Relapsed and Refractory Myeloma Ruben Niesvizky Myeloma Center Myelomacenter.org [email protected].

$Page 1: Relapsed and Refractory Myeloma Ruben Niesvizky Myeloma Center Myelomacenter.org run9001@med.cornell.edu.$
Relapsed and Refractory Myeloma

Ruben NiesvizkyMyeloma Center

[email protected]

Multiple Myeloma: Natural History of Disease

Durie B; International Myeloma Foundation. Concise review of the disease and treatment options: multiple myeloma. 2011/2012 edition;

Kumar SK, et al. Mayo Clin Proc. 2004;79:867-74.

M-P

rote

in L

evel

MGUS or IndolentMyeloma

ActiveMyeloma

Remission

Relapse

FrontlineTherapy

Second- or Third-Line Therapy

Remission duration decreases with each line of therapy

////

Asymptomatic Symptomatic Relapsing Refractory

Outline

• Approach to the patient with RRMM:– Evidence based– Factors to be considered in selecting therapy

• Proteasome inhibitors• Inmunomodulatory Agents• HDAC inhibitors• Alkylating agents

Clinical Considerations for Relapsed/Refractory Disease

• Disease characteristics/prior therapy– Line of therapy– Plateau phase=quiescent period – Aggressiveness of relapse– Relapsed or relapsed and refractory disease– “High risk disease”– Prior therapies (eg SCT, prior IMiD, bortezomib-

based therapy)



based therapy)

Response Duration Decreases With Successive Therapies

• 578 patients; median age 65 years (follow up 55 months)• Overall survival

– One year 72%– Two years 55%– Three years 22%

• 84% died within five years

Figure 3. Duration of response to each treatment

0

2

4

6

8

10

12

1 2 3 4 5 6

Treatment number

Med

ian

res

po

nse

d

ura

tio

n (

mo

nth

s)

Kumar SK, et al. Mayo Clin Proc. 2004;79:867-874.

APEX: Bortezomib Early or Late Relapse

Bortezomib1 prior therapy

n = 132> 1 prior therapy

n = 200

Median TTP (months) 7.0 4.9

CR (%) 10%* 7%†

CR + PR (%) 51%* 37%†

Median Duration of Response (months) 8.1 7.8

1-year Survival 89% 73%

* Evaluable patients, response to bortezomib after 1 prior therapy: n = 128† Evaluable patients, response to bortezomib after >1 prior therapy: n = 187Sonneveld P, et al. Haematologica. 2005;90:146-147. Abstract P140.721.; Data on file; Millennium Pharmaceuticals, Inc.

Time to Progression Overall Survival

2nd Line (LenDex)Median 17.1 months

≥ 3th line(LenDex)Median 10.6 months

2nd Line (LenDex)Median 42 months

≥ 3th line(LenDex)Median 35.8 month

Improved Outcomes with the Early Use of LenDex : TTP and OS

Stadmauer EA et al. Eur J Haematol 2009; 82:426-32



based therapy)

Kumar SK, et al. Bone Marrow Transplant. 2008;42:413-420.

Time to Progression After SCT Correlates With OS After Initial Relapse

6 12 18 24 30 360

5

10

15

20

25

30

35

Time to relapse from SCT (months)

Me

dia

n e

stim

ate

d s

urv

iva

l fro

m r

ela

pse

(m

on

ths)



based therapy)

Frontline vs Relapsed Refractory

Response to Therapy

Survival Outcomes

Toxicities and Co-morbidities

Toxicities and Co-

morbidities

Response to Therapy Survival Outcomes

Trea

tmen

t Nai

ve

Rela

psed

and

Re

frac

tory

High risk features G

enomic instability

Relapsed /Refractory

Outcomes in Relapsed and Refractory Multiple Myeloma

Adapted from: Durie BGM. Multiple Myeloma. International Myeloma Foundation. 2011/2012 edition.Jagannath S. Clin Lymphoma Myeloma. 2008;8 Suppl 4:S149-S156.

