Transcript transplant bone marrow

Considerations for Optimizing
Transplant in Multiple Myeloma
Patient Management
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Considerations for Optimizing
Transplant in Multiple Myeloma
Patient Management
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
Hallmarks of MM
Lytic lesions,
Pathologic fractures,
Hypercalcemia
Anemia
Plasma cell
Bone destruction
Marrow infiltration
MULTIPLE MYELOMA
Monoclonal globulins
Urine: Renal failure
Blood: Hyperviscosity,
Cryoglobulins,
Neuropathy
Tissue: Amyloidosis
Carr et al, 1999.
Reduced globulins
Infection
Incidence and Mortality by
Race/Ethnicity and Gender
Male
Age,[1]
years
(range)
All Races
Female
Incidence*[2]
Mortality*[2]
7.9
4.2
Age,[1]
years
(range)
Incidence*[2] Mortality*[2]
5.1
2.7
White
70 (61-78)
7.5
4.0
72 (62-81)
4.5
2.4
Black
65 (57-74)
15.1
7.6
67 (57-76)
11.2
5.3
Asian/Pacific
Islander
69 (60-77)
4.6
2.2
70 (59-78)
3.0
1.4
4.6
3.2
4.2
2.3
7.3
3.5
4.8
2.3
American
Indian/Alaska
Native
Hispanic
65 (55-74)
66 (56-76)
*Age-adjusted rates per 100,000
[1] Costa et al. Biol Blood Marrow Transplant. 2015 Apr;21:701-706.
[2] SEER Stat Fact Sheets: Myeloma. Available at http://seer.cancer.gov/statfacts/html/mulmy.html. Accessed August 2015.
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
ASSESSING AND MONITORING
RESPONSE TO THERAPY
MRD Assessment in MM
• Remains a research tool
– Indications are that lower levels of MRD predict for better
outcomes
– Can contribute to better definition of response
– Potential to monitor efficacy of therapy
• Best, easily exportable method
– Optimal time point is still under investigation
• Even patients who achieve MRD state can relapse, so all
may not be able to stop therapy
• Unsure if changing therapy based on depth of response
alters survival outcomes
• Unsure of next steps for MRD
Sherrod, et al. Bone Marrow Transplant. 2015;Jul 20. [Epub ahead of print]
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
New Molecular MRD Tests Under
Development for MM
ASO-PCR
VDJ Sequencing
Exome
Sequencing
Mass
Spectrometry
Universal
Assay
No
(patient specific
primers)
Yes
“Yes/No”
Yes
Sensitivity
10-5
10-6
Unknown
Unknown
Bone marrow
aspirates
Bone marrow
aspirates or
plasma
Bone marrow
aspirates or
plasma
Urine or serum
Inter-observer
Variation
Likely
Unknown
Unknown
Likely low
Study Clonal
Evolution
No detection
Limited detection
Yes
Yes
Likely
Maybe overcome
with plasma
samples
Maybe overcome
with plasma
samples
Likely
Sample
Analyzed
Can Overcome
Sampling Error
Mailankody, et al. Nature Reviews Clinical Oncology. 2015;12:286–295.
AUTOLOGOUS TRANSPLANT
When and How?
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
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.
Indications for HSCTs in the US—
2012
Pasquini MC, Zhu X. 2014 CIBMTR Summary Slides. Available at: http://www.cibmtr.org
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 (200 mg/m2) is the
Best 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
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
Suggested Age-adjusted Dosing of Melphalan[2]
Melphalan
Age <65 years
Dose level 0
Age 65–75 years
Dose level −1
Age >75 years
Dose level −2
0·25 mg/kg
days 1–4 every 4–6
weeks
0·18 mg/kg
days 1–4 every 4–6
weeks
0·13 mg/kg
days 1–4 every 4–6
weeks
• 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.
Risk-adapted Melphalan Dosing
Dose-Reductions in Obese Patients
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
Vogl, et al. ASH 2008. Abstract 3333.
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.
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
Phase 1
Phase 2a
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%
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.
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
• Up to 50% of newly diagnosed patients have a decrease in creatine
clearance and ∼9% require dialysis because of severe renal
impairment [1]
• No change in the pharmacokinetics of high-dose melphalan in
patients with renal failure[2,3]
– Outcome similar to patients with preserved renal function
• Similar results observed in a series of 81 MM patients with renal
failure (38 patients on dialysis)[4]
– Renal failure did not affect the quality of stem cell collections or
engraftment
– Median OS >52 months (similar to patients with normal renal function)
– CR rate was not significantly affected by dialysis dependence (37%
in dialysis patients vs 33% in the non-dialysis group; P=.07)
[1] Knudsen L, et al. Eur J Haematol.1994; 53: 207–212. [2] Tricot, et al. Clin Cancer Res. 1996;2:947-952. [3] Jagannath, et al. Blood.
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.
Special Issues with Melphalan:
Mucositis
• MEL-ASCT is associated with severe oral mucositis
(OM)
– OM develops in 45%-75% of patients[1,2]
– Predictors of severe OM[1]
• High serum creatinine
• High mg/kg melphalan
– Severe OM risk and/or duration was significantly
associated with:[2]
• Higher chemotherapy dose/kg of body weight
• Poor performance status
• NOT related to age
[1] Grazziutti ML,et al. Bone Marrow Transplant. 2006;38(7):501-506. [2] Blijlevens N, et al. J Clin Oncol. 2008;26(9):1519-1525.
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)
• FDA Approved March 2016
– 1st drug to gain FDA approval for the high-dose conditioning indication in MM
• Captisol-enabled melphalan (CE-melphalan) approved for two indications
in MM
– High-dose conditioning treatment prior to HSCT for patients with MM
– Palliative treatment for MM patients who are not candidates for oral therapy
• Approval based on multicenter, open-label, phase 2b study of 61 patients
(5 relapsed prior to HSCT; 56 with newly diagnosed disease)1
– 200 mg/m² CE-melphalan, administered in 100 mg/m² doses on day 3 and
day 2 before transplantation
– ORR:95%; CR: 31% (16% stringent CRs) [as determined by investigator
assessment]
– No treatment-related mortality; no new safety signals
1. Hari, et al. Biol Blood Marrow Transplant. 2015;21:2100-2105.
44
CE-Melphalan (Propylene Glycol-free):
Phase 2a Pharmacokinetic Study
Results from the Phase 2a study (N=24)
• CE-Melphalan is bioequivalent to standard Melphalan
– Propylene glycol-free
– More stable following reconstitution
– Longer infusion times / higher doses possible with CE-Melphalan
(propylene glycol-free) could improve response to treatment
• The efficacy and safety profile were consistent with that
already established for high-dose Melphalan
conditioning with ASCT for MM
– 100% of patients achieved myeloablation and engraftment
– Most frequent AEs included fatigue, nausea, and hypokalemia
Aljitawi, et al. Bone Marrow Transplantation. 2014;49:1042–1045.
