Considerations for Optimizing Transplant in Multiple Myeloma Patient Management - PowerPoint Presentation

Slide1

Considerations for Optimizing Transplant in Multiple Myeloma Patient Management

PARAMESWARAN HARI MD

MEDICAL COLLEGE OF WISCONSIN

Slide2

Support AcknowledgementThis activity has been made possible

through an

unrestricted educational

grant from Spectrum Pharmaceuticals

2

Slide3

Accreditation Information

Physician Accreditation Statement:

This activity has been planned and implemented in accordance with the Essential Areas and Policies of the Accreditation Council for Continuing Medical Education (ACCME) through the joint-sponsorship of Medical Education Resources (MER) and

PleXus

Communications. MER is accredited by the ACCME to provide continuing medical education for physicians.

Credit Designation:

Medical Education Resources designates this live activity for a maximum of 1.0 AMA PRA Category 1 Credit(s). Physicians should only claim credit commensurate with the extent of their participation in the activity.  Nursing Accreditation:  Medical Education Resources is an approved provider of continuing education by the Colorado Nurses Association, an accredited approver by the American Nurses Credentialing Center's Commission on Accreditation. This CE activity provides 1.0 contact hours of continuing nursing education. Medical Education Resources is a provider of continuing nursing education by the California Board of Registered Nursing, Provider #CEP 12299, for 1.0 contact hour. Pharmacists:Educational Review Systems is accredited by the Accreditation Council for Pharmacy Education (ACPE) as a provider of continuing pharmacy education. This program is approved for 1 hour (0.1 CEUs) of continuing pharmacy education credit.  Proof of participation will be posted to your NABP CPE profile within 4 to 6 weeks to participants who have successfully completed the post-test. Participants must participate in the entire presentation and complete the course evaluation to receive continuing pharmacy education credit.UAN  # 0761-9999-16-015-L01-PCertificates will be mailed to participants in 4-6 weeks

3

Slide4

Faculty Disclosure

Faculty:

Disclosures

:

Slide5

Learning Objectives

After

completing this program, participants should be able to:

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)

Differentiate treatment strategies for patients with newly diagnosed multiple myeloma who are eligible for HDT/ASCTIdentify barriers in access to HDT/ASCT for MMReview the rationale for conditioning regimens in patients with multiple myeloma who are eligible for HDT/ASCTCompare and contrast pertinent data regarding a new formulation of melphalan

Slide6

Myeloma Overview

Slide7

Revised International Staging System (R-ISS) for MM

R-ISS

I (n =

871)

I

ncluding

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 levelR-ISS II (n = 1,894)Including all the other possible combinations

Palumbo, et al.

JCO.

2015;33(26):2863-2869

.

5-Year OS*

5-Year PFS*

R-ISS I

82%

55%

R-ISS II

62%36%R-ISS III40%24%

*At

a median follow-up of 46 months

Slide8

Indications for Considering Treatment

(IMWG Consensus Guidelines)

At

least one of the

CRAB

Criteria

(evidence of end organ damage)Rajkumar, et al. Lancet Oncology. 2014;15(12):e538-48.

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”

Slide9

Available Therapies and Phases of Treatment for MM

Initial Therapy

Consolidation / Maintenance

Treatment of

Relapsed Disease

ASCT

if eligible*

Supportive Care

*Transplant eligibility may impact initial treatment decisions

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

Slide10

Treatment Goals for MM

Disease Response and Survival

Rapid cytoreduction to relieve symptoms

Minimize treatment-related toxicity

Prolong

survival – Overall Survival

Symptom ControlAmeliorate pain and other disease-related symptomsPrevent further organ damagePreserve performance status and quality of life

Slide11

AUTOLOGOUS TRANSPLANTATIONTransplant Vs Conventional Therapy

Slide12

0.75 (0.65, 0.87)

0.77 (0.59, 1.00)

0.70 (0.51, 0.96)

0.72 (0.62, 0.83)

*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.