Relapsed FrontlineTreatment

Expectedsurvival (months) 20-50

Sensitivity totherapy Sensitive

Treatment limitations/comorbidities

Peripheral neuropathy

(~15% at diagnosis)

14-16

Less Sensitive/Resistant

>80% incidence of peripheral neuropathyCompromised marrow

reserveCytopenia

6-10

Resistant

Intolerant to or ineligible for

available therapy

Elderly population ( risk for heart, lung, renal, liver dysfunction, diabetes)

Nature of Relapse

• How did the patient present?– 80% share clinical features with presentation

• Has been a shift on presentation?– Intact immunoglobulin to light chain only– Non-secretory relapse– Extra medullar disease


Nature of Relapse


• 35% relapse both light chain and intact Ig• 49.6% intact Ig• 10% free light chain only

Survival according to paraprotein and FLC secretion at first relapse.

Brioli A et al. Blood 2014;123:3414-3419

©2014 by American Society of Hematology

Survival from relapse according to paraprotein and FLC secretion at relapse for patients with IgG and IgA paraproteins.

Brioli A et al. Blood 2014;123:3414-3419


Nature of Relapse


• 35% relapse both light chain and intact Ig• 49.6% intact Ig• 10% free light chain only

• Has been a shift on presentation?– Intact immunoglobulin to light chain only– Non-secretory relapse– Extra medullar disease


Progression-free survival according to the presence of extramedullary (EM) involvement at diagnosis.

Varettoni M et al. Ann Oncol 2009;21:325-330

© The Author 2009. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: [email protected]

Outcome according to baseline PET/CT.

Zamagni E et al. Blood 2011;118:5989-5995


Patient Heterogeneity


• Toxicity considerations– Peripheral neuropathy– Thrombotic risk– Myelosuppression– Impact of prior therapies (eg, SCT, other cumulative toxicity)

ANY PROGRESS?

Kumar et al. Blood. 2008 Brenner et al. Blood. 2008

Overall survival in 6-year intervals from time of diagnosis

Time (months)

Pro

po

rtio

n o

f p

atie

nts

0

0.2

0.4

0.6

0.8

1.0

0 20 40 60 80 100 120 140

2001–2006 1995–20002001–2006

1989–19941983–19881977–19821971–1976


Kumar et al: Leukemia Nov 2013

> 65 años

< 65 años

BortezomibCarflizomibIxazomibOprozomib

Proteosome Inhibitors

Proteasome Inhibitors

Outcomes Correlate with Depth of Response

Quality of Response: Survival

Niesvizky et al., Br J Haematol. 2008 Oct;143(1):46-53


Benefits of Retreatment

Bortezomib Retreatment– A Retrospective Multicenter Survey

Retrospectively collected data- multicenter non-interventional survey of pts who received bortezomib for a second time (retreatment)

►Patients: 65 pts,19 centers; median age 65 yrs

Hrusovsky I, et al. ASH 2007, abstract #2720

►Results: 49 evaluable (modified ITT)

Bortezomib mg/m2 Initial Re-

treatment

1.3 94% 86%

1.0 2% 12%

other 8% 4%

+ Dex 39% 61%

Median 4 prior therapies

RetreatmentInitial

bortezomibDiagnosis

52 mos

Mean of 5 cycles

Mean of 4 cycles

6 pts received additional therapy

Best Response

mon

ths

Patients (n)

Treatment Outcomes

Safety: AE occurring in > 2 patients

Retreatment

Median

% P

atie

nts

Treatment received

Petrucci et al, Br J Haem 2013,160,649-659

Petrucci et al, Br J Haem 2013,160,649-659


Carflilzomib

Carfilzomib IV on days 1, 2, 8, 9, 15 and 16 every 28 days20 mg/m2 in Cycle 1

and 27 mg/m2 from Cycle 2 and beyond

(maximum 12 cycles)

Study 003-A1: Open-Label Phase 2b Study of Single-Agent Carfilzomib in Relapsed and Refractory Multiple Myeloma

(R/R MM)

• Primary endpoint: ORR • IMWG response criteria (IRC assessed)

• Secondary endpoints• CBR (ORR+ MR), DOR, OS, PFS, TTP, safety

Siegel D, et al. Blood. 2012;120:2817-25.

