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Considerations for Optimizing
Transplant in Multiple Myeloma
Patient Management
PARAMESWARAN HARI MD
MEDICAL COLLEGE OF WISCONSIN
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This activity has been made possible through
an unrestricted educational grant from
Spectrum Pharmaceuticals
2
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Faculty Disclosure
Faculty:
:
Disclosures
Learning Objectives
After completing this program, participants should be able to:
1.
Identify factors that might determine eligibility for and timing of
high-dose chemotherapy (HDT) followed by autologous stem
cell transplant (ASCT) in patients with multiple myeloma (MM)
2.
Differentiate treatment strategies for patients with newly
diagnosed multiple myeloma who are eligible for HDT/ASCT
3.
Identify barriers in access to HDT/ASCT for MM
4.
Review the rationale for conditioning regimens in patients with
multiple myeloma who are eligible for HDT/ASCT
5.
Compare and contrast pertinent data regarding a new
formulation of melphalan
MYELOMA OVERVIEW
Revised International Staging
System (R-ISS) for MM
•
R-ISS I (n = 871)
– Including ISS stage I (serum β2-microglobulin level < 3.5 mg/L and serum
albumin level ≥ 3.5 g/dL)
– No high-risk CA [del(17p) and/or t(4;14) and/or t(14;16)]
– Normal LDH level (less than the upper limit of normal range)
•
R-ISS III (n = 295)
– Including ISS stage III (serum β2-microglobulin level > 5.5 mg/L)
– High-risk CA or high LDH level
•
R-ISS II (n = 1,894)
– Including all the other possible combinations
5-Year OS*
5-Year PFS*
R-ISS I
82%
55%
R-ISS II
62%
36%
R-ISS III
40%
24%
Palumbo, et al. JCO. 2015;33(26):2863-2869.
*At a median follow-up of 46 months
Indications for Considering Treatment
(IMWG Consensus Guidelines)
• At least one of the CRAB Criteria (evidence of end organ damage)
CRAB Criteria
•
•
•
•
Hypercalcemia
Serum calcium >2.75 mmol/L (>11 mg/dL)
Renal Failure
Serum creatinine ≥ 2 mg/dL or creatinine clearance
<40 mL per min
Anemia
Hemoglobin >20 g/L below the lower limit of normal,
or a hemoglobin value <100 g/L
Bone
Lytic lesions, pathologic fractures, or severe
osteopenia
≥60% clonal bone marrow plasma cells
Serum involved/uninvolved free light chain ratio ≥100
>1 Focal bone lesion (≥5mm) on MRI
“Clinical judgement”
Rajkumar, et al. Lancet Oncology. 2014;15(12):e538-48.
Available Therapies and Phases of
Treatment for MM
Treatment Options
Conventional chemotherapy (e.g., alkylating agents)
Steroids (corticosteroids)
Autologous stem cell transplant (ASCT)
Newer therapies
• Proteasome inhibitors
• Immunomodulatory agents
• Monoclonal antibodies
• HDAC inhibitors
Initial
Therapy
Consolidation /
Maintenance
Treatment of
Relapsed Disease
ASCT
if eligible*
Supportive Care
*Transplant eligibility may impact initial treatment decisions
Treatment Goals for MM
• Disease Response and Survival
– Rapid cytoreduction to relieve symptoms
– Minimize treatment-related toxicity
– Prolong survival – Overall Survival
• Symptom Control
– Ameliorate pain and other disease-related
symptoms
– Prevent further organ damage
– Preserve performance status and quality of life
AUTOLOGOUS
TRANSPLANTATION
Transplant Vs Conventional Therapy
Meta-analysis of PFS: Standard
Chemotherapy vs Autologous SCT
Favors HDT
Favors SDT
PFS (95%CI)
IFM90
0.61 (0.42, 0.89)
MAG90*
0.42 (0.30, 0.58)
MAG91
0.76 (0.57, 1.02)
MRC7
0.68 (0.54, 0.85)
S9321
0.87 (0.72, 1.06)
PETHEMA*
0.85 (0.60, 1.22)
HOVON*
0.85 (0.63, 1.14)
M97G*
0.48 (0.34, 0.66)
IFM9906*†
1.80 (1.30, 2.50)
Combined
0.75 (0.59, 0.96)
Sensitivity/Sub-group
Analyses
0.75 (0.65, 0.87)
Excluding Non-Standard
RCTs
0.77 (0.59, 1.00)
RCTs preferring PBSCs
0.70 (0.51, 0.96)
RCTs with Longer Followup
0.72 (0.62, 0.83)
RCTs with Lower
Crossover ‡
.
1
.
5
1
5
Hazard Ratio of Progression
10
• *Nonstandard study
• † Patients aged >65 years
‡ Two negative studies (HOVON, IFM9906) with missing crossover information were omitted from this analysis.
Figure from: Koreth J, et al. Biol Blood Marrow Transplant. 2007;13:183-196.
AHCT Has Changed Natural History
of MM: Population-level Data
Changes in MM relative survival ratio in the Netherlands
≤ 65 years
> 65 years
Figure from Schaapveld M, et al. Eur J Cancer . 2009;46:160.