Favors HDT

Favors SDT

PFS (95%CI)

IFM90

MAG90*

MAG91

MRC7

S9321

PETHEMA*

HOVON*

M97G*

IFM9906

*†

Combined

Sensitivity/Sub-group Analyses

Excluding Non-Standard RCTs

RCTs preferring PBSCs

RCTs with Longer Follow-up

RCTs with Lower Crossover

‡

0.61 (0.42, 0.89)

0.42 (0.30, 0.58)

0.76 (0.57, 1.02)

0.68 (0.54, 0.85)

0.87 (0.72, 1.06)

0.85 (0.60, 1.22)

0.85 (0.63, 1.14)

0.48 (0.34, 0.66)

1.80 (1.30, 2.50)

0.75 (0.59, 0.96)

.1

.5

1

5

10

Hazard Ratio of Progression

Meta-analysis of PFS: Standard Chemotherapy vs Autologous SCT

Slide13

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.

AHCT Has Changed Natural

History of MM: Population-level Data

Slide14

Cyclophosphamide, Lenalidomide, Dexamethasone

Lenalidomide

High-dose Melphalan + ASCT

Induction

Consolidation

Maintenance

CY (3g/m

2

)

MOBILIZATION

CY (3g/m

2

)

MOBILIZATION

Induction

Four

28-day cycles of lenalidomide (25 mg on days 1–21) and dexamethasone (40 mg on days 1, 8, 15, and 22)

Collection

Lenalidomide

Lenalidomide + Prednisone

Lenalidomide+ Prednisone

High-dose Melphalan + ASCT

vs

Chemotherapy + Lenalidomide Followed

by L

enalidomide + Prednisone vs Lenalidomide Maintenance in MM

Gay, et al.

Lancet Oncol.

2015;16:1617-1629.

Slide15

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 therapyLenalidomide + prednisone: 37.5 monthsLenalidomide: 28.5 months (HR = 0.84, P = .34).4-year OSHigh-dose melphalan + ASCT: 86% Chemotherapy + lenalidomide: 73% (HR = 2.40, P = .004).

Longer PFS with High-dose Melphalan + ASCT

vs

Chemotherapy + Lenalidomide

Gay, et al.

Lancet Oncol.

2015;16:1617-1629.

Slide16

Palumbo,

et

al.

N Engl J Med.

2014;371:895-905

.

Phase 3 MPR Consolidation vs Tandem MEL200Lenalidomide + low-dose Dexamethasone Induction4 cycles(N = 402)MPR6 cycles(n = 202)

MEL 200

(n = 200)

Lenalidomide Maintenance

10 mg, d 1-21

(n = 98)

No Maintenance

(n = 104)

MPR: melphalan, prednisone, lenalidomide

Lenalidomide Maintenance

10 mg, d 1-21

(n = 100)

No Maintenance

(n = 100)

Slide17

Survival

Tandem Transplant, NO Len

Tandem Transplant + Len

63% of relapsed non transplant pts received ASCT

Progression Free Survival

Tandem Transplant + Len

NO Transplant + NO Len

CR Rates

Post Consolidation

Post Maintenance

Tandem MEL

15.7%

35.7%

MPR Consolidation

20%

33.8%

Tandem

MEL-200

Improves OS

Palumbo,

et

al.

N Engl J Med.

2014;371:895-905

.

Slide18

Mel200-ASCT vs Chemotherapy + Lenalidomide: PFS

Gay, et al.

Blood

. 2014;124:Abstract 198.

1.00

0.75

0.50

0.25

0

0 10 20 30 40 50 60 70 80

Months

PFS (% of patients)

HR, .55; 95% CI, .45-.69;

P

< .0001

Mel200-ASCT: PFS 41 months

CC + R: PFS 26 months

Median Follow-up from Randomization: 4 Years

Slide19

1.00

0.75

0.50

0.25

0

0 10 20 30 40 50 60 70 80

Months

OS (% of patients)

HR, .59; 95% CI, .40-.87;

P

= .008

Mel200-ASCT: OS 84%

CC + R: OS 71%

Gay, et al.