Study Population (N=266)Relapsed from ≥2 prior lines of therapy• Must include bortezomib• Must include thalidomide or

lenalidomideRefractory to last regimen

CBR = clinical benefit rate; DOR = duration of response; IMWG = International Myeloma Working Group; IRC = Independent Review Committee; MR = minimal response; ORR = overall response rate; OS = overall survival; PFS = progression-free survival

Single-Agent Carfilzomib: Response Rates

*IRC-determined; 11 patients had unconfirmed response

CR*(n=1)

VGPR(n=13)

PR(n=47)

MR(n=34)

SD(n=81)

PD(n=69)

0

5

10

15

20

25

30

35

0.4%

5.1%

18.3%

13.2%

31.5%

26.8%

Perc

enta

ge o

f Pati

ents

ORR = 24%

CBR = 37%

DCR = 69%

TTR: 1.9 mo (≥PR) and 1.0 mo (≥MR)DOR: 7.8 mo (≥PR) and 8.3 mo (≥MR)

Subset analyses of higher risk populations showed similar response rates(e.g., unfavorable cytogenetics, baseline peripheral neuropathy)


N = 257 response-evaluable population

CR = complete response; PD = progressive disease; PR = partial response; SD = stable disease; TTR = time to response; VGPR = very good partial response

Single-Agent Carfilzomib: PFS, OS


Prop

ortio

n al

ive

and

with

out p

rogr

essi

on

Months

Median PFS = 3.7 mo (95% CI 2.8–4.6)

1.0

0.8

0.6

0.4

0.2

0.00 3 9 12 186 15

Prop

ortio

n su

rviv

ing

Months

Median OS = 15.6 mo (95% CI 13.0–19.2)

0 3 12 21 27

1.0

0.8

0.6

0.4

0.2

0.0

156 9 18 24

N = 257 response-evaluable population

39

Phase II Trial of Carfilzomib Plus Len/Dex in R/R MM (1-3 prior lines of therapy)

Response (N = 52 pts receiving maximal planned dose) n (%)

ORRStringent CRCRVGPRPRSD

40 (77)2 (4)1 (2)

19 (37)18 (35)

3 (6)

Median duration of response, mos (range) 22.1 (9.5-38.0)

Wang M, et al. Blood. 2013;122:3122-3128.

Week 1 Week 2 Week 3 Week 4: rest

Carfilzomib20/27 mg/m2 IV*

Dexamethasone40 mg/d PO

Lenalidomide d1-d2125 mg/d PO

D1/D2 D8/D9 D15/D16

D1 D8 D15 D22

*20 mg/m2 cycle 1 days 1 and 2 only,27 mg/m2 thereafter

Phase III ASPIRE Trial: Carfilzomib + Len/Dex vs Len/Dex in R/R MM (ongoing)

Study Population (N=780)• Measurable disease• 1-3 prior regimens• Relapse or PD• Response to ≥1 prior regimen• Exclusion factors:

• Bortezomib-refractory• Len/dex-refractory• Prior carfilzomib

CRdCarfilzomib

27 mg/m2 IV day 1, 2, 8, 9, 15, and 16 (20 mg/m2 on days 1, 2 of cycle 1 only)

Lenalidomide25 mg Days 1-21

Dexamethasone40 mg once weekly

RdLenalidomide25 mg Days 1-21

Dexamethasone40 mg once weekly

• Stratify: Prior bortezomib, prior lenalidomide, β2 microglobulin level

• Primary endpoint: PFS

Available at: http://clinicaltrials.gov/ct2/show/NCT01080391. Accessed April 29, 2014.

