Multiple Myeloma:
Overview and Therapeutic Approaches
Presented as a Live Webinar
Wednesday, August 14, 2013
and
Wednesday, September 11, 2013
Planned and conducted by ASHP Advantage and supported by educational grants from Millennium: The Takeda Oncology Company and Onyx Pharmaceuticals, Inc.
Multiple Myeloma: Overview and Therapeutic Approaches
W E B I N A R I N F O R M A T I O N
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Multiple Myeloma: Overview and Therapeutic Approaches
A C T I V I T Y F A C U L T Y
Tippu Khan, Pharm.D., BCOP, CPP
Clinical Specialist, Bone Marrow Transplant UNC Hospitals
Chapel Hill, North Carolina
Tippu Khan, Pharm.D., BCOP, CPP, is Clinical Specialist in Bone Marrow Transplant (BMT) at University of North Carolina (UNC) Hospitals and Adjunct Clinical Assistant Professor at UNC Eshelman School of Pharmacy in Chapel Hill, North Carolina. In addition, he serves as Resident Advisor for the postgraduate year one (PGY-1) and two (PGY-2) residency programs at UNC Hospitals. Prior to coming to North Carolina, Dr. Khan was Clinical Pharmacy Specialist in Leukemia and BMT for Shands Healthcare at the University of Florida and Adjunct Clinical Assistant Professor at the University of Florida College of Pharmacy in Gainesville, Florida.
Dr. Khan received his Doctor of Pharmacy degree from Purdue University School of Pharmacy and
Pharmaceutical Sciences in West Lafayette, Indiana. His postgraduate training consisted of a pharmacy practice residency accredited by the American Society of Health-System Pharmacists (ASHP) at Wishard Health
Services/Purdue University and an ASHP-accredited specialty residency in hematology/oncology at Clarian Health Partners in Indianapolis, Indiana. Dr. Khan is currently working on his Master of Healthcare
Administration degree at the University of North Carolina Gillings School of Global Public Health in Chapel Hill. Dr. Khan is a board-certified oncology pharmacist (BCOP) and Certified Pharmacy Practitioner (CPP). As faculty for the American College of Clinical Pharmacy (ACCP)/ASHP Oncology Pharmacy Preparatory Review Course, he lectures on the topics of acute leukemias, tumor lysis syndrome, myelodysplastic syndromes, and multiple myeloma. He also is a professional materials reviewer for the ACCP/ASHP oncology review course and the ACCP pharmacotherapy review course.
Multiple Myeloma: Overview and Therapeutic Approaches
D I S C L O S U R E S T A T E M E N T
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:
- Tippu Khan, Pharm.D., BCOP, CPP
- Christopher A. Fausel, Pharm.D., M.H.A., BCOP
- 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.
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Multiple Myeloma:
Overview and New
Therapeutic Approaches
Tippu Khan, Pharm.D., BCOP, CPP
University of North Carolina Hospitals and Clinics Chapel Hill, North Carolina
What is multiple myeloma (MM)?
Kuehl WM et al. Nature Rev Cancer. 2002; 2:175-87.
MGUS Smoldering myeloma Intramedullary myeloma Extramedullary myeloma Myelomacell line
Normal long-lived plasma cell
Germinal-center B cell
BM stromal cell dependence IL-6 dependence
Angiogenesis Bone destruction
Increased DNA-labeling index
A Progressive B-cell Disorder
Men Women
Incidence 7.4 per 100,000 4.7 per 100,000 Deaths 4.4 per 100,000 2.7 per 100,000
http://seer.cancer.gov/csr/1975_2009_pops09/
• 10% of all hematological malignancies in U.S. • Disease characteristics
– Median age of onset is 66 years – Men > Women
– African American 2x incidence and mortality as Caucasians
• 2012 Seer data (all races)
How often will I see this?
M-protein spillage Neuropathy (33%) Renal compromise (30%) Immune deficiency Infection (15%) Marrow infiltration/
Bone destruction Hypercalcemia (15-20%) Bone pain (75%) Lytic lesions (70%)
Anemia (70%)
Plasma cells in blood (Multiple myeloma)
hyperCalcemia
Renal disease
Anemia
Bone disease
Bird JM et al. Br J Haem. 2011; 154:32-75. Kyle RA et al. Br J Haem. 2003; 121:7749-57.
What should I look out for?
Dimopoulos M et al. Blood. 2011; 117:4701-05.
Maybe it is myeloma, what
should I do next?
• History and physical exam • Complete blood count with differential • Blood chemistry, including
– Calcium – Serum creatinine – Lactate dehydrogenase – Albumin
–β-2 microglobulin (β2M)
• Bone marrow aspiration and biopsy with cytogenetics and plasma cell labeling index (PCLI)
• Chromosomal analysis
– Conventional karyotyping (cytogenetics) – Fluorescent in situ hybridization (FISH)
Dimopoulos M et al. Blood. 2011; 117:4701-05.
Maybe it is myeloma, what
should I do next?