Blood

. 2014;124:Abstract 198.

Mel200-ASCT vs Chemotherapy + Lenalidomide: OS

Median Follow-up from Randomization: 4 Years

Slide20

Transplant Outcomes I

mproving

O

ver Time

Probability, %

Years

1995-99 72% 47%2000-04 81%* 55%*2005-10 86%

*

#

57%

*

0

1

2

5

100

0

20

40

60

80

90

10

30

50

70

0

100

20

40

60

80

90

10

30

50

70

2005-2010 (n=2,223)

1995-1999 (n=686)

2000-2004 (n=1,464)

3

4

* vs. 1995-1999, P<0.05

#

vs. 2000-2004, P<0.05

Costa LJ et al.

Biol

Blood Marrow Transplant. 2013 Nov;19(11):1615-24

Slide21

IFM 2005-01/2006-02 n=482

PETHEMA n=390

GIEMEMA n=480

HOVON-65 n=827

Bortezomib induction

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

Consolidation

Len x 2

--

VTD

TD

--

Maintenance

Random:

Len vs Obs

Random: IFN, Thal or VT

All:

Dex

Assigned: Bort

Thal

Sonneveld.

J Clin Oncol

. 2013;31(26):3279-87.

Bortezomib-based vs Non-bortezomib—based Induction Treatment Before ASCT

Slide22

Bortezomib-based

v

s Non-bortezomib—based Induction Treatment Before ASCT

Sonneveld, et al.

J Clin Oncol

. 2013;31:3279-3287.

Median TTP

37.5 months vs 31.3 months;

P

< 0.0001

Slide23

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%

[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.

Earlier Phase Studies: Induction Regimens for Transplantation-Eligible Pts

RVD

[1

]

Pts Achieving ≥ VGPR (%)

KRd

[2]

KTd

[4]

]

CyBorD

[5]

Ixazomib/RD

[7]

67

81

68

60

58

100

80

60

40

20

0

Slide24

Autologous transplantationEarly vs Late HCT

Slide25

RVDx3

RVD x 5

Lenalidomide

Melphalan 200 AHCT

+ RVD x 2

Induction

Consolidation

Maintenance

CY (3g/m

2

) MOBILIZATION

Goal: 5 x10

6

cells/kg

RVDx3

CY (3g/m

2

)

MOBILIZATION

Goal: 5 x10

6

cells/kg

Randomize

Collection

Lenalidomide

AHCT at relapse

Early vs Late SCT: Ongoing

Phase 3

Study in Newly

Diagnosed MM

SCT Candidates (IFM/DFCI 2009)

ClinicalTrials.gov Identifier: NCT01208662

RVD: lenalidomide

, bortezomib and dexamethasone

Slide26

IFM 2009: Best Response.

RVD arm

N=350

Transplant arm

N=350

p-value

CR49% 59% VGPR29% 29%

0.02

PR

20%

11%

<PR

2%

1%

At least

VGPR

78% 88%0.001 Neg

MRD

by

FCM , n (%)

228 (65%)

280 (80%)

0.001

Attal M et

al Blood 2015 126:391

Slide27

IFM 2009: PFS (9/2015)

Median PFS,

months

34

43

4-year PFS

35%47%

Hazard ratio (95% CI)

1

0.69

(0.56-0.84)

<0.001

Attal M et

al Blood 2015 126:391

Slide28

IFM/DFCI 2009: PFS according to MRD (FCM)

post consolidation (9/2015).

RVD Arm

Transplant Arm

Attal M et

al Blood 2015 126:391

Slide29

AUTOLOGOUS transplant Who, When and How?

Slide30

Transplant Ineligible vs Transplant E

ligible

Transplant I

neligible

Poor performance status

Elderly and frail

Unable to perform activities of daily livingDecompensated comorbiditySocial economic factors

Patient choice

Very low

-

risk disease

Asymptomatic myeloma

Solitary plasmacytoma

Age should not be considered an absolute contraindication for SCT

Transplant E

ligible

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.

