New Paradigms, New Treatments in Relapsed/Refractory Disease: An Update

Kenneth C. Anderson, M.D.

Jerome Lipper Multiple Myeloma CenterDana-Farber Cancer Institute

Harvard Medical School

Conflict of Interest: Kenneth C. Anderson, M.D.

Consultancy: Celgene, Onyx, Sanofi Aventis, and Gilead

Scientific Founder: Acetylon, Oncopep

Integration of Novel Therapy

Into Myeloma Management Bortezomib, Lenalidomide, Thalidomide, Doxil, Carfilzomib, Pomalidamide

Target MM in the BM microenvironment to overcome conventional drug resistance in vitro and in vivo

Effective in relapsed/refractory, relapsed,induction, consolidation, and maintenance therapy

Eight FDA approvals and median survival prolonged from 3-4 to 6-7 years, with additional prolongation from maintenance

New approaches needed to treat and ultimately prevent relapse

Relapsed or Intolerant

There is a well defined and recognizedunmet need in multiple myeloma treatment

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

Unmet Need

Relapsed Frontline Treatment

Expectedsurvival (m)

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)

Overview of Phase III Trials with Len and Bortezomib in Relapsed/Refractory MM

1. Weber DM, et al. N Engl J Med. 2007;357:2133-2142. 2. Dimopoulos M, et al. N Engl J Med. 2007;357:2123-2132. 3. Richardson PG, et al. Blood. 2007;110:3557-3560. 4. Orlowski RZ, et al. J Clin Oncol. 2007;25:3892-3901. 5. Weber D, et al. Blood. 2007;110:Abstract 412.

Regimen Trial ORR, %

CR or nCR, %

≥ VGPR, %

DOR, Mos

TTP or PFS, Mos

Median OS, Mos

Len + dex MM-009[1] 61 24 NE16 11

35[5]

Len + dex MM-010[2] 60 25 NE 17 11

Bortezomib APEX[3] 43 16 NE 86

30

VdoxMMY-3001[4] 44 13 27

109 NE

Efficacy and Toxicity by Bortezomibschedule

46.8 mg/m267.6 mg/m267.6Total planned dose

4%16%NAPN discontinuation

35%32%NAPFS @ 3 years

2%14%13%Grade 3-4

NA

44%

30%

VMP*(VISTA)

40 mg/m2

21%

23%

VMP once weekly N=190

Sensory PN

43%Any grade

41 mg/m2Total delivered dose

27%CR

VMP twice weekly N=63

**MateosMateos et al. J et al. J ClinClin OncolOncol 2010; 2010; PN: peripheral neuropathy

Palumbo et al. ASH 2010 abstr 620.

SC vs IV Bortezomib for Relapsed/Refractory Myeloma

EQUIVALENT EFFICACY

Peripheral Neuropathy Bortezomib IV

(N=74)

Bortezomib SC (N=148)

P-value*

Any PN event, % 53 38 0.04

Grade 2, % 41 24 0.01

Grade 3, % 16 6 0.03

Risk factors for PN, %

Grade 1 PN at baseline 28 23

Diabetes at baseline 11 13

Exposure to prior neurotoxic agents 85 86

*P-values are based on 2-sided Fisher’s exact test

Moreau et al, ASH 2010 abstr 312

• Lenalidomide induces caspase 8 mediated apoptosis of MM cells in BM in vitro and in vivo; Dex (caspase 9) enhances response

• Synergistic MM cell toxicity of lenalidomide (caspase 8) with Bortezomib (caspase 9>8) in vitro and in vivo (dual apoptotic signaling)

• Phase I-II trials show that majority (58%) of patients refractory to either agent alone respond to the combination

• Phase I-II trials show 100% response with 74% CR/VGPR and 52% CR/nCR when used as initial therapy, including molecular responses.

Bortezomib, Lenalidomide and Dex Therapy

Richardson et al. JCO 2009; 27:5713-19.Richardson et al. Blood 2010; 116:679-86.

Carfilzomib: A Novel Proteasome (Chymotryptic) Inhibitor

• Novel chemical class with highly selective

and irreversible proteasome binding

• Improved antitumor activity with

consecutive day dosing

• No neurotoxicity in animals

• Durable responses in relapsed and relapsed/ refractory MM w/o neuropathy

• Carfilzomib lenalidomide Dex versus lenalidomide Dex phase III trial for new drug approval

Demo et al. Cancer Res 2007; 67:6383 Kirk et al., Blood 2008, 112: 2765 Siegal et al. Blood 2012:120:2817.