High-dose Melphalan + ASCT vs Chemotherapy +
Lenalidomide Followed by Lenalidomide +
Prednisone vs Lenalidomide Maintenance in MM
Induction
Four 28-day cycles of lenalidomide
(25 mg on days 1–21) and
dexamethasone (40 mg on days 1,
8,Induction
15, and 22)
CY (3g/m2)
MOBILIZATION
High-dose Melphalan +
ASCT
Lenalidomide
Lenalidomide
+ Prednisone
Gay, et al. Lancet Oncol. 2015;16:1617-1629.
Collection
Consolidation
Maintenance
CY (3g/m2)
MOBILIZATION
Cyclophosphamide,
Lenalidomide,
Dexamethasone
Lenalidomide
Lenalidomide+
Prednisone
Longer PFS with High-dose Melphalan + ASCT
vs Chemotherapy + Lenalidomide
• Median follow-up was 52.0 months
• Median PFS with consolidation therapy
– High-dose melphalan + ASCT: 43.3 months
– Chemotherapy + lenalidomide: 28.6 months
(HR for the first 24 months = 2.51, P < .0001)
• Median PFS with maintenance therapy
– Lenalidomide + prednisone: 37.5 months
– Lenalidomide: 28.5 months
(HR = 0.84, P = .34).
• 4-year OS
– High-dose melphalan + ASCT: 86%
– Chemotherapy + lenalidomide: 73%
(HR = 2.40, P = .004).
Gay, et al. Lancet Oncol. 2015;16:1617-1629.
Phase 3 MPR Consolidation vs
Tandem MEL200
Lenalidomide + low-dose Dexamethasone Induction
4 cycles
(N = 402)
MPR
6 cycles
(n = 202)
Lenalidomide
Maintenance
10 mg, d 1-21
(n = 98)
MEL 200
(n = 200)
No
Maintenance
(n = 104)
MPR: melphalan, prednisone, lenalidomide
Palumbo, et al. N Engl J Med. 2014;371:895-905.
Lenalidomide
Maintenance
10 mg, d 1-21
(n = 100)
No
Maintenance
(n = 100)
Tandem MEL-200 Improves OS
CR Rates
Post Consolidation
Tandem MEL
MPR Consolidation
Post Maintenance
15.7%
35.7%
20%
33.8%
Progression Free Survival
Survival
Tandem Transplant + Len
Tandem Transplant, NO Len
NO Transplant + NO Len
Tandem Transplant + Len
Palumbo, et al. N Engl J Med. 2014;371:895-905.
63% of relapsed non transplant pts received ASCT
Mel200-ASCT vs Chemotherapy +
Lenalidomide: PFS
Median Follow-up from Randomization: 4 Years
PFS (% of patients)
1.00
0.75
Mel200-ASCT: PFS 41 months
0.50
0.25
0
CC + R: PFS 26 months
HR, .55; 95% CI, .45-.69; P < .0001
0
10
20
30
40
Months
Gay, et al. Blood. 2014;124:Abstract 198.
50
60
70
80
Mel200-ASCT vs Chemotherapy +
Lenalidomide: OS
Median Follow-up from Randomization: 4 Years
1.00
OS (% of patients)
Mel200-ASCT: OS 84%
0.75
CC + R: OS 71%
0.50
0.25
0
HR, .59; 95% CI, .40-.87; P = .008
0
10
20
30
40
Months
Gay, et al. Blood. 2014;124:Abstract 198.
50
60
70
80
Transplant Outcomes Improving
Over Time
100
100
90
90
80
80
2005-2010 (n=2,223)
Probability, %
70
70
2000-2004 (n=1,464)
60
60
50
50
1995-1999 (n=686)
40
40
30
30
20
20
10
10
* vs. 1995-1999, P<0.05
#
vs. 2000-2004, P<0.05
0
Years
0
1995-99
2000-04
2005-10
0
1
2
72%
81%*
86%*#
3
4
47%
55%*
57%*
Costa LJ et al. Biol Blood Marrow Transplant. 2013 Nov;19(11):1615-24
5
Bortezomib-based vs Non-bortezomib—
based Induction Treatment Before ASCT
IFM 200501/2006-02
n=482
PETHEMA
n=390
GIEMEMA
n=480
HOVON-65
n=827
VD±DCEP
VTD
VTD
PAD
Control
induction
VAD ±DCEP
VMBCP or
TD
TD
TD
ASCT
1 or 2 (or RIC)
1
2
1 or 2
Len x 2
--
VTD
TD
--
Random:
Len vs Obs
Random:
IFN, Thal or
VT
All:
Dex
Assigned:
Bort
Thal
Bortezomib
induction
Consolidation
Maintenance
Sonneveld. J Clin Oncol. 2013;31(26):3279-87.
Bortezomib-based vs Non-bortezomib—
based Induction Treatment Before ASCT
Median TTP
37.5 months vs 31.3 months;
P< 0.0001
Sonneveld, et al. J Clin Oncol. 2013;31:3279-3287.