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]
AUTOLOGOUS
TRANSPLANTATION
Transplant Vs Conventional Therapy
Prospective, Randomized Studies
Evaluating HSCT for the Treatment of MM
Study
Barlogie 2006[1]
Bladé 2005[2]
Fermand 2005[3]
Palumbo 2004[4]
Child 2003[5]
Segeren 2003[6]
Attal 2003[7]
Attal 1996[8]
Treatment
n
Chemotherapy
255
HDT + HSCT
261
Chemotherapy
83
HDT + HSCT
81
Chemotherapy
96
HDT + HSCT
94
Chemotherapy
99
HDT + HSCT
95
Chemotherapy
196
HDT + HSCT
197
Chemotherapy
129
HDT + HSCT
132
Single HSCT
199
Double HSCT
200
Chemotherapy
100
HDT + HSCT
100
OS Benefit
EFS Benefit
NS
NS*
NS
NS*
NS
NS
Yes
Yes
Yes
Yes*
NS
NS
Yes
Yes
Yes
Yes
*Progression-free survival.
All studies included were published between 1996 and 2006.
OS, overall survival; EFS, event-free survival HDT, high-dose chemotherapy; HSCT, haematopoietic stem cell transplant; NS, not significant.
[1] Barlogie B, et al. J Clin Oncol 2006;24:929–936. [2] Bladé J, et al. Blood 2005;106:3755–3759. [3] Fermand JP, et al. J Clin Oncol 2005;23:9227–9233.
[4] Palumbo A, et al. Blood 2004;104:3052–3057. [5] Child. JA, et al. N Engl J Med 2003;348:1875–1883. [6] Segeren CM, et al. Blood 2003;101:2144–2151. 7.
Attal M, et al. N Engl J Med. 2003;349:2495–2502. [8] Attal M, et al. N Engl J Med. 1996;335:91–97.
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.
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.
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
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)
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.
Modern Induction + AHCT
Induction
Induction
Post AHCT
>VGPR (%)
>VGPR (%)
Median PFS and OS
HOVON-50
TAD
37
66
34 months / 73 months
Lokhorst et al.
VAD
18
54
25 months / 60 months
Vel/Dex
38
54
36 months/ 3-year OS: 81
Harousseau et al.
VAD
15
37
30 months / 77% @ 3 yrs
GIMEMA MMY-3006
VTD
62
87
2yr PFS: 85% / OS: 96%
TD
31
69
2yr PFS 75% / OS: 91%
HOVON65 / HD4
PAD
42
62
PFS 35 mo
Sonneveld et al.
VAD
14
36
PFS 28 mo
IFM 2007-02
Vel/Dex
36
58
PFS 30 mo
Moreau et al.
VtD
49
74
IFM 2005-01
Cavo et al.
PFS 26 mo
52 of 53 pts progression
CFZ, LEN,
free after a median of 9.7
Zimmerman et al
78
97
and DEX
months
Similar data available
for Carfilzomib Thalidomide Combination
Hari P and McCarthy. BBMT. 2013;19(1 Suppl):S20-5. Zimmerman, et al. ASCO 2015. Abstract 8510,
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
AUTOLOGOUS
TRANSPLANTATION
Early vs Late HCT
Upfront vs Delayed Transplant
70
PSCT (early)
PSCT (late)
60
Months
50
40
30
20
10
0
Median OS
Median EFS
TWSTT
PSCT = peripheral stem cell transplant; TWISTT = time without symptoms, treatment, and treatment toxicity.
Fermand J, et al. Blood. 1998;92:3131-3136
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
Ongoing 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
ALLOGENEIC
TRANSPLANTATION
ASCT vs Allogeneic SCT
Trial
Type of SCT
N
Garban et al, 2006
IFM 99-03 & 99-04
Auto-Auto
or
Auto-Allo
284
Bruno et al, 2007
Auto-Auto
or
Auto-Allo
Rosinol et al, 2008*
PETHEMA/GEM 2000
Auto-Auto
or
Auto-Allo
Kirshnan et al, 2011
BMT CTN 0102
Auto-Auto
or
Auto-Allo
Bjorkstrand et al, 2011
Auto-Auto
or
Auto-Allo
Median EFS
(months)
P Value
35
.07
31.7
35
29
54
.02
.01
35
80
26
58
110
.40
.90
19
NR
46% PFS at 3-years
survival
43% PFS at 3-years
survival
80% at 3-years
survival
7% at 3-years
survival
19% PFS at 60
months
357
39% PFS at 60
months
P Value
47.2
NS
162
710
Median OS
(months)
.671
.004
.191
60% at 60
months
.753
63% at 60
months
*Only patients with suboptimal response (<nCR) first ASCT were considered for a second transplantation.
NR = not reached.
Garban F, et al. Blood. 2006;107:3474-3480. Bruno B, et al. N Engl J Med. 2007;356:1110-1120. Rosinol L, et al. Blood.
2008;112:3591-3593. Krishnan A, et al. Lancet Oncol. 2011;12:1195-1203. Bjorkstrand B, et al. J Clin Oncol. 2011;29:3016-3022.
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
Multiple Myeloma: US Cooperative
Group Trials—Feb 2015
• CALGB 100104 Len vs Pl
• CTN 0702 Phase 3
• S0777- Rd vs VRd
• E1A06 - MPT vs. MPR
• E3A06 Phase 2
Asymptomatic
& Early
•
E3A06 R vs.
Obs
•
A061202
Plasmacytoma
Z vs ZI
Stem Cell
Transplant
Induction
Rx
•
•
•
E1A11: CRd vs VRd
S1211: VRd vs. VRd Elo
BMTCTN 1302: High-risk Allo
•
DETERMINATION:
RVD Early vs Late HSCT
A:Rd vs Rd Dara for HSCT
Eligible & ineligible
Correlative sciences for
HSCT ineligible
•
•
Relapse
Maintenance
Non
Transplant
Consolidation
•
•
•
•
•
•
•
E1A11 R 2 yrs vs PD
•
BMT CTN 1401
Len vs Len DC Vaccine
•
post Auto
Extension of R 0702
S:R vs RI post Auto?
•
A: R Dara vs R post
HSCT?
S1304: K high and
low dose
A061202
PDI vs PD
RRMM: no prior
BMT
PDI vs HSCT?
Relapse after
ASCT PDI vs no
PDI consolidation
P and I
maintenance?