• Skeletal survey
• Urinalysis, 24-hour urine collection
• Serum protein electrophoresis (SPEP) and urine protein electrophoresis (UPEP) with immunofixation to identify and quantify “M” (monoclonal) protein
– SPEP shows a monoclonal spike in 85% of patients with multiple myeloma
• 50-70% IgG, 15-25% IgA, 10-20% light chain only (kappa or lambda), 1-5% IgD
– UPEP shows a globulin spike in 75% of patients – Serum β2M and C-reactive protein (β2M is elevated in
patients with renal dysfunction)
MGUS Asymptomatic Myeloma
Symptomatic Myeloma M-protein in serum 30 g/L M-protein in serum ≥ 30
g/L
M-protein in serum or urine Bone marrow clonal plasma
cells 10% and low level of plasma cell infiltration in trephine biopsy (if done)
Bone marrow clonal
plasma cells ≥ 10% Bone marrow (clonal) plasma cells or plasmacytoma. If flow cytometry performed, most plasma cells will show “neoplastic” phenotype.
No evidence of other B-cell proliferative disorders No related organ or tissue impairment (no end-organ damage, including bone lesions)
No related organ or tissue impairment (no end-organ damage, including bone lesions)
Related organ or tissue impairment: Calcium > 11.5 mg/dL Creatinine > 2 mg/dL Hemoglobin < 10 g/dL or 2 g/dL
normal
Bone disease (lytic or osteopathic)
Bird JM et al. Br J Haem. 2011; 154:32-75. Kyle RA et al. Br J Haem. 2003; 121:7749-57.
Question #1: Is this MM active?
Stage International Staging System (ISS) Median Survival I β2M < 3.5 mg/L
Albumin ≥ 3.5 g/dL
62 months II Neither stage I nor stage III 44 months III β2M ≥ 5.5 mg/L 29 months
Greipp PR et al. J Clin Oncol. 2005; 23:3412-20. Dispenzieri A et al. Mayo Clin Proc. 2007; 82:323-41. Kumar SK et al. Mayo Clin Proc. 2009; 84:1095-110.
Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) High Risk Intermediate Risk Standard Risk
FISH del 17p FISH t(4;14) Hyperploidy FISH t(14;16) Cytogenetic del 13q FISH t(11;14) FISH t(14;20) Cytogenetic hypoploidy FISH t(6;14)
Question #2: How bad is it?
Avet-Loiseau H et al. Leukemia. 2013; 27:711-17.
Question #2: How bad is it?
• IMWG re-evaluated outcomes in 12,137 patients worldwide based on ISS staging and cytogenetic abnormalities
• Analysis evaluated overall survival and progression free survival based on del(13), t(4;14), del(17p), t(11;14), and t(14;16)
IMWG Prediction of 4 yr Outcomes based on FISH and ISS
FISH Negative t(4;14)/del17 FISH Positive t(4;14)/del17
OS (%) PFS (%) OS (%) PFS (%)
Stage I 71 39 45 20
Stage II 71 39 33 11
Stage III 45 20 33 11
A. Preparation for allogeneic stem cell transplant B. Determination of autologous transplant eligibility C. Selection of appropriate chemotherapy
induction regimen D. Active surveillance
The first step upon diagnosis of
multiple myeloma is
?
Induction Therapy (primary therapy) Consolidation Therapy If response, transplant (if eligible) or continue myeloma therapy If no response, rescue with secondary therapyMaintenance Therapy
if relapse, rescue with salvage
therapy
• Unfortunately, despite recent advances, MM remains incurable
• Goal of therapy remains disease control, improved quality of life, and prolonged survival
Question #3: What should my
therapy goals be?
Rajkumar VS. Blood.2011; 117:4691-95. Response Criteria IMWG Complete response (CR)
Negative serum and urine immunofixation Disappearance of soft tissue plasmacytomas
≤ 5% plasma cells in bone marrow Very good
partial response (VGPR)
Serum and urine M-protein detectable by immunofixation but not electrophoresis or
≥ 90% reduction in serum M-protein plus urine M-protein
100 mg per 24 hr Partial
response (PR) ≥ 50% reduction in serum M-protein and 24-hr urine M-protein or to 200 mg per 24 hr≥ 90% reduction in Stable disease
(SD) Not meeting criteria for CR, VGPR, PR, or progressive disease (PD)
Question #4: How will I know if
they are responding?
Rajkumar VS et al. Blood. 2011; 117:4691-95.
Question #5: What are my
therapy options?
• Fundamental treatment decision remains a choice between a hematopoietic cell transplant (HCT) based versus a non-HCT based strategy
• High dose chemotherapy followed by autologous HCT remains the treatment of choice
Rajkumar VS et al. Blood.2011; 117:4691-5.
Question #5: What are my
therapy options?
• Decision is based on multiple factors
– Response to initial therapy – Age
• Some trials limited HCT to patients < 65 years of age, though HCT may be option for selected patients > 65 years of age
• Risk of regimen-related toxicity may increase in patients > 70 years of age and requires dose reduction
• Performance status
Rajkumar VS et al. Blood. 2011; 117:4691-5.
Question #5: What are my
therapy options?
• Decision based on multiple factors
– No or few comorbidities
– Adequate renal function: renal failure can increase the morbidity and mortality of MM
• Studies have shown that HCT is feasible in patients with compromised renal function • Most centers will reduce the melphalan dose from
200 mg/m2140 mg/m2
– Adequate pulmonary function – No active infection
A. Preparation for allogeneic stem cell transplant
•First-line allogeneic HCT not indicated
B. Determination of autologous transplant eligibility C. Selection of appropriate chemotherapy
induction regimen
•Autologous HCT remains treatment of choice in eligible patients
D. Active surveillance
•Not indicated Polling Q Revisited
The first step upon diagnosis of multiple
myeloma is
?