Regimens
Survival
Bortezomib/lenalidomide/
dexamethasone (RVD)[1]
18-mo PFS: 75%
18-mo OS: 97%
Carfilzomib/lenalidomide/
dexamethasone (KRd)[2,3]
12-mo PFS: 97%[2]
24-mo PFS: 92%[2]
3-yr PFS: 79%[3]
3-yr OS: 96%[3]
Carfilzomib/thalidomide/
dexamethasone (KTd)[4]
3-yr PFS: 72%
Bortezomib/
cyclophosphamide/
dexamethasone (CyBorD)[5]
5-yr PFS: 42%[6]
5-yr OS: 70%[6]
Ixazomib/lenalidomide/
dexamethasone[7]
12-mo PFS: 88%
12-mo OS: 94%
Pts Achieving ≥ VGPR (%)
Earlier Phase Studies: Induction
Regimens for Transplantation-Eligible Pts
100
81
80
60
67
68
60
58
40
20
0
[1] Richardson, PG et al. Blood. 2010;116:679-686. [2] Jakubowiak A, et al. Blood. 2012;120:1801-1809.
[3] Jasielec J, et al. ASH 2013. Abstract 3220. [4] Sonneveld P, et al. Blood. 2015;125:449-456. [5] Reeder CB, et al. Blood.
2010;115:3416-3417. [6] Reeder CB, et al. ASH 2013. Abstract 3192. [7] Kumar SK, et al. Lancet Oncol. 2014;15:1503-1512.
AUTOLOGOUS
TRANSPLANTATION
Early vs Late HCT
Early vs Late SCT: Ongoing Phase 3 Study
in Newly Diagnosed MM SCT Candidates
(IFM/DFCI 2009)
Randomize
RVDx3
CY (3g/m2)
MOBILIZATION
Goal: 5 x106
cells/kg
Induction
RVDx3
Collection
CY (3g/m2)
MOBILIZATION
Goal: 5 x106 cells/kg
Melphalan 200 AHCT
+ RVD x 2
Consolidation
Lenalidomide
Maintenance
RVD: lenalidomide, bortezomib and dexamethasone
ClinicalTrials.gov Identifier: NCT01208662
AHCT at relapse
RVD x 5
Lenalidomide
IFM 2009: Best Response.
RVD arm
N=350
Transplant arm
N=350
CR
49%
59%
VGPR
29%
29%
PR
20%
11%
<PR
2%
1%
At least VGPR
78%
88%
0.001
228 (65%)
280 (80%)
0.001
Neg MRD by FCM , n
(%)
Attal M et al Blood 2015 126:391
p-value
0.02
IFM 2009: PFS (9/2015)
100
HDT
90
no HDT
80
70
60
50
P<0.001
40
30
20
Median PFS, months
34
43
4-year PFS
35%
47%
1
0.69 (0.56-0.84)
10
Hazard ratio (95% CI)
0
0
12
<0.001
24
36
48
153
128
27
24
Months of follow-up
N at risk
HDT
no HDT
350
350
309
296
Attal M et al Blood 2015 126:391
261
228
IFM/DFCI 2009: PFS according to MRD (FCM)
post consolidation (9/2015).
RVD Arm
Transplant Arm
100
100
MRD pos
MRD pos
90
90
MRD neg
80
70
70
Patients (%)
80
60
P<0.001
50
40
60
50
30
20
20
10
10
0
0
12
24
36
48
P<0.001
40
30
0
MRD neg
0
12
75
135
54
113
36
48
30
86
4
17
Months of follow-up
Months of follow-up
N at risk
MRD pos 89
MRD neg 140
24
22
72
2
14
Attal M et al Blood 2015 126:391
N at risk
MRD pos 65
MRD neg 172
57
166
43
151
AUTOLOGOUS TRANSPLANT
Who, When and How?
Transplant Ineligible vs
Transplant Eligible
Transplant Ineligible
• Poor performance status
– Elderly and frail
– Unable to perform activities of daily
living
– Decompensated comorbidity
• Social economic factors
• Patient choice
• Very low-risk disease
– Asymptomatic myeloma
– Solitary plasmacytoma
• Age should not be considered
an absolute contraindication for
SCT
Transplant Eligible
• Good performance status
• Adequate organ function
– Compensated comorbidities
• Social economic factors
– Adequate care givers
– Adequate support for transport to
and from transplant center
– Ability to comply with peritransplant
follow-up care
• Willing to proceed
Rajkumar SV, et al. Mayo Clin Proc. 2005;80(10):1371-1382. Harousseau JL, et al. N Engl J Med. 2009;360(25):2645-2654.
CR vs nCR: P = .1
CR vs PR: P = .05
nCR vs PR: P = .9
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
OS (Probability)
EFS (Probability)
Influence of Response After Induction: Superior
Outcome When CR is Achieved Before ASCT
0 12 24 36 48 60 72 84 96
Mos
CR (n = 101)
nCR (n = 96)
Lahuerta JJ, et al. J Clin Oncol. 2008;26:5775-5782.
CR vs nCR: P = .1
CR vs PR: P = .07
CR vs SD: P = .02
nCR vs PR vs SD: P = .9
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
0 12 24 36 48 60 72 84 96
Mos
PR (n = 346)
SD (n = 63)
PD (n = 26)
Outcomes with/without Pre-ASCT
Salvage
PFS
100
OS
100
P = .3470
90
P = .2622
90
80
80
70
70
60
NO SALVAGE
(n=251)
50
40
0
NO SALVAGE
(n=251)
P = NS
0
2
4
6
Years
Vij, et al. Blood. 2012;120(21): Abstract 597
30
SALVAGE
(n=324)
20
10
50
40
SALVAGE
(n=324)
30
60
20
10
P = NS
8
10
0
2
4
6
Years
8
0
10
International Myeloma Working Group (IMWG)
Consensus Recommendations for Cell Doses
• Is there an optimum CD34+ cell dose to be
infused?