28-day cycles

Press release-PFS 26.3 vs 17.6 HR 0.69:

Phase 1b Study of High-Dose Carfilzomib + Dexamethasone in R/R MM

Badros A, et al. ASH 2012. Abstract 4036.

Study population: N=22 (expanded 007 cohort)Median prior regimens: 4

Regimen: (28-day cycles)Carfilzomib 20/45 or 20/56 mg/m2 30-min IV D1,2,8,9,15,16

Dexamethasone 20 mgD1,2,8,9,15,16 then 40 mg D22

Endpoint CFZ20/45

CFZ20/56 Total

ORR, % 57 50 55

CR, % 0 0 0

VGPR, % 14 50 25

PR, % 43 0 30

DOR NR NR

PFS, months 5.4 6.0

Treatment-emergent Grade ≥3 AE, %

CFZ20/45

CFZ20/56 Total

HematologicThrombocytopeniaAnemiaLymphopenia

292914

502525

362718

NonhematologicHypertensionHypophosphatemiaPneumonia

14147

00

13

999

SafetyEffi

cacy

CFZ = carfilzomib

Phase III ENDEAVOR: Carfilzomib + Dex vs Bortezomib/Dex in R/R MM1

1. ClinicalTrials.gov. Available at: http://clinicaltrials.gov/ct2/show/NCT01568866. Accessed March 26, 2014.2. Vij R, et al. Blood. 2012;119:5661-5670.

Study Population (N=888)• Measurable disease• Responsive to

at least 1 prior therapy• Relapsed following 1-3 prior

treatment regimens• ECOG PS 0-2

CdCarfilzomib

20/56 mg/m2 IV D1,2, 8, 9, 15, 16

Dexamethasone20 mg PO or IV D1, 2, 8, 9, 15, 16, 22, 23

28-day cycle

VdBortezomib

1.3 mg/m2 IV or SC D1, 4, 8, & 11

Dexamethasone20 mg PO or IV D1, 2, 4, 5, 8, 9, 11, 12

21-day cycle

Treat until PD or unacceptable toxicity• Stratify: Prior PI, prior lines of therapy, ISS, bortezomib IV vs. SC


Note use of higher carfilzomib dose—based on results from 004 trial, which suggested dose-response relationship of carfilzomib2

http://clinicaltrials.gov/ct2/show/NCT01568866?term=NCT01568866&rank=1



Novel PIs Under Investigation in R/R MM

Agent Status

Ixazomib Two phase I studies showed activity of single-agent ixazomib[2,3]

OprozomibPhase 1 dose-escalation study showed some activity in patients with heavily pretreated hematologic malignancies, including MM[4]

1. Richardson PG, et al. ASH 2011. Abstract 302.2. Lonial S, et al. ASCO 2012. Abstract 8017.3. Kumar S, et al. ASCO 2013. Abstract 8514.4. Savona MR, et al. ASH 2012. Abstract 203.

Ixazomib: Oral Proteasome Inhibitor

Ixazomib treatment duration and response.

Kumar S K et al. Blood 2014;124:1047-1055



Oprozomib





OPomDex Study Design (Phase 1b)


UbUb

UbUb

Ub

Substrates

+

ThalidomideLenalidomidePomalidomide


Immunomodulating Agents


Pomalidomide in Relapsed/Refractory Multiple Myeloma

• POM + LoDEX achieved responses in pts with prior LEN and/or BORT treatment, including those who are refractory1-4