Oral melphalan and prednisone 1962 1983 1984 1986 1996 1999 2003 High-dose melphalan VAD ABMT High-dose dexamethasone PB HCT Thalidomide LenalidomideABMT = autologous bone marrow transplantation VAD = vincristine, doxorubicin, dexamethasone
PB HCT = autologous peripheral blood hematopoietic cell transplant
Bortezomib 2005 Carfilzomib 2012 2013 Pomalidomide
Question #5: What are my therapy
options? A historical perspective
A. Vincristine, doxorubicin, dexamethasone B. Melphalan, prednisone, bortezomib C. Bortezomib, thalidomide, dexamethasone D. Autologous transplant, no induction necessary
For a patient eligible for autologous transplant, the most appropriate induction
Not a transplant candidate
based on physiologic age, performance status, and co-morbidity
Potential transplant candidate Conventional chemotherapy or clinical trial Nonalkylator-based induction
Stem cell harvest
Adapted from Rajkumar SV et al. Mayo Clin Proc. 2005; 80:1371-82.
Question #5: What are my therapy
options? Therapy
algorithm
Summary of Common Induction Regimens
RR (%) CR (%) PFS / EFS OS (%) MP vs. CCT 53 vs. 60 NR NR 23 vs. 24.4 @5yr MP vs. MPT 48 vs. 76 7 vs. 28 27% vs. 54% @2yr 64 vs. 84 @3yr MP vs. MPB 35 vs. 71 4 vs. 30 NR 54 vs. 68 @3yr MP vs. MPL 50 vs. 68 12 vs. 33 (CR +VGPR) 12mo vs. 15mo NR VMP vs. VMPT 89 vs. 81 24 vs. 38 56% vs. 41% @3yr 89 vs. 87 @3yr
Myeloma Trialists’ Collaborative Group. J Clin Oncol. 1998; 16:3832-42. Palumbo A et al. Lancet. 2006; 367:825-31.
San Miguel JF et al. N Engl J Med. 2008; 359:906-17. Mateos MV et al. J Clin Oncol. 2010; 28:2259-66. Palumbo A et al. J Clin Oncol. 2010; 28:5101-9.
Question #5: What are my therapy
options? Non-HCT Candidate
NCCN Guidelines Version 2.2013.
Preferred induction regimens
– Melphalan, prednisone, bortezomib (category 1) – Melphalan, prednisone, lenalidomide (category 1) – Melphalan, prednisone, thalidomide (category 1) – Lenalidomide, low-dose dexamethasone (category 1) – Bortezomib, dexamethasone (category 2A)
Question #5: What are my therapy options? Non-HCT Candidate
Barlogie B et al. N Engl J Med. 1984; 310:1353-6. Samson D et al. Lancet. 1989;334:882-5. Rifkin RM et al. Cancer. 2006; 106:848-58. Weber D et al. J Clin Oncol. 2003; 21:16-9. Rajkumar SV et al. J Clin Oncol.2006;24:431-6.
Question #5: What are my therapy
options? HCT Candidate
Summary of Common Induction Regimens
RR (%) CR (%) PFS / EFS OS VAD 55-84 28 NR 36-44mo VAD vs. BD 63 vs. 78 NR 29.7mo vs. 36mo 77% vs. 81% @ 3yr T vs. TD 36 vs. 72 0 vs. 16 NR NR TD vs. D 63 vs. 46 43.8 vs. 15.8 (CR+VGPR) 14.9mo vs. 6.5mo NR LD vs. D 78 vs. 48 NR 52% vs. 32% @3yr 94% vs. 88% @1yr (NS) LD vs. Ld 79 vs. 68 50 vs. 40 (CR+VGPR) NR 87% vs. 96% @1yr VTD vs. TD 76 vs. 44 35 vs. 14 56.2mo vs. 28.2mo 74% vs. 65% @ 4yr Rajkumar SV et al. J Clin Oncol. 2008; 26:2171-7.
Zonder JA et al. Blood. 2010; 116:5838-41. Rajkumar SV et al. Lancet Oncology. 2010; 11:29-37.
Rosinol L et al. Blood. 2012; 120:1589-96.
NCCN Guidelines Version 2.2013.
Preferred induction regimens
– Bortezomib, doxorubicin, dexamethasone (category 1) – Bortezomib, thalidomide, dexamethasone (category 1) – Bortezomib, dexamethasone (category 1)
– Lenalidomide, dexamethasone (category 1)
– Bortezomib, lenalidomide, dexamethasone (category 2A) – Bortezomib, dexamethasone, cyclophosphamide
(category 2A)
Question #5: What are my
therapy options? HCT Candidate
A. Vincristine, doxorubicin, dexamethasone
•Multiple regimens have demonstrated improved outcomes compared to VAD
B. Melphalan, prednisone, bortezomib
•AVOID melphalan-based therapy if eligible for autologous transplant
C. Bortezomib, thalidomide, dexamethasone
•Bortezomib, thalidomide, dexamethasone shown to have superior outcomes compared with TD D. Autologous transplant, no induction necessary
•Not a front-line option, patient needs induction first Polling Q revisited
For a patient eligible for autologous transplant, the most appropriate induction
strategy is:
?