– Cell doses > 3 × 106 CD34+ cells/kg associated with better outcomes[1-3]
– Studies primarily retrospective
– Recommendation: the issue of optimal CD34+ cell dosing in aHSCT for MM
requires a prospective clinical trial
• Is there an optimal dose of CD34+ cells to be
collected?
– Recommendations[1]
• Minimum target of 4 × 106 CD34+ cells/kg should be collected
• If feasible an average of 8-10 × 106 CD34+ cells/kg should be collected
– These targets allow most patients to undergo at least 2 aHSCT, each with
an optimal cell dose
aHSCT, autologous hematopoietic stem cell transplantation; MM, multiple myeloma.
[1] Desikan JR, et al. Br J Haematol. 2001;112:242-247. [2]Bensinger W, et al. J Clin Oncol. 1995;13:2547-2555.
[3] Weaver CH, et al. Blood. 1995;86:3961-3969. [4] Giralt S, et al. Leukemia. 2009;23:1904-1912
Myeloma X: High-dose Melphalan + Salvage
ASCT vs Cyclophosphamide in R/R MM
Randomized 1:1
R/R MM;
>18 mos after prior ASCT
(N = 293)
•
•
•
•
•
PAD induction
2-4 cycles
Melphalan 200mg/m2 IV + ASCT
(n = 89)
Cyclophosphamide
400mg/m2 PO/wk x12 cycles
(n = 85)
PAD induction therapy: Bortezomib + Doxorubicin + Dexamethasone 2-4 cycles
PBSC mobilization and harvesting if applicable
Removed from study if PD or CD34+ cells <2x106/kg
Primary endpoint: time to disease progression
Secondary endpoints: OR, PFS, OS, toxicity, safety, pain, QoL
Cook G, et al. Lancel Oncol. 2014;15:874-885.
Myeloma X: Response Rates with High-dose
Melphalan/2nd ASCT vs Cyclophosphamide
sCR/CR
VGPR
PR
SD
80
60
PFS
40
20
39.3%
P = .012
ek
we
C-
AS
CT
0
22.4%
ly
%Patients treated
100
• ≥ VGPR rate: 59.5% after salvage ASCT vs 47.1% after
cyclophosphamide (OR: 0.38 [95% CI: 0.2-0.7]; P = .0036)
Cook G, et al. Lancet Oncol. 2014;15:874-885.
Barriers to Autologous Transplant
Access
SOCIAL
ECONOMIC
Age
Ethnicity and race
Language
Culture
Health literacy
Patient/family attitudes
Caregiver availability
Socioeconomic status
Education
Number of wage earners
Employment status
Insurance coverage
Place of residence
Transportation
ACCESS TO
TRANSPLANT
PROVIDER
Physician referral
Provider attitudes/biases
Provider expertise
Provider diversity
Adapted from: Majhail NS, et al. Biol Blood Marrow Transplant. 2010;16(8):1070-1075.
HEALTH CARE
SYSTEM
Limited number of HCT
centers
Workforce shortage
Capacity limitations
Infrastructure
issues
Elderly Patients and Black Patients Are
Less Likely to Obtain HCT Referral
• Survey of hematologists/oncologists in the United
States about HCT referral practices
• The odds of not receiving HCT are listed in the
table
OR
(95% CI)
P
Age, 60 years vs 30 years
8.29
(5.89, 11.69)
<.001
Race, black vs white patients
2.35
(1.93, 2.87)
<.001
Characteristic
CI, confidence interval; OR, odds ratio.
Pidala J, et al. Bone Marrow Transplant. 2013;48:63–67.
Factors to be Considered in the
Treatment of Elderly Patients
•
Lower functional capacity (performance status, activities of daily living
[ADL score], cognitive function)
•
Comorbidities (renal, pulmonary, hepatic, cardiac, bone marrow)
•
Disability
•
Frailty (weakness, poor endurance, weight loss, low physical activity, slow
gait speed)
•
A higher prevalence of unfavorable prognostic factors (β2-microglobulin
≥3.5 μg/mL, albumin <3.5 g/dL, hemoblobin <10 g/dL, International Staging
System [ISS] stage III)
•
Polypharmacy
•
Lower capacity to tolerate toxicity
•
Therapy should be adjusted according to risk groups defined by age,
comorbidity, organ function, disability, and frailty
Ludwig, et al. Oncologist. 2012;17: 592–606
ROLE OF MAINTENANCE
THERAPY
Maintenance in Myeloma
• PFS advantage[1-3]
• OS improvements?[2]
• Toxicities of treatment
– Myelosuppression[3]
– Second primary malignancies[3,4]
– Quality of life
• Unclear whether all patients benefit from maintenance
• Unclear which agent and duration of therapy
[1] Attal M, et al. ASH 2013. Abstract 406. [2] McCarthy PL, et al. N Engl J Med. 2012;366:1770-1781.