Study Phase N Treatment Population Median Prior Tx (Range) ≥ PR

Lacy4

2 60POM: 2 mg(28/28-day cycle)Dex: 40 mg/week

1-3 prior Tx, relapsed/refractory

2 (1-3) 65%


LEN-refractory 4 (1-14) 32%

2 35POM: 2 mg (28/28-day cycle)DEX: 40 mg/week

LEN- and BORT- refractory

6 (3-9) 26%


1-3 prior Tx, LEN-refractory

2 (1-3) 37%

2 35POM: 4 mg(28/28-day cycle)DEX: 40 mg/week

LEN- and BORT- refractory

6 (2-11) 29%

55

3. Lacy MQ et al. Blood. 2011;118:2970.4. Lacy MQ et al. Blood. 2011;118: Abstract 3963.

1. Lacy MQ et al. J Clin Oncol. 2009;27:5008.2. Lacy MQ et al. Leukemia. 2010;24:1934.

Pomalidomide

Pts, n

Median No. Prior

Regimens

Refractory to Recent

Therapy (%) ORR (%)

Pomalidomide ± dex1 191 5 100 2534

Pomalidomide, dex2 70 6 NR 2629

Pomalidomide, dex3 84 5 85 3435

Pomalidomide, cyclophosphamide, prednisone4 32 NR

(1 to 3) 44* 59

Pomalidomide, dex, clarithromycin5 46 NR

(at least 3) NR 60

*Len specifically

4. Palumbo A et al. Blood. 2011;118. Abstract 632.5. Mark TM et al. Blood. 2011;118. Abstract 635.

1. Vij R et al. J Clin Oncol. 2012;30. Abstract 8016. 2. Lacy MQ et al. Blood. 2011;118:2970.3. Leleu X et al. Blood. 2011;118. Abstract 812.

ClaPd: Study Design

A single-center, phase 2 study of Clarithromycin combined with Pomalidomide + Low Dose Dexamethasone in RRMM

p.o., orally; b.i.d., twice a day; RRMM, relapsed, refractory MM.

1 2 8 9 15 16 21 22 28Day

Dex 40mg PO

Dex 40mg PO

Dex 40mg PO

Dex 40mg PO

Pomalidomide 4 mg PO

Clarithromycin 500mg PO BID

Clarithromycin???

Results

98 patients completed at least 1 cycle of ClaPD.

– median number of cycles received was 6 (range 1–25)

– median study follow-up was 9.6 months (range 1.0–25.6)

In responding patients, median time to PR was 1 cycle (range 1–7).

Median time to best response was 2 cycles (range 1-14).

Best Response (IMWG Criteria)

n (%) Overall(N = 98)

ORR (≥ PR) 56 (57)

CBR (≥ MR) 65 (66)

sCR 6 (6)

VGPR 17 (17)

PR 33 (34)

MR 9 (9)

SD 23 (23)

PD 10 (10)

IMWG, International Myeloma Working Group; CBR, clinical benefit rate; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.

Treatment History With Len/Bort Did Not Influence Response to ClaPD

Best Response (IMWG Criteria)n (%) Overall

(N = 98)Lenalidomide

refractory(N = 83)

BortezomibRefractory

(N = 82)

Lenalidomide and bortezomib refractory

(N = 72)

ORR (≥ PR) 56 (57) 47 (63) 46 (56) 39 (54)

CBR (≥ MR) 65 (66) 56 (67) 54 (65) (65)

sCR 6 (6) 6 (7) 5 (6) 5 (7)

VGPR 17 (17) 13 (16) 13 (16) 9 (13)

PR 33 (34) 28 (34) 28 (34) 25 (35)

MR 9 (9) 8 (10) 8 (10) 8 (11)

SD 23 (23) 18 (22) 19 (23) 16 (22)

PD 10 (10) 8 (12) 9 (11) 9 (13)

IMWG, International Myeloma Working Group; MR, minimal response; PD, progressive disease; sCR, stringent complete response; SD, stable disease.

thuang

suggest to indent MR

ResultsOS by cytogenetic risk OS by double-refractory state

0 200 400 600 800Time (days)

Number of patients at risk Relapsed 41 26 16 10 0Refractory 54 33 18 9 0

1.00

Surv

ival

(%)

