide, dexamethasone
Pomalidomide, dexamethasone
Thalidomide, dexamethasone
Bendamustine
Bortezomib, vorinostat
Lenalidomide, bendamustine,
dexamethasone
NCCN Guidelines Version 2.2013 Multiple Myeloma. www.nccn.org
13
Secondary Primary Malignancies
Study
N
% with second
malignancy
Median time to 2nd
malignancy
Retrospective single site
589
3
35 months
Randomized, phase III,
lenalidomide vs. placebo
maintenance post HSCT
614
5.5 - L
1 - placebo
44 months
Randomized, phase III,
lenalidomide vs. placebo
maintenance post HSCT
460
6.5 - L
2 - placebo
17.5 months post HSCT
Randomized, phase III,
lenalidomide vs. placebo
maintenance post MPL
459
3.9 - L
1.3 - placebo
25 months
Retrospective single site
279
3.5
354 days (Imid)
415 days (no Imid)
Hasskarl et al. Leuk Lymphoma. 2011; 52:247-59; Attal M et al. Blood. 2010; 116:310;
McCarthy PL et al. Blood. 2010; 116:37; Palumbo A et al. Blood. 2010; 116:310;
Ormerod A et al. Clin Lymphoma Myeloma Leuk. 2012; 12:113-7.
Adjusting Therapy for End-organ
Dysfunction
Drug
Primary route of
metabolism
Recommendations for
dosage modification
Melphalan
Hydrolysis
Yes – reduce dose in HSCT
conditioning to 140 mg/m2
Thalidomide
Renal
None
Lenalidomide
Renal
Adjust dose with CrCl < 60
mL/min
Pomalidomide
Hepatic
None (not well studied in
hepatic and renal dysfunction)
Bortezomib
Hepatic
Yes – reduce for elevated
bilirubin
Carfilzomib
Peptidase cleavage
None
and epoxide hydrolysis
Bisphosphonates
Renal
Yes - renal
14
Multiple Myeloma: Current Approaches to
Managing Relapse and Refractory Disease
SELECTED REFERENCES
1. Anderson KC. Therapeutic advances in relapsed or refractory multiple myeloma. J Natl Compr Canc Netw.
2013; 11:676-9.
2. Anderson KC. The 39th David A. Karnofsky lecture: bench-to-bedside translation of targeted therapies in
multiple myeloma. J Clin Oncol. 2012; 30:445-52.
3. Attal M, Lauwers-Cances V, Marit G et al. Lenalidomide maintenance after stem-cell transplantation for
multiple myeloma. N Engl J Med. 2012; 366:1782-91.
4. Body JJ. Bisphosphonates for malignancy-related bone disease: current status, future developments.
Support Care Cancer. 2006; 14:408-18.
5. Dimopoulos M, Spencer A, Attal M et al. Lenalidomide plus dexamethasone for relapsed or refractory
multiple myeloma. N Engl J Med. 2007; 357:2123-32.
6. Dunstan CR, Felsenberg D, Seibel MJ. Therapy insight: the risk and benefits of bisphosphonates for the
treatment of tumor-induced bone disease. Nat Clin Pract Oncol. 2007; 4:42-55.
7. Durie BGM, Harousseau JL, Miguel JS et al. International uniform response criteria for multiple myeloma.
Leukemia. 2006; 20:1467-73.
8. Hasskarl J, Ihorst G, De Pasquale D et al. Association of multiple myeloma with different neoplasms: systemic
analysis in consecutive patients with myeloma. Leuk Lymphoma. 2011; 52:247-59.
9. Kropff M, Bisping G, Schuck E et al. Bortezomib in combination with intermediate dose dexamethasone and
continuous low-dose oral cyclophosphamide for relapsed multiple myeloma. Br J Haematol. 2007; 138:3307.
10. Leleu X, Attal M, Arnulf B et al. Pomalidomide plus low-dose dexamethasone is active and well tolerated in
bortezomib and lenalidomide-refractory multiple myeloma: Intergroupe Francophone du Myelome 2009-02.
Blood. 2013; 121:1968-75.
11. McCarthy PL, Owzar K, Hofmeister CC et al. Lenalidomide after stem cell transplantation for multiple
myeloma. N Engl J Med. 2012; 366:1770-81.
12. Migliorati CA, Schubert MM, Peterson DE et al. Bisphosphonate-associated osteonecrosis of mandibular and
maxillary bone: an emerging oral complication of supportive care cancer therapy. Cancer. 2005; 104:83-93.
13. National Comprehensive Cancer Network. Recent Updates to NCCN Clinical Practice Guidelines in Oncology
Version 2. 2013. http://www.nccn.org/professionals/physician_gls/recently_updated.asp (accessed 9 Aug
2013).
14. Niesvizky R, Martin TG III, Bensinger WI et al. Phase Ib dose-escalation study of carfilzomib, lenalidomide,
and low-dose dexamethasone in relapsed or progressive multiple myeloma. Clin Cancer Res. 2013; 19:224856.
15. Orlowoski RZ, Nagler A, Sonneveld P et al. Randomized phase III study of pegylated liposomal doxorubicin
plus bortezomib compared to bortezomib alone in relapsed, refractory multiple myeloma: combination
therapy improves time to progression. J Clin Oncol. 2007; 25:3892-901.
16. Ormerod A, Fausel CA, Abonour R et al. Observations of second primary malignancy in patients with multiple
myeloma. Clin Lymphoma Myeloma Leuk. 2012; 12:113-7.
17. Palumbo A, Cavo M, Bringhen S et al. Aspirin, warfarin or enoxaparin thromboprophylaxis in patients with
multiple myeloma treated with thalidomide: a phase III, open-label, randomized trial. J Clin Oncol. 2011;
29:986-93.