[3] Attal M, et al. N Engl J Med. 2012;366:1782-1791. [4] Palumbo A, et al. Lancet Oncol. 2014;15:333-342.
The Deeper the Response, the
Longer PFS
Figure from: Bruno Paiva et al. Blood . 2015;125:3059-3068
MM MRD Testing by Flow Cytometry:
U.S. in 2015
53 year old female with myeloma
Abnormal plasma cells at diagnosis: CD19-, CD45-,
CD38 dim, CD20-, CD56+, CD81, CD27 dim
Now MRD work-up post therapy
100,000 cells 500,000 cells 1 Million cells 3 Million cells
5
3
10
2
4
10
3
10
2
10
2
10
3
10
4
10
No abnormal
plasma cells
3
10
10
2
10
3
10
4
10
5
4
10
3
10
2
10
10
5
CD19 APC
4
10
2
10
10
10
10
CD56 PC7
CD56 PC7
CD56 PC7
4
10
5
5
10
CD56 PC7
5
10
10
2
10
3
10
4
10
5
10
2
10
3
10
4
10
5
CD19 APC
CD19 APC
CD19 APC
6 abnormal
plasma cells
12 abnormal
plasma cells
30 abnormal
plasma cells
Mailankody et al. Nature Reviews. 2015;12:286–295
Features of Currently Available
Techniques to Monitor MRD in MM
MFC (≥8-color)
ASO-PCR
NGS
PET/CT
∼100%
60% to 70%
∼90%
∼100%*
Reproducibility among centers
High
High
Not reported
Moderate at MRD
Availability in individual
laboratories around the world
High
Intermediate
Limited
Intermediate
Important but not
mandatory
Mandatory
Mandatory
Important but not
mandatory
2-3 h
≥5 d (follow-up), 3-4 wk
(target identification)
≥7 d
2h
Cost per sample
∼350 USD
∼500 USD (follow-up),
∼1500 USD at diagnosis
(target identification)
∼700 USD
∼2000 USD
Sensitivity
10−5 to 10−6
10−5 to 10−6
10−6
High (4 mm)
Yes (directly; high
accuracy)
Yes
Yes
Yes
Fresh sample
Needed (<36 h)
Not needed
Not needed
NA
Patchy sample
Impacts
Impacts
Impacts
No impact
Yes
No
No
No
Ongoing
(EuroFlow/IMF)
Yes, since 15 y
(EuroMRD)
Not reported
No
Applicability
Diagnostic sample
Time
Quantitative
Global cell characterization
Standardization
Table from: Bruno Paiva et al. Blood . 2015;125:3059-3068
Imaging of Residual Disease in MM
PET/CT[1,2]
• PET may be useful
for some, but not all,
patients
PFS
(CR Pts After First-line Therapy)
1.0
PET CR
median: 90 mos
• Variability in PET
approaches across
different studies and
institutions
PFS (Proportion)
0.8
0.6
0.4
NO PET CR
median: 50 mos
0.2
P = .010
0
0
12
24
[1] Zamagni E, et al. Blood. 2011;118:5989-95. [2] Zamagni E, et al. ASH 2013. Abstract 1936.
36
Mos
48
60
72
Awaited Phase 3 Upfront
Transplant Study: BMT CTN 0702
Lenalidomide
Maintenance
Register
and
Randomize
MEL
200mg/m2
RVD x 4
Lenalidomide
Maintenance
MEL
200mg/m2
Lenalidomide
Maintenance
Primary End Point PFS
RVD: lenalidomide, bortezomib and dexamethasone
ClinicalTrials.gov Identifier: NCT01109004
CAN WE CHANGE
CONDITIONING?
Conditioning Regimens for MM
• Anti Myeloma activity
– Standard
• MELPHALAN; TBI (total body radiation)
– Investigational
• TOXICITY
–
–
–
–
Mortality (TRM) – very low for MEL 200 mg/m2
GI toxicity – dose limiting toxicity
Pulmonary Syndrome
Arrhythmias
• COST
– Days in Hospital
– Cost of procurement
– Timely availability – e.g TBI / Thiotepa in the USA
High-dose Melphalan is the Most
Frequently Used Conditioning Regimen
Regimen
MEL
88%
MEL + others (TBI)
8%
BU-MEL
1%
BU-CY
CIMBTR 2010
Frequency of Use
2.5%
Melphalan Dose for Transplant
• MEL 200 mg/m2 is standard
• MEL 200 – popularized by Royal Marsden , UK
(Cunningham, et al)
• IFM 90 randomized trial (Attal, et al) established ASCT
as standard of care
– Used MEL 140 + 8 Gy TBI as conditioning
• Retrospective EBMT study (Bjorkstrand, et al)
– OS and PFS better for MEL over MEL TBI
• IFM 95-02 Randomized study of MEL 200 vs MEL 140 +
TBI ( total body irradiation)
High-dose Melphalan (200 mg/m2) is the Proven
Conditioning Regimen for MM Survival
100
90
MEL 200
Overall Survival Rate
80
70
60
TBI + MEL 140
50
40
30
20
10
P = 0.05
0
0
Moreau, P. et al. Blood;2002;99:731-735.