Slide31

Influence of Response After

Induction: Superior

Outcome When CR

is

Achieved Before ASCT

0

0.2

0.4

0.6

0.8

1.0

0

Mos

EFS (Probability)

12

24

36

48

84

96

0.1

0.3

0.5

0.7

0.9

60

72

CR (n = 101)

nCR (n = 96)

PR (n = 346)

SD (n = 63)

PD (n = 26)

CR vs nCR:

P

= .1

CR vs PR:

P

= .05

nCR vs PR:

P

= .9

Mos

OS (Probability)

12

24

36

48

84

96

0

0.2

0.4

0.6

0.8

1.0

0

0.1

0.3

0.5

0.7

0.9

60

72

CR vs nCR:

P

= .1

CR vs PR:

P

= .07

CR vs SD:

P

= .02

nCR vs PR vs SD:

P

= .9

Lahuerta JJ, et al.

J Clin Oncol

. 2008;26:5775-5782.

Slide32

Outcomes with/without Pre-ASCT Salvage

Years

0

2

4

10

8

6

100

0

20

40

60

80

90

10

30

50

70

SALVAGE

(n=324)

NO SALVAGE

(n=251)

PFS

Years

0

2

4

10

8

6

0

100

20

40

60

80

90

10

30

50

70

SALVAGE

(n=324)

NO SALVAGE

(n=251)

OS

P

= NS

Vij, et al.

Blood

. 2012;120(21): Abstract 597

P

= NS

P

= .3470

P

= .2622

Slide33

International Myeloma Working Group (IMWG) Consensus Recommendations for Cell

Doses

Is there an optimum CD34+ cell dose to be

infused

?

Cell doses > 3 × 10

6 CD34+ cells/kg associated with better outcomes[1-3]Studies primarily retrospectiveRecommendation: the issue of optimal CD34+ cell dosing in aHSCT for MM requires a prospective clinical trialIs 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 × 10

6

CD34+ cells/kg should be collected

These targets allow most patients to undergo at least 2 aHSCT, each with an optimal cell dose

[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

aHSCT, autologous hematopoietic stem cell transplantation; MM, multiple myeloma.

Slide34

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

Myeloma

X: High-dose Melphalan + Salvage ASCT vs Cyclophosphamide in R/R MM

Cook G, et al.

Lancel Oncol

. 2014;15:874-885.

PAD induction

2-4 cycles

R/R MM;

>18 mos

after prior ASCT

(N = 293)

Randomized 1:1

Melphalan 200mg/m

2

IV +

ASCT

(n = 89)

Cyclophosphamide

400mg/m

2

PO/wk x12 cycles

(n = 85)

Slide35

39.3%

22.4%

P

= .012

≥ VGPR rate: 59.5% after salvage ASCT vs 47.1% after cyclophosphamide

(

OR: 0.38 [95% CI: 0.2-0.7];

P

= .0036)

Myeloma X: Response Rates with High-dose Melphalan/2

nd

ASCT vs Cyclophosphamide

Cook G, et al.

Lancet Oncol

. 2014;15:874-885.

PFS

Slide36

Barriers to

Autologous Transplant

Access

HEALTH CARE SYSTEM

Limited number of HCT centers

Workforce shortage

Capacity limitations

Infrastructure

issues

ACCESS TO TRANSPLANT

SOCIAL

Age

Ethnicity and race

Language

Culture

Health literacy

Patient/family attitudes

Caregiver availability

ECONOMIC

Socioeconomic status

Education

Number of wage earners Employment status Insurance coverage

Place of residence

Transportation

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.

Slide37

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

Pidala J, et al.

Bone Marrow Transplant. 2013;48:63–67.CharacteristicOR

(95% CI)

P

Age,

60 years vs 30 years

8.29

(5.89,

11.69

)

<.001

Race,

black vs white patients2.35(1.93, 2.87)<.001

CI, confidence interval; OR, odds ratio.

Slide38

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)DisabilityFrailty (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)PolypharmacyLower

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

Slide39

Role of Maintenance Therapy

Slide40

Maintenance in Myeloma

PFS advantage

[1-3]

OS improvements?