APPENDIX OF ADDITIONAL
SLIDES FOR CUSTOMIZING
PRESENTATIONS
MYELOMA OVERVIEW
Multiple Myeloma:
A Plasma Cell Malignancy
• Multiple myeloma is a B-cell
malignancy derived from antibodyproducing plasma cells in the bone
marrow
• Myeloma cells crowd out and
interfere with the development and
function of normal cells in the bone
marrow
• The abnormal accumulation of
myeloma cells in the bone marrow
and production of M-protein have
direct and indirect effects on the
blood, skeleton, and kidneys
Durie. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation. 2011/2012
edition; Multiple Myeloma Research Foundation. Multiple Myeloma Disease Overview. 2011.
What Is Multiple Myeloma?
• Cancer of the plasma cells in bone marrow
• Growth of myeloma cells
– Disrupts normal bone marrow function
– Reduces normal immune function
– Results in abnormal production and release of
monoclonal protein into blood and/or urine
– Destroys and invades surrounding bone
Bone marrow
Barlogie et al. In: Williams Hematology. 7th ed. 2006:1501. Durie. International Myeloma Foundation. 2007. www.myeloma.org.
Incidence Patterns of MM by Race
and Age: 1973-2005 (SEER-9)
Age Distribution by Race
Figures from: Waxman, et al. Blood. 2010;116:5501-5506.
Age-Specific Incidence
Incidence of MM according to
Gender, Race/Ethnicity, and Age
100
90
80
Cases /100,000
70
60
white male
50
white female
black male
40
black female
30
20
10
0
25-29
years
30-34
years
35-39
years
Figure courtesy of Drs. Costa and Hari.
40-44
years
45-49
years
50-54
years
55-59
years
60-64
years
65-69
years
70-74
years
75-79
years
80-84
years
Age at Diagnosis of MM According
to Gender and Race/Ethnicity
Cumulative percentage of cases
100
90
80
70
60
Black women, 67
50
White men, 70
Black men, 65
White women, 71
40
30
20
10
0
0
20
40
60
Years
Figure courtesy of Drs. Costa and Hari.
80
100
120
AHPCT Utilization in MM According
to Gender and Race/Ethnicity
Number of Newly Diagnosed Cases
25000
Number of First AHPCT
25000
22357
20000
20000
17839
15000
15000
9618
10000
10000
6638
4264
5000
3246
2044
847 957
4820
4081
5000
2850
2710
1369
1025 643
212 237
0
1903
616 592
228 165
0
18-49
Black men
50-64
Black women
Figure courtesy of Drs. Costa and Hari.
65+
18-49
White men
50-64
White women
65+
1239
MM Risk Categories
Risk Factors
FISH
Cytogenetics
β2-microglobulin*
PCLI
Gene expression profile
Standard Risk (80%)
(Expected OS: 6-7 Yrs)
High Risk (20%)
(Expected OS: 2-3 Yrs)
t(11;14), t(6;14)
del(17p), t(4;14)*
t(14;16), +1q21
Hyperdiploidy
Hypodiploidy
del(13q)
Low (< 3.5 mg/L)
High (≥ 5.5 mg/L)
< 3%
High (≥ 3%)
Good risk
High risk
*Patients with t(4;14), β2-microglobulin < 4 mg/L, and Hb ≥ 10 g/dL
may have intermediate-risk disease.
Dispenzieri A, et al. Mayo Clin Proc. 2007;82:323-341. Kumar SK, et al. Mayo Clin Proc. 2009;84:1095-1110. Mikhael JR, et al.
Mayo Clin Proc. 2013;88:360-376. NCCN. Clinical practice guidelines in oncology: multiple myeloma. v.1.2015. Chng WJ, et al.
Leukemia. 2014;28:269-277.
History of MM
1844
First
documented
case
1845
Abnormal
urine protein,
later termed
Bence Jones
protein
1975
Durie-Salmon
staging system
1939
Serum
protein spike
identified
1895
Description of
plasma cells
1956
Light chains
types (later
termed kappa
and lambda)
recognized
1928
First large
case series
of MM
2012
Carfilzomib
2005
International
Staging System
Cytogenetic
classification
2015
Panobinostat
1840 1850 1860 1870 1880 1890 1900 1910 1920 1930 1940 1950 1960 1970 1980 1990 2000 2010
1845
Steel and
quinine
1844
Rhubarb and
orange peel
1947
Urethane
1958
Melphalan
1962
Corticosteroids
1983
ASCT
1999
Thalidomide
2002
Bortezomib
Lenalidomide
2013
Pomalidomide
2015
Elotuzumab
Daratumumab
Ixazomib
Novel agents in development
Kyle. Blood. 2008;111:2962; Durie. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation; 2011/2012
edition; KYPROLIS [package insert]. Onyx Pharmaceuticals, Inc. July 2012; POMALYST [package insert]. Celgene Corporation. February 2012.
MM is Characterized by a Pattern
of Remission and Relapse
Asymptomatic
Symptomatic
Relapsing
Refractory
Disease Burden
Remission duration decreases
with each line of therapy
Active
Myeloma
Relapse
Remission
MGUS or
Indolent
Myeloma
//
Front-line
Therapy
//
2nd or 3rd-line
Therapy
Durie. Concise Review of the Disease and Treatment Options: Multiple Myeloma. International Myeloma Foundation; 2011/2012 edition;
Kumar. Mayo Clin Proc. 2004;79:867.
Diagnostic Workup for MM
Test
•
•
•
•
•
Serum protein electrophoresis and immunofixation
Serum immunoglobulins quantitative
Serum free light chain assay
Total serum protein, serum albumin, creatinine, calcium, electrolytes, lactate
dehydrogenase, β2-microglobulin
Hemoglobin, white blood cell count, differential count, platelet count
•
•
Urine protein electrophoresis and immunofixation
24 h urine for total protein, light chains
Bone marrow
•
•
Aspirate and biopsy for plasma cell count, morphology, amyloid*
Cytogenetic evaluation and fluorescence in-situ hybridisation for the detection of
del 13, del 17p13, t(4;14), t(11;14), t(14;16), 1q+
Bones
•
Skeletal survey (conventional x-ray) or low-dose CT scan without contrast
Whole body
•
•
MRI*, PET-CT*, CT*
Tissue biopsy for solitary or extraosseous plasmacytoma*
Additional Tests
•
•
Heavy light chains
Gene expression profile
Blood
Urine
*Useful under some circumstances.
Röllig, et al. Lancet. 2015;385:2197-2208.
Overview of MM
MGUS
Smoldering MM
Clonal protein in serum Clonal protein in serum
or urine
or urine, and
Plasmocytosis
(10%-60%) in BM or
M spike ≥ 3g/dL in
serum or ≥ 500 mg/24h
in urine
No routine treatment
Slide courtesy of Dr. Costa.
Symptomatic MM
Clonal protein in serum or urine
Clonal plasmocytosis in BM or tissue
Morbidity or Imminent threat of
morbidity
Hypercalcemia
Renal insufficiency
Anemia
Bone lesions
Clonal PC in marrow ≥60%.