10
20
30
Months
40
50
Melphalan
Bifunctional Alkylator
• L – Phenyl Alanine Mustard
• Initially synthesized in the
1950s
• Forms adducts and crosslinks
DNA
• CSF penetration ??
PK issues
• Rapidly disappears from
plasma
• T ½ – less than 8hrs
• Unstable in aqueous media
• Eliminated by spontaneous
degradation (1% / 10 min)
• Clearance is independent of
creatinine clearance ? Maybe
• RENAL IMPAIRMENT and
MEL - controversial
Intensification of MEL
MEL 220 mg/m2
(French single arm study)[1]
Escalating MEL to 300 mg/m2 [2]
• Cardiac toxicity reported
• Amifostine for protection
• No obvious superiority over
MEL 200 (historical)
• MTD was MEL 280 mg/m2
• At least 2 other MEL 280
studies in progress or
completed
• At higher MEL doses
–
–
–
–
–
Atrial Fibrillation
Hepatic Necrosis
Cardiac Death
Severe Mucositis
Increased deaths
[1] Moreau, et al. Bone Marrow Transplant. 1999;23:1003-1006. [2] Philips, et al. Biol Blood Marrow Transplant. 2004;10:473-483.
Risk-adapted Melphalan Dosing
Suggested Melphalan Dose-adjustment for Patients with Renal Impairment[1]
CrCl >15 < 60 mL/min
CrCl < 15 mL/min or the
patient is on hemodialysis
140 mg/m2
140 mg/m2
High-dose Melphalan
Dose-Reductions in Obese Patients[3]
Median
MEL
MEL 200
cases
MEL TBI
cases
Normal
Overweight
Obese
Severe Obese
Total MEL
340
370
370
376
Dose / m2
198
193
167
172
Total MEL
245
250
276
272
Dose/m2
140
137
131
125
• Melphalan dose may also be adjusted due to comorbidities
[1] Dimopoulos, et al. JCO. 2010;28:4976-4984. [2] Palumbo A, Anderson K. N Engl J Med. 2011;364:1046-1060.
3. Vogl, et al. ASH 2008. Abstract 3333.; BBMT 2011 Dec;17(12):1765
MEL 280 mg/m2 MCW Study
Comparison of Results with Previous Studies
Study
OS (years)
EFS (years)
IFM 90
4.5
2.5
IFM 94*
4.3
2.3
IFM 99-04*
3.9
2.0
S9321
4.0
1.9
TT1*
5.7
2.6
MRC 7
4.5
2.6
MEL 280 /m2
5.6
1.8
*Median OS and EFS similar to prior tandem ASCT studies TT1 and IFM94
from the pre-novel drug era
Randhawa, et al. ASMBT BMT Tandem Meetings 2013. Abstract 42.
Current Variations for High-dose MEL
• Fractionated Melphalan
– 50 mg/m2 days 1-4
– NO prospective or retrospective comparison to
standard Melphalan dosing is available
– Rationale – Reduce Toxicity
• Fractionated MEL
– 100 mg/m2 x 2 days
MEL-100 x2 vs MEL-200 X1
Response
Category
2-Day Dosing Melphalan 1-Day Dosing Melphalan
(n=185)
(n=93)
P-value
sCR
23 (12%)
8 (8%)
CR
55 (30%)
21 (23%)
VGPR
41 (22%)
21 (23%)
PR
45 (24%)
35 (38%)
sCR+CR
78 (42%)
29 (31%)
.09
ORR
164 (89%)
85 (91%)
.5
Parmar, et al. Bone Marrow Transplantation. 2014;49:761–766.
.3
MEL 200 vs Bortezomib-MEL
MEL 200 vs. Bortezomib MEL – Matched pair
BOR-MEL
(n = 46)
MEL 200
(n = 115)
P
CR
35%
11%
.001
VGPR
35%
43%
PR
26%
43%
CR+VGPR
70%
54%
Response
Mucositis Grade 3-4
Median duration Mucositis
.078
47%
9 days (2-13)
GI – diarrhea G1-2
72%
Skin Reactions G1-2
34%
Neuropathy
8%
Headache
28%
Roussel, et al. Blood. 2010;115:32-37.
Other Conditioning Regimens
Currently in Use
• Classic
– Busulfan Cyclophosphamide
– Busulfan – Melphalan
– Busulfan – Cyclophosphamide – Thiotepa
• Variations of MEL
– Escalated doses
– Fractionated MEL
• Newer
–
–
–
–
Targeted Marrow Radiation + MEL
MEL + Bortezomib
MEL + Arsenic Trioxide
MEL + Carfilzomib
Promising Investigational
Preparative Regimens
Preparative
Regimens
# of
Patients
Year(s)
CR/VGPR
Overall
Response
Overall
Survival
Toxicity
Type of
Study
Intravenous
BUMEL
102
2005-2008
CR: 17%
58%
2-year: 82%
Day 100 treatment related
mortality: 1%
Phase 1
NA
5-year OS:
59% BEAM vs
46% Mel (NS)
NA
Retrospective
BEAM vs MEL
Bortezomib
and MEL
Bortezomib
given before
or after MEL
179
54
39
NA
NA
2007
CR: 32%
≥VGPR:
70%
NA
CR: 21%
≥VGPR:
51%
Bortezomib
with iv BUMEL
20
2010
≥VGPR:
77%
Near CR or
better: 54%
MEL280 with
Palifermin
19
2007-2009
100 days:
≥VGPR:
27%
PG-free MEL
15
2010-2011
94%
Estimated 2yr: 96%
87%
Median OS:
36.7 months
100%
NA
100 days:
53%
NA
Modified from: Aljitawi, et al. J Comp Eff Res. 2012;1:57-70.