0.75

0.50

0.25

00 200 400 600 800

Time (days)

1.00

Surv

ival

(%)

0.75

0.50

0.25

0

Number of patients at risk Relapsed 26 18 13 6 0Refractory 74 44 23 14 0

Not double-refractoryDouble-refractory

Standard riskHigh risk

Adverse cytogenetics did not appear to influence risk of death as of last study follow-up.HR 1.05, 95%CI (0.49,2.26), P = 0.888

A history of being double-refractory, however, approached a significant effect on survival time. HR 2.67, 95%CI (0.93,7.69), P = 0.068

IFM 2010-02: Study design

N = 50•RRMM•Exposed to Len•del 17p and/or t(4;14)•Measurable disease•ECOG 0–2•PNn > 1 x109/L•Plat ≥ 75 x109/L•Hb ≥ 8 g/dL•CrCl ≥30 mL/min

Pomalidomide4 mg/day, po, days 1–21 (of 28 d cycle)

Dexamethasone40 mg, po, days 1, 8, 15, 22

Aspirin/LMWHonce daily, continuously

Until progression

Safety analysis by DMC after 15 patients recruited

End-pointsPrimary: TTPSecondary: Safety, Response rate (CBR), DoR, OS, PFS, EFS, cytogenetic groups

Median follow-up: 8.2 months

n (%) n (%)

Progression 25 (69) Death other cause 1 (3)

Toxicity 9 (25) Sponsor decision 1 (3)

At data cut-off, 36 patients (72%) had discontinued trial

O/N Median 95% CI

ITT population 33 / 50 2.9 [2.7;5.0]

8-month TTP, % 22

del17p 12 / 22* 7.3 [2.7;14.7]

8-month TTP, % 41

t(4;14) 24 / 32* 2.8 [1.9;4.0]

8-month TTP, % 12.4

del17p

t(4;14)ITT

IFM 2010-02: Time To Progression (ITT)

O/N Median 95% CI

ITT population 26 / 50 12 [4.9;15.5]

8-month OS, % 55

del17p 12 / 22* 12 [2.4;-]

8-month OS, % 58

t(4;14) 16 / 32* 9.2 [4.6;-]

8-month OS, % 50

IFM 2010-02: Overall Survival

Shah JJ, et al. Blood. 2013;122:690.

Phase I/II: Carfilzomib/Pomalidomide/LoDEX (Car-Pom-d) in R/R MM

Carfilzomib*20/27 mg/m2 (D1-2, 8-9, 15-16)

Pomalidomide*4 mg (D1-21)

Dexamethasone*40 mg weekly (20 mg after cycle

4)

*Dosing based on MTD established in phase 1• Primary endpoint: ORR • Secondary endpoints:

• DOR, TTP, PFS, time to next therapy, OS

Study Population (N=79)• Relapsed and/or refractory

measurable MM• Lenalidomide-refractory

28-day cycles (cycles 1-6)

CarfilzomibD1-2, 15-16

Pomalidomideunchanged

Dexamethasoneunchanged

Maintenance(cycles 7+)

• Treatment continued until PD or unacceptable toxicity• All patients received antiviral treatment and aspirin 81 mg

or low molecular weight heparin

Car-POM-d in R/R MM: Efficacy

Cytogenetic Risk (by mSMART)

Response, % High (n = 18)

Intermediate (n = 19)

Standard (n = 38)

All Pts(N = 79)

ORR 78 53 74 70

VGPR 22 26 32 27

PR 56 26 42 43

• Median PFS: 9.7 mos; median DOR: 17.7 months; median OS not reached

• No significant difference in PFS or OS based on cytogenetics

• 80% of pts with del(17p) were alive at 12 mos; 58% were progression-free

Shah JJ, et al. Blood. 2013;122:690.