Involved:uninvolved SFLC >100
>1 focal lesions on MRI
Treatment usually indicated
TREATMENT PARADIGM AND
GOALS
Common Approach to Initial
Treatment of MM
Patients with Newly Diagnosed MM Needing Systemic Therapy
Transplant-eligible Patient
Three-drug Regimen
• Bortezomib,
cyclophosphamide,
dexamethasone
• Bortezomib,
doxorubicin,
dexamethasone*
• Bortezomib,
lenalidomide,
dexamethasone*
• Bortezomib,
thalidomide,
dexamethasone*
Two-drug Regimen
• Lenalidomide,
dexamethasone*
• Bortezomib,
dexamethasone*
Single Autologous SCT‡
Transplant-ineligible Patient
Three-drug Regimen
• Melphalan,
prednisone,
bortezomib*
• Melphalan,
prednisone,
thalidomide*
Two-drug Regimen
• Lenalidomide,
dexamethasone*
• Bortezomib,
dexamethasone*
• Melphalan,
prednisone*†
• Bendamustine,
prednisone*†
• Dexamethasone†
Consider Maintenance
. *Treatment combinations with evidence from randomized-controlled trials
†Melphalan + prednisone, bendamustine + prednisone, or dexamethasone can be used if novel drugs are not available or contraindicated
‡Consider allogeneic stem-cell transplantation in young patients with deletion 17p and HLA-identical siblings.
Röllig, et al. Lancet. 2015;385:2197-2208.
Common Approach to Treatment of
Relapsed/Progressive MM
Patients with Relapsed or Progressive MM
Transplant-eligible Patient
Previous SCT
>12-18 months ago
Previous SCT
<12-18 months ago
Transplant-ineligible Patient
Previous treatment
without novel drugs
Previous treatment
with novel drugs
<6-9
months
ago
Consider re-induction
and Autologous SCT
Change
regimen
Novel drug +/- steroid and +/- alkylator or anthracycline
*Available clinical trial applicable to all patients
Röllig, et al. Lancet. 2015;385:2197-2208.
>6-9
months
ago
Consider
repeating
previous
regimen
Indications for Hematopoietic SCT
in the US, 2012
Pasquini MC, Zhu X. Current uses and outcomes of hematopoietic stem cell transplantation: 2014 CIBMTR
Summary Slides. Available at: http://www.cibmtr.org
MM Treatment Lines for Transplant
Eligible Patients
First-line Treatment
Initial
IMID:Thal-Len
Proteasome Inhibitor: Bor-Car
Steroids: Dex-Pred
Alkylator: Cyclo-Mel
Anthracycline: LipoDnr-Adr
SCT/
Consolidation
SCT or
non-SCT consolidation
Maintenance
Maintenance
Observation
IMID:Thal-Len
Proteasome Inh-Bor
Steroids:Dex-Pred
Relapsed
Rescue
IMID:Thal-Len-Pom
Proteasome Inh:Bor-Car
Steroids: Dex-Pred
Alkylators:Mel-Cy-Benda
HDACi: Panobinostat
Anthracycline
Investigational
SCT at relapse / Second SCT
.
Bor/Dex = bortezomib, dexamethasone; Bor/Dex/Dox = bortezomib, dexamethasone, doxorubicin; Bor/Thal/Dex = bortezomib,
thalidomide, dexamethasone; Len/Dex = lenalidomide, dexamethasone; SCT = stem-cell transplant; Thal/pred = thalidomide,
prednsione; Bor/Liposomal/Dox = bortezomib, liposomal doxorubicin; HDACi= histone deacetylase inhibitor
NCCN, 2015
NCCN Guidelines for Initial
Therapy of Transplant Candidates
Preferred Regimens
• Bortezomib/dexamethasone
• Bortezomib/cyclophosphamide/
dexamethasone
Other Regimens
• Carfilzomib/lenalidomide/
dexamethasone
• Dexamethasone
• Bortezomib/doxorubicin/
dexamethasone
• Liposomal doxorubicin/
vincristine/dexamethasone
• Bortezomib/lenalidomide/
dexamethasone
• Thalidomide/dexamethasone
• Bortezomib/thalidomide/
dexamethasone
• Lenalidomide/dexamethasone
NCCN (National Comprehensive Cancer Network) Guidelines. Multiple Myeloma. V.2.2016.
NCCN Guidelines for Initial Therapy
of Non-Transplant Candidates
Preferred Regimens
Other Regimens
•
Bortezomib/dexamethasone
•
Dexamethasone
•
Bortezomib/cyclophosphamide/
dexamethasone
•
Liposomal doxorubicin/
vincristine/dexamethasone
•
Bortezomib/lenalidomide/
dexamethasone
•
Melphalan/prednisone
•
Thalidomide/dexamethasone
•
Lenalidomide/low-dose
dexamethasone
•
Vincristine/doxorubicin/
dexamethasone
•
Melphalan/prednisone/bortezomib
•
Melphalan/prednisone/lenalidomide
•
Melphalan/prednisone/thalidomide
NCCN (National Comprehensive Cancer Network) Guidelines. Multiple Myeloma. V.2.2016.
NCCN Guidelines for Previously
Treated MM
Preferred Regimens
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
•
Repeat induction regimen if relapse at > 6 months
Bortezomib
Bortezomib/dexamethasone
Bortezomib/cyclophosphamide/ dexamethasone
Bortezomib/lenalidomide/ dexamethasone
Bortezomib/liposomal doxorubicin
Carfilzomib
Carfilzomib/dexamethasone
Carfilzomib/lenalidomide/ dexamethasone
Cyclophosphamide/lenalidomide/dexamethasone
Dexamethasone/cyclophosphamide/etoposide/cisplatin
Dexamethasone/thalidomide/cisplatin/doxorubicin/cyclophosphamide/etoposide±
bortezomib
High-dose cyclophosphamide
Lenalidomide/dexamethasone
Panobinostat/bortezomib/dexamethasone
Pomalidomide/dexamethasone
Thalidomide/dexamethasone
NCCN (National Comprehensive Cancer Network) Guidelines. Multiple Myeloma. V.2.2016.
NCCN Guidelines for Previously
Treated MM
Other Regimens
• Bendamustine
• Bortezomib/vorinostat
• Lenalidomide/bendamustine/dexamethasone
NCCN (National Comprehensive Cancer Network) Guidelines. Multiple Myeloma. V.2.2016.
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.
NCCN Guidelines for MM
Maintenance Therapy
Preferred Regimens
Other Regimens
• Bortezomib
• Bortezomib + prednisone
• Lenalidomide
• Bortezomib + thalidomide
• Thalidomide
• Interferon
• Steroids
• Thalidomide + prednisone
NCCN (National Comprehensive Cancer Network) Guidelines. Multiple Myeloma. V.2.2016.