Enlarged version on page 12
Effect of Induction Regimen on Overall Survival Post HCT
N %CR+ PR
Pre-HCT %CR + PR Post-HCT
OS TAD vs. VAD 268 vs. 268 71 vs. 57 84 vs. 76 73mo vs. 60mo BD vs. VAD 223 vs. 218 78.5 vs. 63 80 vs. 77 81% vs. 77% @ 3yr VTD vs. TD 236 vs. 238 93 vs. 79 93 vs. 84 86% vs. 84% @ 3yr PAD vs. VAD 414 vs. 413 78 vs. 54 88 vs. 77 61% vs. 55% @ 5yr VTD vs. VBMCP + V vs. TD 130 vs. 129 vs. 127 85 vs. 75 vs. 62 57 vs. 48 vs. 40 (CR only) 74% vs. 70% vs. 65% @ 4yr
Adapted from Dimopoulos M et al. Blood. 2011; 117:6063-73.
Question #6: Does it matter what
regimen I pick for an HCT candidate?
Question #7: What should I watch
for during induction therapy?
Thalomid (thalidomide) prescribing information (PI), 2013 Feb; Revlimid (lenalidomide) PI, 2013 Jun; Velcade (bortezomib) PI, 2012 Oct (URLs in ref list).
• Thalidomide
– Sedation, fatigue, and constipation – Thrombosis - increased risk
– Peripheral neuropathy with continued therapy – Neutropenia
• Lenalidomide
– Thrombocytopenia/neutropenia – dose adjustment – Renal function – dose adjustment
– Thrombosis • Bortezomib
– Peripheral neuropathy
– Thrombocytopenia/neutropenia – dose adjustment
A. Number of induction cycles that included lenalidomide
B. Use of chemo-mobilization in pre-treated patients
C. Mobilization strategy used with regard to patient age
D. Previous history of intravenous drug abuse
Points to consider for an autologous transplant patient include all of the
following EXCEPT
?
Question #8: What do I need to keep in mind for my HCT candidates?
• Minimum threshold of hematopoietic cells is ≥
2x106CD34+/kgper autologous HCT (aHCT)
• Risk factors for poor mobilization
– Age
– Melphalan exposure
– Extensive prior therapy or prolonged disease duration – Extensive radiotherapy to bone marrow
• More cells may be harvested through chemotherapy-based mobilization strategy
Question #8: What do I need to keep in mind for my HCT candidates?
• Chemo-mobilization with
cyclophosphamide may overcome lenalidomide toxicity
• IMWG recommends
– Cyclophosphamide-based mobilization strategy in patients with > 4 cycles of lenalidomide therapy
– In patients > 65 years of age, consider the use of reduced dose cyclophosphamide- or plerixafor-based mobilization strategy
Question #8: What do I need to keep in mind for my HCT candidates?
• Melphalan 200 mg/m2remains the regimen of
choice
• Beneficial effects of second aHCT in patients with less than VGPR to first aHCT
• IMWG does NOT recommend MAC HCT as part of first-line therapy
• Lack of convincing data proving superiority of
autoRIC over tandem aHCT
A. Number of induction cycles that included lenalidomide
•Increased number of cycles decreases stem cell yield B. Use of chemo-mobilization in pre-treated patients
•Chemo mobilization may overcome lenalidomide use C. Mobilization strategy used with regard to patient
age
•Easier to mobilize younger patients
D. Previous history of intravenous drug abuse
•Does not directly affect transplant success Polling Q revisited
Points to consider for an autologous transplant patient include all of the
following EXCEPT
?
Question #9: What is the plan after
consolidation?
• Maintaining remission remains a primary objective in MM
• IFN-α
– Shown to increase relapse-free survival by 4.4 months (p<0.01) and overall survival by 7 months (p<0.01)
– Randomized trial of maintenance IFN-α
following high-dose melphalan + aHCT revealed no survival benefit
Question #9: What is the plan after
consolidation? Thalidomide
Attal M et al. Blood. 2006; 108:3289-94; Spencer A et al. J Clin Oncol. 2009; 27:1788-93; Morgan GJ et al. Blood. 2012; 119:7-15; Barlogie B et al. N Engl J Med. 2006; 354:1021-30; Lokhorst HM et al. Blood. 2010; 115:1113-20.
Study Treatment Schema Outcomes
IFM 99-02 400 mg/day until progression vs. none 4yr OS = 87% vs. 75% (p<0.04) Australian Alternate day prednisone (AP) alone or in
combination with thalidomide 100 mg daily (increased to 200 mg daily after 14 days if tolerated)
3yr OS = 86% vs. 75% (p< 0.004)
MRC Myeloma IX
Thalidomide 50-100 mg/day until progression vs. none
PFS 30mo vs. 27mo OS @ 3yr = 75% vs. 80% TT2 Thalidomide 100 mg/day x 1 yr 50
mg/day until progression vs. none
@70mo follow up EFS 6yr vs. 4yr
OS 57% vs. 44% Hovon50 Thalidomide 50 mg/day vs. IFN-α 3million
units TIW until progression
VGPR 66% vs. 54% (p=0.005) OS 20mo vs. 31mo
(p=0.009)
Question #9: What is the plan after
consolidation? Lenalidomide
Study Treatment Schema Outcomes
CALGB 100104
Started at 10 mg daily After 3 mo, if patient’s hematologic
profile allowed, then lenalidomide dose escalated to 15 mg daily
4yr OS = 87% vs. 75% (p<0.04)
IFM 2005-02 Lenalidomide 10 mg/day x 3 mo, increased to 15 mg/day if tolerated
EFS 40mo vs. 23mo (p<0.001) OS at 5yr similar MM015 MPR-R vs. MPR
MPR x 9 – 28 day cycles: melphalan 0.18 mg/kg D1-4, prednisone 2 mg/kg D1-4, lenalidomide 10 mg D1-21 MPR-R – MPR + lenalidomide 10 mg D1-21 q 28 day cycle RR 77% vs. 68% PFS 31mo vs. 14mo
McCarthy PL et al. N Engl J Med. 2012; 366:1770-81; Palumbo A et al. N Engl J Med. 2012; 366:1759-69; Attal M et al. N Engl J Med. 2012; 366:1782-91.