[2]

Toxicities of treatment

Myelosuppression[3] Second primary malignancies[3,4]Quality of lifeUnclear whether all patients benefit from maintenanceUnclear 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.

Slide41

Figure from: Bruno

Paiva et al.

Blood

. 2

015;125:3059-3068

The Deeper the Response, the Longer PFS

Slide42

3 Million cells

1 Million cells

500,000 cells

100,000 cells

No abnormal

plasma cells

6 abnormal

plasma cells

12 abnormal

plasma cells

30 abnormal

plasma cells

53 year old

female

with

myeloma

A

bnormal plasma cells at diagnosis:

CD19-

, CD45-

, CD38 dim, CD20-, CD56+,

CD81,

CD27

dim

Now MRD work-up post therapy

MM

MRD Testing by Flow Cytometry: U.S. in 2015

Mailankody et al.

Nature Reviews.

2015;

12:286–295

Slide43

Features of Currently Available Techniques to

Monitor

MRD in MM

MFC (≥8-color)

ASO-PCR

NGS

PET/CTApplicability∼100%60% to 70%∼90%∼100%*Reproducibility among centersHighHighNot reportedModerate at MRDAvailability in individual laboratories around the worldHigh

Intermediate

Limited

Intermediate

Diagnostic sample

Important but not mandatory

Mandatory

Mandatory

Important but not mandatory

Time

2-3 h

≥5 d (follow-up), 3-4 wk (target identification)≥7 d2 hCost per sample∼350 USD∼500 USD (follow-up), ∼1500 USD at diagnosis (target identification)∼700 USD∼2000 USDSensitivity10−5 to 10−6

10

−5

to 10

−6

10−6

High (4 mm)

Quantitative

Yes (directly; high accuracy)

Yes

Yes

Yes

Fresh sample

Needed (<36 h)

Not needed

Not needed

NA

Patchy sample

Impacts

Impacts

Impacts

No impact

Global cell characterization

Yes

No

No

No

Standardization

Ongoing (EuroFlow/IMF)

Yes, since 15 y (EuroMRD)

Not reported

No

Table from: Bruno

Paiva et al.

Blood

. 2

015;125:3059-3068

Slide44

Imaging of Residual Disease in MM

PET may be useful for some, but not all, patients

Variability in PET approaches across different studies and institutions

PET/CT

[1,2]

PFS

(

CR Pts After

First-line

Therapy)

Mos

0

12

24

36

48

60

72

1.0

0.8

0.6

0.4

0.2

0

P

= .010

PET CR

median: 90 mos

NO PET CR

median: 50 mos

PFS (Proportion)

[1

]

Zamagni E, et al

. Blood

. 2011;118:5989-95.

[2

]

Zamagni E, et al. ASH 2013. Abstract 1936.

Slide45

Register and

Randomize

MEL 200mg/m

2

RVD

x 4

Lenalidomide

Maintenance

Lenalidomide

Maintenance

Lenalidomide

Maintenance

MEL 200mg/m

2

Primary End Point PFS

Awaited Phase 3 Upfront Transplant Study: BMT

CTN

0702

ClinicalTrials.gov Identifier: NCT01109004

RVD: lenalidomide

, bortezomib and dexamethasone

Slide46

Can We CHANGE Conditioning?

Slide47

Conditioning Regimens for MM

Anti Myeloma activity

Standard

MELPHALAN; TBI

(total body radiation)

Investigational

TOXICITY Mortality (TRM) – very low for MEL 200 mg/m2GI toxicity – dose limiting toxicityPulmonary Syndrome

Arrhythmias

COST

Days in Hospital

Cost of procurement

Timely availability – e.g TBI / Thiotepa in the USA

Slide48

High-dose Melphalan is the Most Frequently Used Conditioning Regimen

Regimen

Frequency of

Use

MEL

88%

MEL + others (TBI)8%BU-MEL1%BU-CY2.5%CIMBTR 2010

Slide49

MEL 200 mg/m

2

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 Dose for Transplant

Slide50

Moreau

, P. et al.