HN

NH

O HN

O

O

NHO

NO O

O

Epoxyketone

Tetrapeptide

Benefit of Carfilzomib in Relapsed/Refractory MM:

Meaningful ORR, DOR and OS

Response Category Total N = 266, n (%)

1 (0.4)

VGPR 13 (4.9)

PR 47 (17.7)

MR CR

SD 81 (30.5)

PD 69 (25.9)

Not evaluable 21 (7.9)

ORR = 22.9% (95% CI: 18.0, 28.5)

Overall Survival Median OS = 15.4 months (95% CI: 12.5, 19.0)

CBR = 35.7% (95% CI: 30.0, 41.8)

Duration of response Median DOR = 7.8 months (95% CI: 5.6, 9.2)

CRd in Relapsed and Upfront MMWang et al ASCO 2011; Jakubowiak et al ASH 2011

• Response to CRd therapy was high, with an ORR of 78%

– 41% VGPR or better

• CRd well-tolerated with durable responses

• ASPIRE phase 3 open-label, international, multicenter trial comparing CRd to Rd in R/R MM fully enrolled.

• Remarkable extent and frequency of response to CRd upfront (100% ORR, 80% CR,nCR after 12 cycles)

Jakubowiak A. et al., Blood, 2012; 120: 1801-8.

Carfilzomib in Relapsed/Refractory MM

Study Ph BTZ status nMedian prior tx

linesCFZ dose Mode of

admin ORR

PX-171-003-A11

II Relapsed and refractory

266 5 20/27 mg/m2 2-10 min IV infusion

24%

PX-171-0072

I/II Relapsed and/or

refractory

20 4.5 20/56 mg/m2 30-min IV infusion

60%

1. Siegel et al. Blood. 2012;120(14):2817-2825 2. Papadopoulos KP, et al. Blood. 2011;118(21):Abstract and poster 2930.

Phase II Study of Infusional Carfilzomib in Patients with Relapsed or Refractory MM

• CFZ dose of 20/56 mg/m2 administered as a 30-minute IV infusion resulted in high response rates in our BTZ treated/refractory population.

• Response rates were comparable to those seen in PX-171-0071

• CFZ dose of 20/56 mg/m2 was associated with more frequent cardiac and pulmonary toxicities, particularly HTN and pulmonary edema/CHF.

– Possible contribution from “supportive” measures?

• CFZ dose of 20/56 mg/m2 continues to be explored in ongoing Phase II/III studies. Lendvai et al, ASH 2012 Abstr 947

Pomalidomide in Myeloma

MM cells

Bone Marrow Stromal Cells

Dendritic

Cells

IL-6

TNFIL-1A

IL-2

IFN

CD8+ T Cells

C

E

Bone Marrow Vessels

ICAM-1

VEGFbFGF

D

B

NK CellsNK-T Cells

Hideshima et al. Blood 96: 2943, 2000Davies et al. Blood 98: 210, 2001Gupta et al. Leukemia 15: 1950, 2001

Mitsiades et al. Blood 99: 4525, 2002Lentzsch et al Cancer Res 62: 2300, 2002 LeBlanc R et al. Blood 103: 1787, 2004Hayashi T et al. Brit J Hematol 128: 192, 2005

PKCNFAT

PI3K

IL-2

CD28

Pomalidomide With Low-Dose Dexamethasone Relapsed and Refractory Multiple Myeloma

• POM was effective in heavily pretreated patients who had already received LEN and bortezomib and who progressed on their last line of therapy

• The combination of POM with LoDEX improves the ORR due to synergy between immunomodulatory agents and glucocorticoids

– POM + LoDEX, 34%; POM alone, 15%

• Response was durable with POM regardless of the addition of LoDEX

– POM + LoDEX, 8.3 months ; POM alone, 8.8 months

• POM is generally well tolerated, with low rates of discontinuations due to AEs

• Age had no impact on ORR, DoR, or safety

Jagannath S, et al. ASH 2012 abstract 450.

Pomalidomide Plus Low-Dose Dexamethasone (Pom/Dex) in Relapsed Myeloma (345 patients)

• Pom/Dex has high response rates even in heavily pretreated relapsed myeloma

• Pom/Dex is well tolerated

• Toxicity and efficacy are similar between the 2mg and 4mg dose levels

• The strongest predictors of response include the number and type of prior regimens.

• The strongest predictors of TTP and survival include the number and type of prior regimens, LDH, and B2M.

Lacy et al. ASH 2013 Abstr 201.