UbUb

UbUb

Ub

Substrates

+


RomidepsinVorinostatPanobinostat



HDAC inhibitors


Phase 2 trial of the histone deacetylase inhibitor romidepsin for the treatment of refractory multiple myeloma

Niesvizky et al, CancerVolume 117, Issue 2, pages 336-342, 22 SEP 2010

http://onlinelibrary.wiley.com/doi/10.1002/cncr.v117.2/issuetoc

Description Regimen N ORR (> PR), %

HDAC Inhibitors

Romidepsin + bortezomib + dex[4]

25 60

Vorinostat + bortezomib[5] 143 17

Bortezomib + panobinostat +

dex[6]55 34.5

HDAC Inhibitors in RRMM

Vorinostat Bortezomib vs Placebo Bortezomib

Dimopoulos et al, Lancet Oncol. 2013 Oct;14(11):1129-40

Vorinostat: Median PFS: 7·63 months (95% CI 6·87-8·40) Placebo: Median 6·83 months (5·67-7·73) (hazard ratio [HR] 0·77, 95% CI 0·64-0·94;p=0·0100).

PANORAMA 1: Phase III Trial of Panobinostat + Bortezomib + Dex

Study Population (N=768)• Relapse or relapsed/refractory MM

• Bortezomib-refractory excluded• 1-3 prior lines of therapy

PanobinostatBortezomib

Dexamethasone

PlaceboBortezomib

Dexamethasone


Stratification based on prior lines of therapy, prior bortezomib

Richardson PG, et al. ASCO 2014. Abstract 8510.

PANORAMA 1: Primary Endpoint Met (PFS)


UbUb

UbUb

Ub

Substrates

+


MelphalanCyclophosphamideBendamustin


Autotransplant for Refractory MM

PFS OSN = 66Median = 11 mo

N = 66Median = 19 mo

SWOG Trial 8993

Vesole DH, et al. J Clin Oncol. 1999;17:2173-2179.

PBSCT in Relapsed MM

Cook G et al,The Lancet Oncology, Volume 15, Issue 8, Pages 874 - 885, July 2014

PAD

Weekly CTX 400 mg/m2

x 21HD Mel

Induction

Consolidation

TTP median HD Mel 19 months [95% CI 16—25]Cyclophosphamide 11 months [9—12]; hazard ratio 0·36 [95% CI 0·25—0·53]; p<0·0001).

http://www.thelancet.com/journals/lanonc/issue/vol15no8/PIIS1470-2045(14)X7166-4

A Phase 1 Study of Bendamustine and Melphalan Conditioning for Autologous Stem

Cell Transplant with Multiple Myeloma.

Dose Levels for BendamustineDose Level On Day 1 Melphalan

(100mg/m2)On Day 2 Melphalan

(100mg/m2)

1 30 mg/m2

2 60 mg/m2

3 90 mg/m2

4 60 mg/m2 60 mg/m2

5 90 mg/m2 60 mg/m2

6 125 mg/m2 100 mg/m2


UbUb

UbUb

Ub

Substrates

+


FilanesibPalbociclib

MelphalanCyclophosphamideBendamustine


ElotuzumabDaratumumabSAR650984


The Team and Collaborators

Tomer Mark MDMorton Coleman, MDRoger Pearse, MDAdriana Rossi, MDDavid JayabalanKaren Pekle RNPArthur Perry PASusan Matthew, PhD Scott Ely, MD/MPH

Selina Chen-Kiang, PhDMonica Guzman, PhDGiorgio Inghirami, MD

Linda Tegnestam RNKathleen Pogonowski RN

Stanley Goldsmith MDMaureen Lane PhDPaul Christos

Myelomacenter.org

Relapsed and Refractory Myeloma Ruben Niesvizky Myeloma Center Myelomacenter.org [email protected].

Documents

prior imid

sct correlates

multiple myeloma

years kumar sk

line therapyremission

evaluable patients

months2nd line lendexmedian

progression overall