Blood;

2002;99:731-735.

P

= 0.05

High-dose Melphalan (200 mg/m

2

)

is the

Proven Conditioning

Regimen for MM

Survival

0 10 20 30 40 50

100

90

80

70

60

50

40

30

20

10

0

Overall Survival Rate

Months

MEL 200

TBI + MEL 140

Slide51

Melphalan

Bifunctional Alkylator

L – Phenyl Alanine Mustard

Initially synthesized in the 1950s

Forms adducts and crosslinks DNA

CSF penetration ??

PK issuesRapidly 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

Slide52

Intensification of MEL

MEL

220

mg/m

2

(French

single arm study)[1]Cardiac toxicity reported No obvious superiority over MEL 200 (historical)

At least 2 other MEL 280 studies in

progress or completed

Escalating MEL to 300

mg/m

2

[2]

Amifostine

for protection

MTD was MEL 280 mg/m

2

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

.

Slide53

Risk-adapted Melphalan Dosing

[1

]

Dimopoulos, et al

.

JCO.

2010;28:4976-4984. [2] Palumbo A, Anderson K. N Engl J Med. 2011;364:1046-1060.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

High-dose Melphalan

140 mg/m

2

140 mg/m

2

Melphalan dose may also be adjusted due to comorbidities

Dose-Reductions in Obese Patients

[3]

Median MEL

Normal

Overweight

Obese

Severe Obese

MEL 200

cases

Total MEL

340

370

370

376

Dose / m

2

198

193

167

172

MEL TBI cases

Total MEL

245

250

276

272

Dose/m

2

140

137

131

125

3.

Vogl

, et al.

ASH 2008. Abstract

3333.; BBMT

2011 Dec;17(12):

1765

Slide54

Study

OS (years)

EFS (years)

IFM 90

4.5

2.5

IFM 94*4.32.3IFM 99-04*3.92.0

S9321

4.0

1.9

TT1

*

5.7

2.6

MRC 7

4.5

2.6

MEL 280 /m25.61.8

MEL 280 mg/m

2

MCW Study

Comparison of Results with Previous Studies

*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.

Slide55

Current Variations for High-dose MEL

Fractionated Melphalan

50 mg/m

2

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

Slide56

Response

Category

2-Day

Dosing

M

elphalan (n=185

)1-Day Dosing Melphalan (n=93)P-valuesCR23 (12%)8 (8%).3CR55 (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.

MEL-100 x2 vs MEL-200 X1

Slide57

MEL 200 vs Bortezomib-MEL

Mucositis Grade 3-4

47%

Median duration Mucositis

9 days (2-13)

GI – diarrhea G1-2

72%

Skin Reactions G1-2

34%

Neuropathy

8%

Headache

28%

MEL 200 vs. Bortezomib MEL – Matched pair

Response

BOR-MEL

(n = 46)

MEL 200

(n = 115)

P

CR

35%

11%

.001

VGPR

35%

43%

PR

26%

43%

CR+VGPR

70%

54%

.078

Roussel, et al.

Blood

.

2010;115:32-37

.

Slide58

Other Conditioning Regimens Currently in Use

Classic

Busulfan Cyclophosphamide

Busulfan – Melphalan

Busulfan – Cyclophosphamide – Thiotepa

Variations of MEL

Escalated dosesFractionated MELNewer

Targeted Marrow Radiation + MEL

MEL + Bortezomib

MEL + Arsenic

Trioxide

MEL + Carfilzomib

Slide59

Promising Investigational Preparative Regimens

Preparative Regimens

# of Patients

Year(s)

CR/VGPR

Overall

ResponseOverall

Survival

Toxicity

Type of Study

Intravenous

BUMEL

102

2005-2008

CR: 17%

58%

2-year: 82

%

Day 100 treatment related mortality: 1%

Phase 1

BEAM vs

MEL

179

NA

NA

NA

5-year OS: 59% BEAM vs 46% Mel (NS)