Maintenance Therapy in MM:
Summary
• Median PFS after ASCT has improved without
maintenance using better induction
• Maintenance with novel agents further improves PFS
– Toxicity issues are critical
• OS results are improved in some studies of thalidomide,
lenalidomide, and bortezomib maintenance
• Decisions regarding maintenance will be influenced by
– Incidence of toxicity such as secondary cancers
– Outcome after myeloma progression
– Identification of subgroups most likely to benefit
ASSESSING AND MONITORING
RESPONSE TO THERAPY
The Deeper the Response, the
Longer PFS
Figure from: Bruno Paiva et al. Blood . 2015;125:3059-3068
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
Methods for Assessing MRD to
Predict Outcome
8-color Flow[1]
Next Gen Sequencing[2]
TTP (CR Patients)
1.0
100
0.8
80
0.6
60
0.4
MRD –
MRD +
Overall
0.2
0
TTP (%)
PFS (proportion)
PFS
P = .001
n = 26
40
n = 36
MRD –
MRD +
20
0
0
6
12 18 24 30 36 42
Mos
0
50
100
150
Mos
[1] Roussel M, et al. J Clin Oncol. 2014;32:2712-2717. [2] Martinez-Lopez J, et al. Blood. 2014;123:3073-3079.
Response to Therapy in MM
Patients
1 × 1012
Number of
Myeloma
Cells
At diagnosis
Partial response –
50% reduction in M protein
Near complete remission –
immunofixation positive only
Complete remission –
immunofixation negative
Nonquantitative ASO-PCR
1 × 108
1 × 106
MRD
1 × 104
Rajkumar, et al (IMWG consensus criteria). Blood. 2011;117:4691–4695.
Quantitative ASO-PCR
High quality flow cytometry
Deep sequencing
MM MRD Testing by Flow Cytometry:
U.S. in 2014
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
STEM CELL MOBILIZATION
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
Outcomes of Standard Mobilization
Regimens
• Mobilization failure rate for MM is approximately
5%
• A more recent retrospective review of the Mayo
clinic database from December 2007 to January
2011 showed a failure rate of 14% in MM patients
– Failure was defined as collection of <2 x 106 CD34+
cells/kg
Bensinger W, et al. Bone Marrow Transplant. 2009;43(3):181-195. Pavone V, et al. Bone Marrow Transplant. 2006;37:719-724.
Pusic I, et al. Biol Blood Marrow Transplant. 2008;14:1045-1056. Gertz MA, et al. Bone Marrow Transplant. 2010;45(9):13961403.
Mobilization Strategies Used in
Clinical Practice
Approved
• Hematopoietic growth factors
– G-CSF (filgrastim), GM-CSF
(sargramostim)
• Plerixafor injection in
combination with G-CSF
– Approved for used in patients
with NHL and MM
Other Treatment Options
• Hematopoietic growth factors
– Pegfilgrastim
• Chemotherapeutic agents
– Chemotherapy apart from
disease treatment
– Disease-specific regimens
• Growth factor + CT
CT = chemotherapy; G-CSF = granulocyte colony-stimulating factor; GM-CSF = granulocyte-macrophage colony stimulating factor.
Smith TJ, et al. J Clin Oncol. 2006;24:3187-3205. Kobbe G, et al. Bone Marrow Transplant. 2009;43:669-677. Hicks ML, et al.
Transfusion. 2007;47(4):629-635.
Known Risk Factors for Suboptimal
Mobilization
• Poor or failed mobilization is often defined as a collection
of < 1-2 x 10 cells/kg
• Patient characteristics
–
–
–
–
–
–
Aged > 60 years
Underlying disease
Previous radiation therapy and/or chemotherapy
Multiple chemotherapy cycles
Previous treatment with melphalan or carmustine
Novel induction strategies (eg, lenalidomide in MM)
Goterris R, et al. Bone Marrow Transplant. 2005;36(10):847-853. Micallef IN, et al. Hematol J. 2000;1:367-373. Stiff PJ. Bone Marrow
Transplant. 1999;23(Suppl 2):S29-S33 . Wuchter P, et al. Biol Blood Marrow Transplant. 2010;16(4):490-499. Kumar S, et al.
Leukemia. 2007;21:2035-2042. 6. Mazumder A, et al. Leukemia. 2008;22(6);1280-1281. Paripati H, et al. Leukemia. 2008;22:1282108
1284. Popat U, et al. Biol Blood Marrow Transplant. 2009;15:718-723.
Consequences of
Suboptimal Mobilization
• Failure to mobilize a sufficient number of CD34+ cells
may result in:
–
–
–
–
–
Ineligibility for transplantation
Increased number of apheresis days
Need for bone marrow harvest
Repeated attempts at mobilization
Increased resource utilization
• Use of suboptimal apheresis product yield may lead to:
– Delayed, partial, or failed stem cell engraftment
– Potential for increased risk of infections and/or bleeding
– Increased need for transfusions
Pusic I, et al. Biol Blood Marrow Transplant. 2008;14:1045-1056. Gertz MA, et al. Bone Marrow Transplant. 2010(45):1396-1403.
Glaspy JA, et al. Bone Marrow Transplant. 1999;23: Suppl21-S27. Haas R, et al. Blood. 1994;83(12):3787-3794. Schiller G, et al.109
Blood. 1995;86(1):390-397. Stiff P, et al. Bone Marrow Transplant. 1999;23:S29-S33.
Conventional Mobilization Strategies
Growth Factor
• Advantages
– Predictable collection
schedule
– Earlier engraftment
• Disadvantages
– Lower stem cells yields
– More apheresis days
CT
• Advantages
– High stem cell yields
• Disadvantages
– Risk for infection
– Neutropenic fever and
hospitalization
– Less predictable collection
schedule
Pusic I, et al. Curr Pharm Des. 2008;14(20):1950-1961. Gertz MA. Br J Haematol. 2010;150(6):647-662.
AUTOLOGOUS TRANSPLANT
When and How?
High-dose Chemotherapy Prolongs
Survival in MM
Author
Study
Attal et al, 1996
IFM90
Fermand et al, 2005
MAG91
Child et al, 2003
MRC7
Palumbo et al, 2004
IMMSG
Blade et al, 2005
Barlogie, et al, 2006
Slide courtesy of Dr. Costa.