NA
NA
≥Grade 3 mucositis of upper
and lower digestive tract: 47%
1 case of grade 3 peripheral
neuropathy
≥Grade 3 mucositis: 31%
≥Grade 3 neutropenic fever:
56%
≥Grade 3 neutropenic fever:
58%
≥Grade 3 mucositis: 47%
≥Grade 3 hypo-phosphatemia:
37%
Grade 3-4 mucositis: 44%
Asymptomatic atrial fibrillation:
17%
No treatment related deaths
No unexpected toxicity
Phase 2
Phase 1/2
Phase 1-2
Phase 1
Phase 2a
Some other newer regimens
• CAR-MEL – Carfilzomib + Melphalan
• TMI – total marrow irradiation
60
MELPHALAN CHALLENGES
PK Variability
Propylene Glycol
Special Issues
MEL Pharmacokinetics
• Inter-individual variability
– Creatinine Clearance
– Fat free mass
– Hematocrit
• Higher MEL exposure—increased toxicity and
efficacy
• Unbound MEL—sensitive predictor of toxicity
and efficacy
Nath, et al. Br J Clin Pharmacol. 2010;69:484-497.
Special Issues with Melphalan:
Renal Impairment
• Melphalan 140 mg/m2 as effective as melphalan 200
mg/m2 with less toxicity in patients with renal impairment[1]
– Mucositis: 93% (MEL-200) vs 67% (MEL-140); P= .04
– Pulmonary complications
• 57% (MEL-200) vs 17% (MEL-140); P=.007
• 53% (dialysis-dependent) vs 19%; P= .02
– Cardiac complications
• Atrial dysrhythmias significantly more common in MEL-200 group
• 21% (MEL-200) vs 0 (MEL-140); P = .07
– Neurological complications
• More common in MEL -200 group (36% vs 27%, P = .6)
• Significantly more common in dialysis group (47% vs 6%; P = .005)
1. Badros A, et al. Br J Haematol. 2001; 114:822–829.
Special Issues with Melphalan:
Renal Impairment
• Pharmacokinetics of MEL are no different in renal-impaired patients
BUT
– More leukopenia noted in patients with renal impairment in early studies
– MEL-200 poorly tolerated by patients with renal dysfunction
– 60% MEL can be recovered from urine
• Auto-SCT should be performed early in the disease course before
renal failure becomes irreversible1
– MEL-140 is associated with less toxicity and equal efficacy to MEL200 in patients with renal failure
– Renal failure patients with low albumin had a higher treatment-related
mortality and may do better with even lower doses of MEL (70 ± 100
mg/m2)
1. Badros A, et al. Br J Haematol. 2001; 114:822–829.
Cryotherapy Prevents OM in MM
Patients Receiving High-dose Melphalan
• 117 MM patients randomized to receive cryotherapy (CT) + saline
solution (SS) mouth rinse, SS alone, or supersaturated calcium
phosphate rinses[1]
– No OM: 90% of patients in the CT group vs 36% (supersaturated
calcium phosphate rinse) and 34% (SS) (P < .0001)
– No grade 3-4 OM in the CT group
• Meta analysis of 7 RCTs including 458 patients with hematological
malignancies undergoing HSCT[2]
– Oral cryotherapy significantly reduced
• The incidence of severe OM
• OM severity
• The duration of total parenteral nutrition use
• The length of hospitalization
[1] Toro, et al. BBMT . 2014;20 :S204 - S205. [2] Wang, et al. PLoS One. 2015; 10(5): e0128763.
Special Issues with Melphalan:
Administration
• When reconstituted, Melphalan rapidly hydrolyzes ~1%
every 10 minutes
• Manufacturer recommendations:
– Dilute dose in NS to </= 0.45 mg/mL and infuse over at least 15
minutes
– Complete the infusion within 60 minutes of reconstitution of the vial
• BMT programs should verify that infusions have ended
before the Melphalan expiration time/date
Special Issues with Melphalan:
Administration
• Example: Patient 2.1 m2 ordered 200 mg/m2
• A dose of 420 mg diluted in 933 mL NS (0.45 mg/mL)
must infuse @ 1867 mL/h administer the dose over 30
minutes
• The dose is prepared as 2 bags (466.5 mL each) to
infuse simultaneously with each pump @ 933 mL/h
– A typical infusion pump has a maximum infusion rate of 999
mL/h
Special Issues with Melphalan:
Stability
• Highly unstable in solution
• 10% per loss of activity/ hr
• Propylene Glycol (PG)
– Additive to MEL
– Toxic in the ICU setting when given as continuous infusion
– Rate of PG infusion exceeds FDA guidelines when MEL bolus
given currently
CE-Melphalan (Propylene Glycol-free):
Phase 2a Pharmacokinetic Study
Melphalan Plasma Concentration

Bioequivalence demonstrated
Concentration (ng/mL)
• Cmax:
• AUC 0-t:
• AUC-inf:
112%
110%
110%
Successful myeloablation (Day +3)
 Successful engraftment (Day +11)

CE-Melphalan HCl
Melphalan
No additional toxicities:
 Treatment-emergent AEs (100%)
– Common AEs: nausea, vomiting,
hypokalemia, fatigue, decreased
appetite, dizziness, and
thrombocytopenia

Treatment-emergent SAEs (29%)
– Febrile neutropenia, mucosal
inflammation, sepsis and extreme
fatigue
Aljitawi, et al. Bone Marrow Transplantation. 2014;49:1042–1045.