Question #9: What is the plan after
consolidation? Bortezomib
Study Treatment Schema Outcomes HOVON65/GMMG-HD4VAD vs. PAD Improved PFS (28 vs. 35mo) Improved OS in multivariate analysis GEM2005MAS65 VT vs. VP in elderly patients Median PFS (39 vs. 32mo) OS @5yr – 69% vs. 50%
Sonneveld P et al. J Clin Oncol. 2012; 30:2946-55. Mateos MV et al. Blood. 2012; 120:2581-8.
Question #10: What happens if
consolidation therapy doesn’t work?
What is multiple myeloma (MM)?
Kuehl WM et al. Nature Rev Cancer. 2002; 2:175-87.
MGUS Smoldering myeloma Intramedullary myeloma Extramedullary myeloma Myelomacell line
Normal long-lived plasma cell
Germinal-center B cell
BM stromal cell dependence IL-6 dependence
Angiogenesis Bone destruction
Increased DNA-labeling index
A Progressive B-cell Disorder
MGUS Asymptomatic
Myeloma
Symptomatic Myeloma
M-protein in serum 30 g/L M-protein in serum ≥ 30 g/L
M-protein in serum or urine Bone marrow clonal plasma
cells 10% and low level of plasma cell infiltration in trephine biopsy (if done)
Bone marrow clonal plasma cells ≥ 10%
Bone marrow (clonal) plasma cells or plasmacytoma. If flow
cytometry performed, most plasma cells will show “neoplastic” phenotype.
No evidence of other B-cell proliferative disorders No related organ or tissue impairment (no end-organ damage, including bone lesions)
No related organ or tissue impairment (no end-organ damage, including bone lesions)
Related organ or tissue impairment:
Calcium > 11.5 mg/dL Creatinine > 2 mg/dL
Hemoglobin < 10 g/dL or 2 g/dL
normal
Bone disease (lytic or osteopathic)
Bird JM et al. Br J Haem. 2011; 154:32-75. Kyle RA et al. Br J Haem. 2003; 121:7749-57.
Stage International Staging System (ISS) Median Survival
I β2M < 3.5 mg/L Albumin ≥ 3.5 g/dL
62 months
II Neither stage I nor stage III 44 months
III β2M ≥ 5.5 mg/L 29 months
Greipp PR et al. J Clin Oncol. 2005; 23:3412-20. Dispenzieri A et al. Mayo Clin Proc. 2007; 82:323-41. Kumar SK et al. Mayo Clin Proc. 2009; 84:1095-110.
Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART)
High Risk Intermediate Risk Standard Risk
FISH del 17p FISH t(4;14) Hyperploidy
FISH t(14;16) Cytogenetic del 13q FISH t(11;14)
FISH t(14;20) Cytogenetic hypoploidy FISH t(6;14)
Question #2: How bad is it?
Summary of Common Induction Regimens
RR (%) CR (%) PFS / EFS OS (%) MP vs. CCT 53 vs. 60 NR NR 23 vs. 24.4 @5yr MP vs. MPT 48 vs. 76 7 vs. 28 27% vs. 54% @2yr 64 vs. 84 @3yr MP vs. MPB 35 vs. 71 4 vs. 30 NR 54 vs. 68 @3yr MP vs. MPL 50 vs. 68 12 vs. 33 (CR +VGPR) 12mo vs. 15mo NR VMP vs. VMPT 89 vs. 81 24 vs. 38 56% vs. 41% @3yr 89 vs. 87 @3yr
Myeloma Trialists’ Collaborative Group. J Clin Oncol. 1998; 16:3832-42. Palumbo A et al. Lancet. 2006; 367:825-31.
San Miguel JF et al. N Engl J Med. 2008; 359:906-17. Mateos MV et al. J Clin Oncol. 2010; 28:2259-66. Palumbo A et al. J Clin Oncol. 2010; 28:5101-9.
Question #5: What are my therapy
options? Non-HCT Candidate
Barlogie B et al. N Engl J Med. 1984; 310:1353-6. Samson D et al. Lancet. 1989;334:882-5. Rifkin RM et al. Cancer. 2006; 106:848-58. Weber D et al. J Clin Oncol. 2003; 21:16-9. Rajkumar SV et al. J Clin Oncol.2006;24:431-6.
Question #5: What are my therapy
options? HCT Candidate
Summary of Common Induction Regimens
RR (%) CR PFS / EFS OS
VAD 55‐84 28% NR 36‐44mo
VAD vs. BD 63 vs. 78 NR 29.7mo vs.36mo 77% vs. 81% @ 3yr T vs. TD 36 vs. 72 0% vs. 16% NR NR TD vs. D 63 vs. 46 43.8% vs. 15.8% (CR+VGPR) 14.9mo6.5mo vs. NR LD vs. D 78 vs. 48 NR 52% vs. 32% @3yr 94% vs.(NS) 88% @1yr LD vs. Ld 79 vs. 68 50% vs. 40% (CR+VGPR) NR 87% vs. 96% @1yr VTD vs. TD 76 vs. 44 35 vs. 14 56.2mo vs. 28.2mo 74% vs. 65% @ 4yr Rajkumar SV et al. J Clin Oncol. 2008; 26:2171-7.