PETHEMA
USIG
Treatment
Patients
(n)
CR
(%)
EFS
(months)
OS
(months)
CT
100
5
18
44
Auto Tx
100
22
27
57
CT
96
20
19
48
Auto Tx
94
36
25a
48
CT
200
9
20
42.3
Auto Tx
201
44
32
54.1
CT
98
6
16
43
Auto Tx
97
25
28
58+
CT
83
11
33
66
Auto Tx
81
30
42
61
CT
255
11
16%
38%
11
at 7 years
at 7 years
Auto Tx
261
17%
38%
P value
.03
.03
< .001
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)
MELPHALAN CHALLENGES
PK Variability
Propylene Glycol
Special Issues
CE-Melphalan (Propylene Glycol-free):
Phase 2a Pharmacokinetic Study
A Phase 2a, Open-Label, Randomized, Pharmacokinetic Comparative, Cross-Over Study
of Melphalan HCl for Injection and Standard Melphalan for Injection for Myeloablative
Conditioning in Multiple Myeloma Patients Undergoing Autologous Transplantation
Screening
Period
Randomization
Baseline
tests for
study and
infectious
disease
testing
Study Period
Day -3
Day -2
CE-Mel
Standard
Mel
100mg/m2 IV
Over 30 min
100mg/m2 IV
Over 30 min
Day 1
Rest Day
Day -3
Standard
Mel
100mg/m2 IV
Over 30 min
Day -2
CE-Mel
100mg/m2 IV
Over 30 min
Follow-up Period
Day 0
ASCT
Day +7
ASCT
Daily CBC &
weekly safety
assessments
until ANC
engraftment
ASCT
Day +14
Daily CBC &
weekly
safety
assessment
s until ANC
engraftment
ASCT
Day +21
ASCT
Day +30
Daily CBC &
weekly safety
assessments
until ANC
engraftment
Daily CBC &
weekly safety
assessments
until ANC
engraftment
Date of Engraftment
Enrollment (N=24)
Aljitawi, et al. Bone Marrow Transplantation. 2014;49:1042–1045.
Up to 7 days
after Date of
Engraftment
End of Study
Evaluations
CE-Melphalan (Propylene Glycol-free):
Efficacy Overview
• All patients (100%) achieved myeloablation and
engraftment
– Median time to myeloablation: 3 days
– Median time to neutrophil engraftment:11 days
Time and Rate of
Myeloablation
Experienced
Myeloablation
Time to
Myeloablation
(study days)
Yes
Total
(N=24)
24 (100%)
Mean
2.9
SD
1.21
Median
3.0
Min
0
Max
5
Aljitawi, et al. Bone Marrow Transplantation. 2014;49:1042–1045.
Time and Rate of
Engraftment
Experienced
Engraftment
Time to
Engraftment
(study days)
Yes
Total
(N=24)
24 (100%)
Mean
11.0
SD
1.08
Median
11.0
Min
9
Max
13
CE-Melphalan (Propylene Glycol-free):
Safety Overview
• Adverse event safety profile appears consistent with what has been
reported with high-dose standard Melphalan
– No patients discontinued prematurely
– Prolonged QRS in 2 pts receiving standard Melphalan first (1 required
hospitalization for observation)
• Left bundle branch block pattern resolved within 2 days
• Pts subsequently received CE-Melphalan without further complications
Treatment-emergent AEs ≥50% of Patients
Nausea
100%
Diarrhea
96%
Vomiting
88%
Hypokalemia
88%
Fatigue
83%
Thrombocytopenia
75%
Decreased appetite
63%
Dizziness
63%
Aljitawi, et al. Bone Marrow Transplantation. 2014;49:1042–1045.
CE-Melphalan (Propylene Glycol-free):
Results Overview
Results from the Phase 2a study (N=24):
•
•
CE-Melphalan is propylene glycol-free
–
More stable following reconstitution
–
Longer infusion times / higher doses possible with CE-Melphalan (propylene glycol-free)
could improve response to treatment
CE-Melphalan (propylene glycol-free) is bioequivalent to standard
Melphalan
– CE-Melphalan (propylene glycol-free) peak and systemic exposure were slightly
greater than with standard Melphalan
•
The efficacy and safety profile were consistent with that already
established for high-dose Melphalan conditioning with ASCT for MM
– 100% of patients achieved myeloablation and engraftment
– Most frequent AEs included fatigue, nausea, and hypokalemia
Aljitawi, et al. Bone Marrow Transplantation. 2014;49:1042–1045.
CE-Melphalan (Propylene Glycol-free)
• FDA Approved March 2016
– 1st drug to gain FDA approval for the high-dose conditioning indication in MM
• Captisol-enabled melphalan (CE-melphalan) approved for two indications
in MM
– High-dose conditioning treatment prior to HSCT for patients with MM
– Palliative treatment for MM patients who are not candidates for oral therapy
• Approval based on multicenter, open-label, phase 2b study of 61 patients
(5 relapsed prior to HSCT; 56 with newly diagnosed disease)1
– 200 mg/m² CE-melphalan, administered in 100 mg/m² doses on day 3 and
day 2 before transplantation
– ORR:95%; CR: 31% (16% stringent CRs) [as determined by investigator
assessment]
– No treatment-related mortality; no new safety signals
1. Hari, et al. Biol Blood Marrow Transplant. 2015;21:2100-2105.
119
AUTOLOGOUS TRANSPLANTATION
Transplant vs Conventional Therapy
Initial Therapy
Tandem
Early vs Late
Transplant Outcomes Improving
Over Time
Does anyone
have a
reference for
this data?
100
90
80
100
90
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
1995-99
2000-04
2005-10
0
0
1
2
72%
81%*
86%*#
3
4
5
47%
55%*
57%*
Expansion of ASCT Transplantation for
MM in US
Does anyone
<50 years
50-64 years
have a
reference for
this data?
≥ 65 years
AHCT Has Changed Natural History
of MM: Population-level Data
Changes in MM 5-year relative survival ratio in Sweden
Figure from Kristinsson SY, et al. J Clin Oncol . 2007;15:1993.
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.
AUTOLOGOUS
TRANSPLANTATION
Transplant vs Conventional Therapy
Conventional Chemotherapy vs ASCT:
Historic Randomized Studies—Median OS
Median Survival
Patients
(n)
Age
IFM90[1]
200
<65
MAG91[2]
190
MRC7[3]
403
<65
PETHEMA[4]*
164
S9321[5]
516
Median
Follow Up
Conventional
Chemotherapy
ASCT
44 months
57 months
50 months
55 months
42 months
42 months
55 months
<65
42 months
64 months
72 months
≤70
76 months 38% at 7 years
7 years
55-65 56 months
38% at 7 years
*in patients responding to conventional chemotherapy
[1] Attal M et al. N Engl J Med. 1996;335:91. [2] Fermand JP et al. J Clin Oncol. 2005;23:9227. [3] Child A et al. N Engl J Med.
2003;348:1875. [4] Blade J et al. Blood. 2005;106:3755. [5]Barlogie B, et al. JCO. 2006;24:929-936.