NA

Retrospective

Bortezomib and

MEL

 

54

2007

CR: 32%

≥VGPR: 70%

94%

Estimated 2-yr: 96%

≥Grade 3 mucositis of upper and lower digestive tract: 47%

1 case of grade 3 peripheral neuropathy

Phase 2

Bortezomib given before or after

MEL

39

NA

CR: 21%

≥VGPR: 51%

87%

 

Median OS: 36.7 months

≥Grade 3 mucositis: 31%

≥Grade 3 neutropenic fever: 56%

Phase 1/2

Bortezomib

with iv BUMEL

20

2010

≥VGPR: 77%

Near CR or better: 54%

100%

NA

≥Grade 3 neutropenic fever: 58%

≥Grade 3 mucositis: 47%

≥Grade 3 hypo-phosphatemia: 37%

Phase

1-2

MEL280

with Palifermin

19

2007-2009

100 days: ≥VGPR: 27%

100 days: 53%

Grade 3-4 mucositis: 44%

Asymptomatic atrial fibrillation: 17%

No treatment related deaths

Phase 1

PG-free

MEL

15

2010-2011

NA

NA

NA

No unexpected toxicity

Phase 2a

Modified from: Aljitawi, et al.

J Comp Eff

Res.

2012

;

1:57-70

.

Slide60

Some other newer regimens

CAR-MEL – Carfilzomib +

Melphalan

TMI – total marrow irradiation

60

Slide61

Melphalan Challenges PK Variability

Propylene Glycol

Special Issues

Slide62

MEL Pharmacokinetics

Inter-individual variability

Creatinine Clearance

Fat free mass

Hematocrit

H

igher MEL exposure—increased toxicity and efficacyUnbound MEL—sensitive predictor of toxicity and efficacyNath, et al. Br J Clin Pharmacol. 2010;69:484-497.

Slide63

Melphalan 140 mg/m

2

as effective as melphalan 200 mg/m

2 with less toxicity in patients with renal impairment[1]

Mucositis: 93

%

(MEL-200) vs 67% (MEL-140); P= .04Pulmonary complications 57% (MEL-200) vs 17% (MEL-140); P=.00753% (dialysis-dependent) vs 19%; P= .02Cardiac complicationsAtrial dysrhythmias significantly more common in MEL-200 group21% (MEL-200) vs 0 (MEL-140); P = .07Neurological complicationsMore 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

Slide64

Pharmacokinetics

of MEL

are no

different in

renal-impaired patients

BUT

More leukopenia noted in patients with renal impairment in early studiesMEL-200 poorly tolerated by patients with renal dysfunction60% MEL can be recovered from urineAuto-SCT should be performed early in the disease course before renal failure becomes irreversible1MEL-140 is associated with less toxicity

and

equal efficacy to

MEL-200 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/m

2

)

1. Badros A, et al. Br J Haematol. 2001; 114:822–829.

Special Issues with

Melphalan: R

enal Impairment

Slide65

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 groupMeta analysis of 7 RCTs including 458 patients with hematological malignancies undergoing HSCT[2]Oral cryotherapy significantly reducedThe incidence of severe OM

OM

severity

The

duration of total parenteral

nutrition use

T

he

length of

hospitalization

[1

] Toro, et al. BBMT . 2014;20 :S204 - S205. [2] Wang, et al. PLoS One. 2015; 10(5): e0128763.

Slide66

When reconstituted, Melphalan rapidly hydrolyzes ~1% every 10 minutes

Manufacturer recommendations:

D

ilute dose in NS to </= 0.45 mg/mL and infuse over at least 15 minutes

C

omplete the infusion within 60 minutes of reconstitution of the vial

BMT programs should verify that infusions have ended before the Melphalan expiration time/dateSpecial Issues with Melphalan: Administration

Slide67

Example: Patient 2.1 m2

ordered 200 mg/m

2

A dose of 420 mg d

iluted 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/hSpecial Issues with Melphalan: Administration

Slide68

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

Slide69

Bioequivalence demonstrated

Cmax: 112%

AUC 0-t: 110%

AUC-inf: 110%

Successful

myeloablation

(Day

+3)

Successful

engraftment

(Day

+11)

No

additional toxicities:

Treatment-emergent

AEs

(100%)

Common AEs: nausea, vomiting, hypokalemia, fatigue, decreased appetite, dizziness, and thrombocytopenia

Treatment-emergent

SAEs

(29

%)

F

ebrile neutropenia, mucosal inflammation, sepsis and extreme fatigue

Aljitawi, et al

.