15
Multiple Myeloma: Current Approaches to
Managing Relapse and Refractory Disease
18. Palumbo A, Hajek R, Delforge M et al. Continuous lenalidomide treatment for newly diagnosed multiple
myeloma. N Engl J Med. 2012; 366:1759-69.
19. Petrucci MT, Giraldo P, Corrandini P et al. A prospective, international phase II study of bortezomib
retreatment in patients with relapsed multiple myeloma. Br J Haematol. 2013; 160:649-59.
20. Rajkumar SV, Blood E, Vesole D et al. Phase III clinical trial of thalidomide plus dexamethasone compared
with dexamethasone alone in newly diagnosed multiple myeloma: a clinical trial coordinated by the Eastern
Cooperative Oncology Group. J Clin Oncol. 2006; 24:431-6.
21. Rajkumar SV, Jacobus S, Callander NS et al. Lenalidomide plus high-dose dexamethasone versus
lenalidomide plus low-dose dexamethasone as initial therapy for newly diagnosed multiple myeloma: an
open-label randomized controlled trial. Lancet Oncol. 2010; 11:29-37.
22. Richardson PG, Sonneveld P, Schuster MW et al. Bortezomib or high-dose dexamethasone for relapsed
multiple myeloma. N Engl J Med. 2005; 352:2487-98.
23. Richardson PG, Sonneveld P, Shuster M et al. Extended follow-up of a phase III trial in relapsed multiple
myeloma: final time-to-event results of the APEX trial. Blood. 2007; 110:3357-60.
24. Siegel DS, Martin T, Wang M et al. A phase II study of single agent carfilzomib (PX-171-003-A1) in patients
with relapsed and refractory multiple myeloma. Blood. 2012; 120:2817-25.
25. Weber DM, Chen C, Niesvizky R et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in
North America. N Engl J Med. 2007; 357:2133-42.
26. Woo SB, Hellstein JW, Kalmar JR. Narrative review: bisphosphonates and osteonecrosis of the jaw. Ann
Intern Med. 2006; 144:753-61.
16
Multiple Myeloma: Current Approaches to
Managing Relapse and Refractory Disease
SELF-ASSESSMENT
1.
RB, a 71-year old man, was diagnosed with multiple myeloma (MM) five years ago. Over the course of his
three-year disease progression, he received bortezomib and dexamethasone for 4 months (induction
therapy), high-dose chemotherapy with autologous stem cell transplant, and lenalidomide (maintenance
therapy) until his disease progressed. Which of the following therapy options would be most appropriate for
RB in the front-line setting of treating relapsed MM?
a.
b.
c.
d.
2.
Single-agent dexamethasone.
Carfilzomib.
Melphalan and prednisone.
Vincristine, doxorubicin, and dexamethasone.
Since beginning his MM therapy, RB has been taking zoledronic acid 4 mg IV monthly to prevent worsening
of documented lytic lesions on bone scan. On a regular dental exam, he learned that he needs a tooth
extraction. Which of the following would be the most appropriate recommendation regarding RB’s
bisphosphonate therapy?
a.
b.
c.
d.
4.
Continue lenalidomide despite progression.
Discontinue lenalidomide and provide patient with a 6-month treatment reprieve.
Start treatment with bortezomib and dexamethasone.
Offer patient high-dose chemotherapy with allogeneic stem cell transplant regardless of human
leukocyte antigen (HLA) matching.
Following implementation of your treatment from the preceding question, RB enjoys a period of disease
stabilization that lasts 19 months when there is again evidence of disease progression. At this point, what is
the most suitable treatment option?
a.
b.
c.
d.
3.
QUESTIONS
Continue monthly bisphosphonate uninterrupted.
Discontinue bisphosphonate permanently.
Switch to a different bisphosphonate.
Hold bisphosphonate for several months.
Which of the following regimens should be avoided in a patient with end-stage liver disease?
a.
b.
c.
d.
Lenalidomide and dexamethasone.
Bortezomib and dexamethasone.
Thalidomide.
Melphalan and prednisone.
Answers
1.
2.
3.
4.
c
b
d
b
17
Multiple Myeloma: Current Approaches to
Managing Relapse and Refractory Disease
LIST
ADCC
APRIL
BAFF
BAFF-R
BSF-3
CLD
CrCl
ERK
FGFR3
HSCT
ICAM-1
IGF-1
IL-6
Imid
LFA-1
M
MM
MoAb
MPL
MTD
MUC-1
NF-κB
NSAID
SDF-1α
Smad
VCAM-1
VEGF
VEGF-R
VLA-4
OF
ABREVIATIONS
antibody-dependent cell-mediated cytotoxicity
a proliferation-inducing ligand
B-cell activating factor
B-cell activating factor receptor
B-cell stimulating factor-3
carfilzomib, lenalidomide, dexamethasone
creatinine clearance
extracellular signal-regulated kinases
fibroblast growth factor receptor-3
hematopoietic stem cell transplant
intercellular adhesion molecule-1
insulin-like growth factor -1
interleukin-6
immunomodulatory drugs
lymphocyte function-associated antigen-1
monoclonal
multiple myeloma
monoclonal antibodies
melphalan, prednisone, lenalidomide
maximum tolerated dose
mucin-1
nuclear factor κB
nonsteroidal anti-inflammatory drug
stromal cell-derived factor-1α
intracellular proteins that tranduce extracellular signals for the Sma gene
vascular cell adhesion molecule-1
vascular endothelial growth factor
vascular endothelial growth factor receptor
very late antigen-4
18
Multiple Myeloma: Current Approaches to
Managing Relapse and Refractory Disease
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Multiple Myeloma: Current Approaches to Managing
Relapse and Refractory Disease
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