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
Mel200-ASCT vs Chemotherapy +
Lenalidomide
HR (95% CI)
P value
Age <60
0.67 (0.41-1.11)
0.117
Age ?60
0.44 (0.23-0.86)
0.015
KPS 60-70%
0.76 (0.33-1.72)
0.506
KPS 80-100%
0.54 (0.34-0.85)
0.008
ISS I/II
0.55 (0.34-0.89)
0.016
ISS III
0.75 (0.38-1.45)
0.376
No del17, t(4;14), t(14;16)
0.57 (0.34-0.94)
0.029
Del17, t(4;14), t(14,16)
0.60 (0.31-1.14)
0.118
LDH < ULN
0.62 (0.41-0.95)
0.027
LDH ? ULN
0.23 (0.03-1.92)
0.177
Favors Mel200-ASCT
Gay, et al. Blood. 2014;124:Abstract 198.
Favors Chemotherapy + Lenalidomide
-
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
Induction
(40 mg on days
1, 8, 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.
High-dose Melphalan + ASCT vs
Chemotherapy + Lenalidomide: PFS
Total Population
Patients Eligible for
Consolidation
Figures from: Gay, et al. Lancet Oncol. 2015;16:1617-1629.
Patients Eligible for
Maintenance
High-dose Melphalan + ASCT vs
Chemotherapy + Lenalidomide: OS
Total Population
Patients Eligible for
Consolidation
Figures from: Gay, et al. Lancet Oncol. 2015;16:1617-1629.
Patients Eligible for
Maintenance
High-dose Melphalan + ASCT vs
Chemotherapy + Lenalidomide: Safety
• Patients in the chemotherapy + lenalidomide
group had a lower frequency of grade 3/4 AEs
than melphalan + ASCT group
– Hematologic events: 26% vs 84%
– Gastrointestinal events: 5% vs 20%
– Infection: 5% vs 19%
• There was no marked difference between the
maintenance lenalidomide and lenalidomide +
prednisone groups
Gay, et al. Lancet Oncol. 2015;16:1617-1629.
AUTOLOGOUS
TRANSPLANTATION
Initial Treatment
Phase III Trials: Induction Regimens
for Transplant-Eligible Patients
Pts Achieving ≥ VGPR (%)
100
Cavo
PETHEMA/
GEM
IFM
2005-01
HOVON-65
GMMG-HD4
E4A03
80
62
60
60
40
20
50
42
38
28
40
29
15
14
0
[1] Cavo M, et al. Lancet. 2010;376:2075-2085. [2] Rosiñol L, et al. Blood. 2012;120:1589-1596. [3] Harousseau JL, et al. J Clin
Oncol. 2010;28:4621-4629. [4] Sonneveld P, et al. J Clin Oncol. 2012;30:2946-2955. [5] Rajkumar SV, et al. Lancet Oncol.
2010;11:29-37.
Bortezomib-based vs Non-bortezomib—
based Induction Treatment Before ASCT
Overall survival
A Meta-Analysis of Phase III Randomized, Controlled Trials
Sonneveld. J Clin Oncol. 2013;31(26):3279-87.
3-year OS rates
Non-bortezomib—based: 75%
Bortezomib-based: 80%
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.
Effect of Pre-transplant Salvage Therapy Prior
to ASCT in Patients Not Responding to Initial
Induction for MM
Salvage Cohort
Salvage
Chemotherapy
Diagnosis and
Initial Induction
< PR to
induction
Autologous
Transplant
No Salvage
Cohort
Autologous
Transplant
Diagnosis
12 months from diagnosis to ASCT
Vij, et al. Blood. 2012;120(21):abstract 597.
ASCT
MM06-04-12_6.ppt
Lenalidomide/Dexamethasone
Induction Followed by AHCT: OS
• E4A03 trial RD vs. Rd Landmark analysis at 4 mos
• Early SCT after 4 cycles
vs. continued lenalidomide
Probability
• Non randomized,
retrospective,
unplanned post hoc
analysis
• Selection Bias
94%
1.0
0.9
0.8
0.7
0.6
0.5
0.4
0.3
0.2
0.1
0
94% @ 3 yrs
78%
78% @ 3 yrs
Log-rank test: (P = .008)
0
Early SCT: no 141
Early SCT: yes 68
Siegel D, et al. ASH 2010. Abstract 38.Rajkumar, et al. Lancet Oncol. 2010;11:29-37.
Early SCT: no (n =
141)
Early SCT: yes (n = 68)
12
132
68
24
122
64
Mo
36
53
34
48
0
0
AUTOLOGOUS
TRANSPLANTATION
Tandem
Single vs Tandem ASCT
Trial
N
Attal et al, 2003
IFM94
399
Fermand et al, 2003
MAG95
227
Cavo et al, 2007
BOLOGNA 96
321
Goldschmidt et al, 2005
GMMG-HD2
268
Sonneveld et al, 2007
HOVON 24
303
ASCT
CR+VGPR
(%)
Median PFS
(months)
Median OS
(months)
Single
42
25
48
Tandem
50
30*
58*
Single
39
31
49
Tandem
37
33
73†
Single
33
23
65
Tandem
47*
35*
71
Single
NR
23
NYR
Tandem
NR
29*
NYR
Single
13 (CR only)
27*
50
Tandem
32* (CR
only)
24
55
*P < .05.
†OS significant for non-CD34 selected tandem transplants in subset analysis.
NR = not reported.
Attal M, et al. N Engl J Med. 2003;349:2495-502. Fermand JP, et al. Hematol J. 2003;4(Suppl 1):S59. Lazarus, Harry M. and
Laughlin, Mary J. Allogeneic Stem Cell Transplantation. Second Edition. Cleveland, OH; Humana Press, 2010. Cavo M, et al. J Clin
Oncol. 2007;25:2434-2441. myeloma.org/pdfs/Sydney2005_Goldschmidt_P8.pdf. Accessed July 18, 2012. Sonneveld P, et al.
Haematologica. 2007;92(7):928-935.
Tandem Transplantation in MM
Study
Attal et al, 2003
ASCT
IFM94
Single
Age
(years)
< 61
Tandem
Cavo et al, 2007
Sonneveld et al, 2007
Bologna96
HOVON24
Patients
(n)
CR
(%)
EFS
(months)
OS
(months)
7-year
7-year
199
42
25
48
200
50
30
58
7-year
7-year
163
33
23
65
Tandem
158
47
35
71
Single
148
13
21
55
155
32
22
50
Single
Tandem
< 61
< 66
AUTOLOGOUS
TRANSPLANTATION
Early vs Late HCT
Early vs. Late SCT
P (survival)
Early HDT
.
9
.
.8
7
.
.6
.5
4
.
3
.
.2
1.
00
Early HDT
Late HDT
10
20
30
Late HDT
40
50
60
70
80
Months
Figures from Fermand J , et al. Blood. 1998;92:3131.
90
10
0
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
Medical College of WI
ALLOGENEIC TRANSPLANTATION
Survival after Transplant for MM
1998-2008
Does anyone
have a
reference for
this data?