Bone Marrow

Transplantation.

2014;49:1042–1045.

CE-Melphalan HCl

Melphalan

Concentration

(ng/mL)

Melphalan Plasma Concentration

CE-Melphalan (Propylene Glycol-free):

Phase

2a Pharmacokinetic

Study

Slide70

Propylene Glycol-free Melphalan: New IV Formulation for MM Patients Undergoing HSCT

Patients

received

200 mg/m

2

 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 0Patients were evaluated for safety and response through day +100Hari, et al. Biol Blood Marrow Transplant. 2015 Aug 29. [Epub ahead of print]

Slide71

Propylene Glycol-free Melphalan: New IV Formulation for MM Patients Undergoing HSCT

Figure from: Hari, et al

.

Biol Blood Marrow

Transplant

. 2015

Aug 29. [Epub ahead of print]MM Response Assessment*ValueOverall response (sCR, CR, VGPR, or PR)61 (100%)sCR8 (13%)CR5 (8%)

VGPR

37 (61%)

PR

11 (18%)

Stable disease

0 (0%)

Progressive disease

0 (0%)

*Independent

Reviewer

Assessment of response at day +100 after ASCTMyeloablation (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

Slide72

Allogeneic transplantation

Slide73

High-Risk

or

Early-Relapse MM: BMT CTN 1302

Ixazomib

Ages 18-65;

Upfront High Risk MM, or

Early Failures;8/8 match donor

Placebo

R

60-120

days

12 cycles

Fludarabine/Melphalan/Bortezomib

Allo

HCT

ClinicalTrials.gov

Identifier:NCT02440464

Slide74

Conclusions

Slide75

“Improving the

Modern Triple Sequence”

Induction AutoHCT and Maintenance

Randomized trials – Achievement of VGPR/CR or better

Emerging data – PCR or Multicolor Flow based remissions

Second AHCT

ALLO HCT

Other Immune

MRD directed ?

When to stop ?

Implications of prolonged therapy

Better Induction

VGPR before ASCT

TREATMENT of RELAPSE

Biochemical or

Clinical

Are all Relapses the same?

Slide76

Hovon/IFM: Daratumumab Trial in Transplant-eligible NDMM

Slide Courtesy

of P Sonneveld

Endpoints

:

sCR

PFS, OSVTD +

Dara

Dara

Observation

Induction

4 cycles

MaintenanceUntil progression

VTD

R

HDM

ASCT

Stratify by: dara treatment, response, MRD status

R

VTD +

Dara

VTD

Consolidation

2 cycles

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

Slide77

Recently Approved Agents for Treatment of MM

Agent

FDA Approval

Type

Mechanism

Clinical Status

Daratumumab11/2015: MM pts who received ≥3 prior treatmentsHuman IgG1ĸ mAb that binds to a unique epitope on CD38Induces lysis of CD38-expressing tumor cellsAt least 5 clinical trials underway in both untreated and R/R MM patients

Elotuzumab

11/2015: For use in combination with lenalidomide/dexamethasone

to

treat MM pts who have received 1 to 3

prior medications

Humanized IgG1 mAb targeted against SLAMF7

Selectively targets and kills SLAM F7-expressing myeloma cells

Phase 2

trials are evaluating adding elotuzumab to lenalidomide/low-dose dex (ELOQUENT-2, ELOQUENT-1), and bortezomib-dex Phase 1/2 study of lenalidomide-dex-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

Oral 2

nd

-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