Zonder JA et al. Blood. 2010; 116:5838-41. Rajkumar SV et al. Lancet Oncology. 2010; 11:29-37.
Rosinol L et al. Blood. 2012; 120:1589-96.
Effect of Induction Regimen on Overall Survival Post HCT
N %CR+ PR Pre-HCT %CR + PR Post-HCT OS
TAD vs. VAD 268 vs. 268 71 vs. 57 84 vs. 76 73mo vs. 60mo
BD vs. VAD 223 vs. 218 78.5 vs. 63 80 vs. 77 81% vs. 77% @ 3yr
VTD vs. TD 236 vs. 238 93 vs. 79 93 vs. 84 86% vs. 84% @ 3yr
PAD vs. VAD 414 vs. 413 78 vs. 54 88 vs. 77 61% vs. 55% @ 5yr
VTD vs. VBMCP + V vs. TD 130 vs. 129 vs. 127 85 vs. 75 vs. 62 57 vs. 48 vs. 40 (CR only) 74% vs. 70% vs. 65% @ 4yr
Adapted from Dimopoulos M et al. Blood. 2011; 117:6063-73.
Question #6: Does it matter what
regimen I pick for an HCT candidate?
Question #9: What is the plan after
consolidation? Thalidomide
Attal M et al. Blood. 2006; 108:3289-94; Spencer A et al. J Clin Oncol. 2009; 27:1788-93; Morgan GJ et al. Blood. 2012; 119:7-15; Barlogie B et al. N Engl J Med. 2006; 354:1021-30; Lokhorst HM et al. Blood. 2010; 115:1113-20.
Study Treatment Schema Outcomes
IFM 99-02 400 mg/day until progression vs. none 4yr OS = 87% vs. 75% (p<0.04)
Australian Alternate day prednisone (AP) alone or in combination with thalidomide 100 mg daily (increased to 200 mg daily after 14 days if tolerated)
3yr OS = 86% vs. 75% (p< 0.004)
MRC Myeloma IX
Thalidomide 50-100 mg/day until progression vs. none
PFS 30mo vs. 27mo OS @ 3yr = 75% vs. 80% TT2 Thalidomide 100 mg/day x 1 yr 50
mg/day until progression vs. none
@70mo follow up EFS 6yr vs. 4yr
OS 57% vs. 44% Hovon50 Thalidomide 50 mg/day vs. IFN-α 3million
units TIW until progression
VGPR 66% vs. 54% (p=0.005) OS 20mo vs. 31mo
(p=0.009)
Question #9: What is the plan after
consolidation? Lenalidomide
Study Treatment Schema Outcomes CALGB
100104
Started at 10 mg daily
After 3 mo, if patient’s hematologic profile allowed, then lenalidomide dose escalated to 15 mg daily
4yr OS = 87% vs. 75% (p<0.04)
IFM 2005-02 Lenalidomide 10 mg/day x 3 mo, increased to 15 mg/day if tolerated
EFS 40mo vs. 23mo (p<0.001)
OS at 5yr similar
MM015 MPR-R vs. MPR
MPR x 9 – 28 day cycles: melphalan 0.18 mg/kg D1-4, prednisone 2 mg/kg D1-4, lenalidomide 10 mg D1-21 MPR-R – MPR + lenalidomide 10 mg D1-21 q 28 day cycle RR 77% vs. 68% PFS 31mo vs. 14mo
McCarthy PL et al. N Engl J Med. 2012; 366:1770-81; Palumbo A et al. N Engl J Med. 2012; 366:1759-69; Attal M et al. N Engl J Med. 2012; 366:1782-91.
Multiple Myeloma: Overview and Therapeutic Approaches
S E L E C T E D R E F E R E N C E S
1. Attal M, Harousseau JL, Leyvraz S et al. Maintenance therapy with thalidomide improves survival in patients
with multiple myeloma. Blood. 2006; 108:3289-94.
2. 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.
3. Avet-Loiseau H, Durie BG, Cavo M et al. Combining fluorescent in situ hybridization data with ISS staging improves risk assessment in myeloma; an International Myeloma Working Group
collaborative project. Leukemia. 2013;27:711-17.
4. Barlogie B, Smith L, Alexanian R. Effective treatment of advanced multiple myeloma refractory to alkylating
agents. N Engl J Med. 1984; 310:1353-6.
5. Barlogie B, Tricot G, Anaissie E et al. Thalidomide and hematopoietic-cell transplantation for multiple
myeloma. N Engl J Med. 2006; 354:1021-30.
6. Bird JM, Owen RG, D’Sa S et al. Guidelines for the diagnosis and management of multiple myeloma 2011. Br
J Haematol. 2011; 154:32-75.
7. Dimopoulos M, Kyle R, Fermand JP et al. Consensus recommendations for standard investigative workup:
report of the International Myeloma Workshop Consensus Panel 3. Blood. 2011; 117:4701-5.