Propylene Glycol-free Melphalan: New IV
Formulation for MM Patients Undergoing HSCT
•
Patients received 200 mg/m2 of i.v. melphalan as 2 doses of 100 mg/m2 each on
days −3 and −2 followed by a day of rest before ASCT was performed on day 0
–
Patients were evaluated for safety and response through day +100
Hari, et al. Biol Blood Marrow Transplant. 2015 Aug 29. [Epub ahead of print]
Propylene Glycol-free Melphalan: New IV
Formulation for MM Patients Undergoing HSCT
MM Response Assessment*
Overall response (sCR, CR, VGPR, or PR)
Value
61 (100%)
sCR
8 (13%)
CR
5 (8%)
VGPR
37 (61%)
PR
11 (18%)
Stable disease
0 (0%)
Progressive disease
0 (0%)
• Myeloablation (day 5) and engraftment (day 13) were achieved with no mortality
(day 100)
• Low grade 3 mucositis and stomatitis incidence
• No grade 4 mucositis or stomatitis
*Independent Reviewer Assessment of response at day +100 after ASCT
Figure from: Hari, et al. Biol Blood Marrow Transplant. 2015 Aug 29. [Epub ahead of print]
ALLOGENEIC
TRANSPLANTATION
High-Risk or Early-Relapse MM:
BMT CTN 1302
Ages 18-65;
Upfront High Risk MM, or
Early Failures;
8/8 match donor
Fludarabine/Melphalan/Bortezomib
Allo HCT
R
Ixazomib
ClinicalTrials.gov Identifier:NCT02440464
60-120
days
Placebo
12 cycles
CONCLUSIONS
“Improving the Modern Triple Sequence”
Induction AutoHCT and Maintenance
Maintain with
Lenalidomide
or Bortezomib
RELAPSE MONITORING
Consolidation
w/Transplant
ONGOING THERAPY
3 Drug
Induction
CONSOLIDATE
INITIAL
• Randomized trials – Achievement of VGPR/CR or better
• Emerging data – PCR or Multicolor Flow based remissions
TREATMENT
of RELAPSE
Biochemical
or
Clinical
Better
Induction
VGPR before
ASCT
MRD directed ?
When to stop ?
Implications of prolonged therapy
Induction
4 cycles
Consolidation
2 cycles
VTD +
VTD +
Dara
Dara
HDM
R
ASCT
VTD
Slide Courtesy of P Sonneveld
VTD
Stratify by: dara treatment, response, MRD status
Hovon/IFM: Daratumumab Trial in
Transplant-eligible NDMM
MaintenanceUntil
progression
Dara
R
Observation
Endpoints:
• sCR
• PFS, OS
R, randomize; V, bortezomib; T, thalidomide; D, dexamethasone; Dara, daratumumab; ASCT, autologous stem-cell transplant;
sCR, stringent complete response; PFS, progression-free survival; OS, overall survival
Recently Approved Agents for
Treatment of MM
Agent
Daratumumab
Elotuzumab
FDA Approval
11/2015: MM pts who
received ≥3 prior treatments
11/2015: For use in
combination with
lenalidomide/dexamethasone
to treat MM pts who have
received 1 to 3 prior
medications
Type
Human IgG1ĸ
mAb that binds to
a unique epitope
on CD38
Humanized IgG1
mAb targeted
against SLAMF7
Mechanism
Induces lysis
of CD38expressing
tumor cells
Selectively
targets and
kills SLAM
F7-expressing
myeloma cells
Clinical Status
•
At least 5 clinical trials underway
in both untreated and R/R MM
patients
•
Phase 2 trials are evaluating
adding elotuzumab to
lenalidomide/low-dose dex
(ELOQUENT-2, ELOQUENT-1),
and bortezomib-dex
Phase 1/2 study of lenalidomidedex-bortezomib ± elotuzumab in
patients with newly diagnosed,
high-risk myeloma
•
•
Ixazomib
(MLN9708)
11/2015: For use in
combination with
lenalidomide/dexamethasone
to treat MM pts who have
received ≥ 1 prior
medications
2nd-
Oral
generation
proteasome
inhibitor
Potently,
reversibly,
and
selectively
inhibits the
proteasome.
•
Phase 3 study in R/R MM
(TOURMALINE-MM1) or newly
diagnosed myeloma
(TOURMALINE-MM2)
Additional clinical trials in relapsed
and/or refractory myeloma, in
newly diagnosed disease, as
maintenance therapy, and in
asymptomatic (smoldering)
myeloma