Probability of Survival (%)
100
90
80
70
ASCT
(N=22,254)
60
50
40
HLA-matched sibling, Allo
(N=878)
30
20
Unrelated, Allo (N=143)
10
P < .0001
0
0
1
2
3
Years
HLA= human leukocyte antigen.
4
5
6
Medical College of WI
BARRIERS TO HCT IN MM
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
High-Risk Myeloma and Transplant
PFS in TT4 for GEP70 Low-risk Myeloma by Arm and
Metaphase Cytogenetics
• Patients with abnormal metaphase cytogenetics have significantly
better PFS with melphalan 50 m/m2 for 4 days with VTD (light arm
of TT4) vs single dose of melphalan 200 mg/m2 (standard arm of TT4)
• The reverse applied for patient normal metaphase cytogenetics
Figures from: Frits van Rhee, et al. Blood. 2014;124:328-333.
NEWER AGENTS/REGIMENS
EMN 02: Phase 3 Study of VMP with High-dose
Melphalan Followed by VRD Consolidation and
Lenalidomide Maintenance
• 1570 patients (younger than 65 years) randomized from 12 countries
• Newly diagnosed MM: Symptomatic disease, organ damage, measurable disease
VCD
Three 21-day courses
V: 1.3g/m2, d 1,4,8,11
C: 500 mg/m2, d 1,8
D: 40 mg, d 1,4,8,11
Slide courtesy A Palumbo
1°
R
A
N
D
O
M
I
Z
A
T
I
O
N
VMP
Four 42-day courses
V: 1.3g/m2, d 1,4,8,11
M: 9 mg/m2, d 1-4
P: 90 mg/m2, d 1-4
MEL 200
One course
M: 200 mg/m2 day -2
Stem cell support day 0
MEL 200
Two courses
M: 200 mg/m2 day -2
Stem cell support day 0
2°
R
A
N
D
O
M
I
Z
A
T
I
O
N
MAINTENANCE
28-day courses until relapse
R: 10 mg/day, days 1-21
CONSOLIDATION
two 28-day course
V: 1.3 mg/m2 d 1,4,8,11
R: 25 mg/day, d 1-21
D: 40 mg, d 1,4,8,11
MAINTENANCE
28-day course until relapse
R: 10 mg/day, days 1-21
V, bortezomib; C, cyclophosphamide; D, dexamethasone; R, lenalidomide; M, melphalan; P, prednisone
Myeloma XI: Thalidomide and Lenalidomide
Combinations in Myeloma Patients of All Ages
Intensive
Randomize
CTD
CRD
Assess response
PD + NC
CR + VGPR
PR + MR
Randomize
Nothing
CVD
Assess response
CVD
Assess response
High dose Melphalan + ASCT
Slide courtesy F Davies
Lenalidomide versus Placebo
Abbreviations: CTD Cyclophosphamide (500mg p.o. D 1,8,15) Thalidomide (100-200mg p.o. daily) Dexamethasone (40mg p.o. D1-4, 12-15) , CTDa
Cyclophosphamide (500mg p.o. D 1,8,15, 22) Thalidomide (50-200mg p.o. daily) Dexamethasone (20mg p.o. D1-4, 15-18), CRD Cyclophosphamide
(500mg p.o. D 1,8) Lenalidomide (25mg p.o. daily) Dexamethasone (40mg p.o. D1-4, 12-15) , CRDa Cyclophosphamide (500mg p.o. D 1,8) Lenalidomide
(25mg p.o. daily) Dexamethasone (20mg p.o. D1-4, 15-18), CVD Cyclophosphamide (500mg p.o. D 1,8,15) Bortezomib (1.3mg/m 2 i.v. D 1,4,8,11)
Dexamethasone (20mg p.o. D1-2, 4-5, 8-9, 11-12) Melphalan (200mg/m2) ASCT Autologous stem cell transplant.
GEM14 MAIN: Maintenance
Induction
VRDx6
R
MRD
ASCT
Mel-200
Bu-Mel
MRD
Consolidation
VRDcon x 2
MRD
R
Maintenance
LEN/DEX x 2 yrs*
LEN/DEX + MLN9708 x 2 yrs*
* Patients with positive MRD will continue with LEN/DEX for 3 more years
V, bortezomib; D, dexamethasone; R, lenalidomide; MRD, minimal residual disease; LEN/DEX, lenalidomide/dexamethasone
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
Newer Agents in Development for
Treatment of MM
Agent
Type
Mechanism
Ibrutinib
(PCI–32765)
First-in-class selective,
irreversible small
molecular inhibitor of
Bruton’s tyrosine kinase
(BTK)
Inhibitory effects upon OC
function, micro-environmental
interactions important for MM
cell adherence and growth,
MM repopulating cell growth
Indatuximab
Ravtansine
(BT062)
Immunoconjugate
consisting of anti-CD138
chimerized mAb and the
cytotoxic agent
maytansinoid
Tumor Activated Prodrug
(TAP)
• Binds to CD138-positive MM
cells
• Once the immunoconjugate
is internalized into the target
cell, cytoxic DM4 is released
Oprozomib
Orally-administered
epoxyketone proteasome
inhibitor
Primarily targets the
chymotrypsin-like activity of the
20S proteasome
Clinical Status
•
•
Ongoing Phase 2 trial in R/R MM
Phase 1/2 study for use in combination with
carfilzomib ± dex in R/R MM
•
Studies underway for use in combination
with Len/Low-dex in R/R MM
•
Orphan drug designation for the treatment
of MM
Phase 1b/2 studies with dex for R/R MM
Phase 1b/2 studies with dex + lenalidomide
or cyclophosphamide in newly diagnosed
MM
Phase Ib/2 study with melphalan and
prednisone in transplant-ineligible patients
with newly diagnosed MM
•
•
•
Newer Agents in Development for
Treatment of MM
Agent
Pembrolizumab
(MK-3475)
SAR650984
Type
Highly selective
humanized IgG1ĸ
mAb mAb
Humanized version
of a murine antiCD38 Ab
Mechanism
•
•
•
Selinexor
(KCP-330)
Orally bioavailable,
selective inhibitor of
nuclear export
(SINE) compound
•
Blocks the interaction
between PD-1 and its
ligands without ADCC
or CDC activity
Selectively binds to
CD38-expressing
cells and disrupts
intracelllular signaling
First in class, slowly
reversible, potent
SINE compound that
specifically blocks
XPO1
Selectively cytotoxic
for cells with genomic
damage
Clinical Status
•
Ongoing Phase 1 study, both as a
single agent and in combination with
lenalidomide and dexamethasone
•
Ongoing Phase 1b study in
combination with lenalidomide and
dex in R/R MM
Ongoing Phase 1 study as
monotherapy in selected CD38+
hematological malignancies
•
•
Demonstrated anti-MM activity in
preclinical studies and in an ongoing
Phase 1 clinical study, both as a
single agent and in combination with
dexamethasone