8. Dispenzieri A, Rajkumar SV, Gertz MA et al. Treatment of newly diagnosed multiple myeloma based on Mayo
Stratification of Myeloma and Risk-adapted Therapy (mSMART): consensus statement. Mayo Clin Proc. 2007;
82:323-41.
9. Greipp PR, San Miguel J, Durie BG et al. International staging system for multiple myeloma. J Clin Oncol.
2005; 23:3412-20.
10. International Myeloma Working Group. Criteria for the classification of monoclonal gammopathies, multiple
myeloma and related disorders: a report of the International Myeloma Working Group. Br J Haematol. 2003;
121:749-57.
11. Kuehl WM, Bergsagel PL. Multiple myeloma: evolving genetic events and host interactions. Nat Rev Cancer.
2002 Mar; 2:175-87.
12. Kumar SK, Mikhael JR, Buadi FK et al. Management of newly diagnosed symptomatic multiple myeloma:
updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) consensus guidelines. Mayo
Clin Proc. 2009; 84:1095-110.
13. Lokhorst HM, van der Holt B, Zweegman S et al. A randomized phase 3 study on the effect of thalidomide combined with adriamycin, dexamethasone, and high-dose melphalan, followed by thalidomide
maintenance in patients with multiple myeloma. Blood. 2010; 115:1113-20.
14. Mateos MV, Oriol A, Martinez-Lopwz J et al. Maintenance therapy with bortezomib plus thalidomide or bortezomib plus prednisone in elderly multiple myeloma patients included in the GEM2005MAS65 trial. Blood. 2012; 120:2581-8.
15. Mateos MV, Richardson PG, Schlag R et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma; updated follow-up and impact of
subsequent therapy in the phase III VISTA trial. J Clin Oncol. 2010; 28:2259-66.
16. McCarthy PL, Owzar K, Hofmeister CC et al. Lenalidomide after stem-cell transplantation for multiple
Multiple Myeloma: Overview and Therapeutic Approaches
18. Myeloma Trialists’ Collaborative Group. Combination chemotherapy versus melphalan plus prednisone as
treatment for multiple myeloma: an overview of 6,633 patients from 27 randomized trials. J Clin Oncol.
1998; 16:3832-42.
19. 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).
20. Palumbo A, Bringhen S, Caravita T et al. Oral melphalan and prednisone chemotherapy plus thalidomide compared with melphalan and prednisone alone in elderly patients with multiple myeloma: randomized
controlled trial. Lancet. 2006; 367(9513):825-31.
21. Palumbo A, Bringhen S, Rossi D et al. Bortezomib-melphalan-prednisone-thalidomide followed by maintenance with bortezomib-thalidomide compared with bortezomib-melphalan-prednisone for initial
treatment of multiple myeloma: a randomized controlled trial. J Clin Oncol. 2010; 28:5101-9.
22. Palumbo A, Hajek R, Delforge M et al. Continuous lenalidomide treatment for newly diagnosed multiple
myeloma. N Engl J Med. 2012; 366:1759-69.
23. 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.
24. Rajkumar SV, Harousseau JL, Durie B et al. Consensus recommendations for the uniform reporting of clinical
trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011; 117:4691-5.
25. 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 randomised controlled trial. Lancet Oncol. 2010; 11:29-37.
26. Rajkumar SV, Rosinol L, Hussein M et al. Multicenter, randomized, double-blind, placebo-controlled study of thalidomide plus dexamethasone compared with dexamethasone as initial therapy for newly diagnosed
multiple myeloma. J Clin Oncol. 2008; 26:2171-7.
27. Revlimid (lenalidomide) prescribing information. Summit, NJ: Celgene Corporation; 2013 Jun.
http://www.revlimid.com/pdf/MCL_PI.pdf (accessed 9 Aug 2013).
28. Rifkin RM, Gregory SA, Mohrbacher A et al. Pegylated liposomal doxorubicin, vincristine, and dexamethasone provide significant reduction in toxicity compared with doxorubicin, vincristine, and dexamethasone in patients with newly diagnosed multiple myeloma: a phase III multicenter randomized
trial. Cancer. 2006; 106:848-58.
29. Rosinol L, Oriol A, Teruel AI et al. Superiority of bortezomib, thalidomide, and dexamethasone (VTD) as induction pretransplantation therapy in multiple myeloma: a randomized phase 3 PETHEMA/GEM study. Blood. 2012; 120:1589-96.
30. Samson D, Gaminara E, Newland A et al. Infusion of vincristine and doxorubicin with oral dexamethasone as
first-line therapy for multiple myeloma. Lancet. 1989; 2(8668):882-5.
31. San Miguel JF, Schlag R, Khuageva NK et al. Bortezomib plus melphalan and prednisone for initial treatment
for multiple myeloma. N Engl J Med. 2008; 359:906-17.
32. SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations). Updated August 20, 2012.
http://seer.cancer.gov/csr/1975_2009_pops09/ (accessed 9 Aug 2013).
Multiple Myeloma: Overview and Therapeutic Approaches
34. Spencer A, Prince HM, Roberts AW et al. Consolidation therapy with low-dose thalidomide and prednisolone prolongs the survival of multiple myeloma patients undergoing a single autologous stem-cell transplantation
procedure. J Clin Oncol. 2009; 27:1788-93.
35. Thalomid (thalidomide) prescribing information. Summit, NJ: Celgene Corporation; 2013 Feb.
http://www.thalomid.com/pdf/Thalomid_PI.pdf (accessed 9 Aug 2013).
36. Velcade (bortezomib) prescribing information. Cambridge, MA: Millenium Pharmaceuticals, Inc.; 2012 Oct.
http://www.velcade.com/files/PDFs/VELCADE_PRESCRIBING_INFORMATION.pdf (accessed 9 Aug 2013).
37. Weber D, Rankin K, Gavino M et al. Thalidomide alone or with dexamethasone for previously untreated
multiple myeloma. J Clin Oncol. 2003; 21:16-9.
38. Zonder JA, Crowley J, Hussein MA et al. Lenalidomide and high-dose dexamethasone compared with dexamethasone as initial therapy for multiple myeloma: a randomized Southwest Oncology Group trial
Multiple Myeloma: Overview and Therapeutic Approaches
S E L F – A S S E S S M E N T Q U E S T I O N S
1. The incidence and mortality of multiple myeloma in the United States are higher in a. Caucasians compared with African Americans.
b. African Americans compared with Caucasians. c. Asian Americans compared with African Americans. d. Caucasians compared with Asian Americans.
2. When pharmacists provide follow-up care to patients with multiple myeloma receiving bortezomib or thalidomide, they should monitor patients for which of the following adverse effects?
a. Agitation.
b. Peripheral neuropathy. c. Decreased renal function. d. Thrombocytopenia.
3. According to NCCN Guidelines (version 2) published in 2013, all of the following are preferred induction regimens for hematopoietic cell transplant (HCT) candidates EXCEPT
a. Bortezomib, doxorubicin, dexamethasone. b. Lenalidomide, dexamethasone.
c. Bortezomib, dexamethasone, cyclophosphamide. d. Lenalidomide, dexamethasone, cyclophosphamide.
4. TW is a 54-year-old African-American man who presents complaining of back pain and lethargy. Routine laboratory tests reveal serum creatinine 2.1 mg/dL, calcium 10.4 mg/dL, and albumin 2.8 g/dL. Serum protein electrophoresis indicates monoclonal spike of IgG 7.1 g/dL. Urine protein electrophoresis and immunofixation indicates 300 mg/24 hr with kappa fragment. Skeletal survey reveals multiple lytic lesions, and bone marrow biopsy shows 20% plasma cells with β2 microglobulin of 5.7 mg/L. Based on these data and use of the International Staging System (ISS), which of the following would be the most appropriate diagnosis and stage for this patient?
a. High risk monoclonal gammopathy of undetermined significance (MGUS), stage III b. Asymptomatic multiple myeloma, stage III.
c. Symptomatic multiple myeloma, stage III.
5. After diagnosing multiple myeloma, which of the following would be the most appropriate next step in caring for TW?
a. Preparation for allogeneic HCT.
b. Determination of eligibility for autologous HCT. c. Select chemotherapy regimen for induction. d. Active surveillance.
Multiple Myeloma: Overview and Therapeutic Approaches
6. GJ is a 64-year-old woman diagnosed with stage III symptomatic multiple myeloma, and it was determined that she was ineligible for HCT. Which of the following would be an appropriate induction regimen for GJ?
a. Vincristine, doxorubicin, dexamethasone. b. Melphalan, prednisone, lenalidomide.
c. Bortezomib, melphalan, prednisone, thalidomide. d. Melphalan, prednisone.
Answers
1. b 2. b 3. d 4. c 5. b 6. bMultiple Myeloma: Overview and Therapeutic Approaches
L I S T O F A B B R E V I A T I O N S
ABMT autologous bone marrow transplantation
aHCT autologous hematopoietic cell transplantation
AP alternate day prednisone
β2M β-2 microglobulin
BD bortezomib, dexamethasone
BM bone marrow
CCT compare combination chemotherapy
CR complete response
D dexamethasone
EFS event free survival
FISH fluorescent in situ hybridization
HCT hematopoietic cell transplant
IFN-α interferon α
IL-6 interleukin-6
IMWG International Myeloma Working Group
ISS International Staging System
LD lenalidomide, high dose dexamethasone
Ld lenalidomide, low dose dexamethasone
M monoclonal
MAC myeloablative conditioning
MGUS monoclonal gammopathy of undetermined significance
MM multiple myeloma
MP melphalan, prednisone
MPB melphalan, prednisone, bortezomib
MPL melphalan, prednisone, lenalidomide
MPR melphalan, prednisone, lenalidomide with placebo maintenance
MPR-R melphalan, prednisone, lenalidomide with lenalidomide maintenance
MPT melphalan, prednisone, thalidomide
NR non-responsive
OS overall survival
PAD bortezomib, doxorubicin, dexamethasone
PB HCT autologous peripheral blood hematopoietic cell transplant
PCLI plasma cell labeling index
PD progressive disease
PFS progression free survival
PR partial response
RIC reduced intensity conditioning
RR response rate
SCT stem cell transplant
SD stable disease
SPEP serum protein electrophoresis
T thalidomide
TAD thalidomide, doxorubicin, dexamethasone
TD thalidomide, dexamethasone
Multiple Myeloma: Overview and Therapeutic Approaches
VBMCP vincristine, carmustine, melphalan, cyclophosphamide, prednisone
VD bortezomib, dexamethasone
VGPR very good partial response
VMP bortezomib, melphalan, prednisone
VMPT bortezomib, melphalan, prednisone, thalidomide
VP bortezomib, prednisone
VT bortezomib, thalidomide
Multiple Myeloma: Overview and Therapeutic Approaches
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