A Phase III Clinical Trial of Pomalidomide with Low-dose Dex vs. High-dose Dex in

Relapsed/Refractory MM• POM + LoDEX significantly improved PFS and OS

– Median PFS: 3.6 vs 1.8 months

• HR = 0.45; P < .001

– Median OS: not reached vs 7.8 months

• HR = 0.53; P < .001

• Equal benefit in pts refractory to both LEN and BORT

• POM + LoDEX was generally well tolerated

• POM + LoDEX should be considered as a new treatment option for these pts

Dimopoulos et al. ASH 2013 LBA6

MM-005: A Phase 1 Trial of Pomalidomide, Bortezomib, and Low-dose Dexamethasone in

Relapsed or Relapsed/Refractory MM

• POM + BORT + LoDEX (PVD) well tolerated– cohort 5 as the MTD/MPD

• POM 4 mg; BORT 1.3 mg/m2; DEX 10/20 mg

• Responses in RR MM across all cohorts– ORR: 73%, VGPR: 27%, SD: 27% – Responses were rapid; majority are ongoing– Efficacy even with adverse cytogenetics

• Phase III Trial Pom Bort Dex vs Bort Dex for full approval

Richardson et al. ASH 2013 Abstr 727.

Carfilzomib Pomalidomide Dexamethasone (Car-Pom-d) in Relapsed/Refractory MM

• MTD was Carfilzomib 20/27 mg/m2, Pomalidomide 4 mg, and dexamethasone 40 mg

• There are limited G 3 and 4 non hematologic toxicities; the regimen was tolerated well with no unexpected toxicity

• The combination of Car-Pom–d is highly active in this heavily pretreated, refractory patient population

• The combination has encouraging preserved response rate and survival independent of FISH/cytogenetic risk status

≥ VGPR 13% ≥ ORR 50% ≥ CBR 67% PFS (median) 7.4 months OS 90% @ 1 year

Shah et al. ASH 2012 Abstr 74.

1. Development of immune therapies

2. Development of novel agents targeting the MM cell in the BM microenvironment

3. Development of rationally-based combination therapies

4. Utilization of genomics for improved classification and personalized therapy

Myeloma will be a chronic illness, with sustained CR in a significant fraction of patients.

Current and Future Directions

Antibody-dependentCellular cytotoxicity

(ADCC)

ADCC

Effector cells:

MM

FcR

Complement-dependentCytotoxicity (CDC)

CDC

MM

C1q

C1q

Apoptosis/growth arrest

via targetingsignaling pathways

MM

Lucatumumab or Dacetuzumab (CD40)Elotuzumab (CS1)Daratumumab (CD38)XmAb 5592 (HM1.24)

huN901-DM1 (CD56)nBT062-maytansinoid

(CD138)1339 (IL-6)BHQ880 (DKK1)RAP-011 (activin A)Daratumumab (CD38)

Daratumumab (CD38)

MAb-Based Therapeutic Targeting of Myeloma

Tai & Anderson Bone Marrow Research 2011

Phase 2 Elotuzumab Lenalidomide Low-dose Dex in Relapsed/ Refractory MM

• Elotuzumab plus lenalidomide and low-dose dexamethasone has a high ORR in relapsed and relapsed/refractory MM

– 82% for all pts (91% in pts who had received only 1 prior therapy)

– 92% for pts treated with elotuzumab 10 mg/kg

Median PFS was 33 mos for patients receiving elotuzumab 10 mg/kg

• The combination was generally well tolerated

– Most common Grade 3/4 treatment-emergent AEs were neutropenia (16%), thrombocytopenia (16%), and lymphopenia (16%)

– Premedication regimen decreased incidence and mitigated severity of infusion reactions*

Richardson et al. ASH 2012, Lonial et al. ASCO 2013

PHASE I/II STUDY OF DARATUMUMAB CD38 MONOCLONAL ANTIBODY IN

RELAPSED/REFRACTORY MM • Favorable safety profile as monotherapy

• In 15 of 32 (47%) showed benefit

– 4 patients achieving PR (13%)– 6 patients achieving MR (19%)– 5 patients achieving SD (16%)

• At doses 4mg/kg and above, 8 of the 12 patients had at least MR (66%)

• To be combined with lenalidomide dexamethasone

Plesner et al. ASH 2012 Abstr 73.

Phase I Trial of Vaccination with DC/MM Fusions in Relapsed Refractory MM

• Well tolerated, no autoimmunity

• Induced tumor reactive lymphocytes in a majority of patients

• Induced humoral responses to novel antigens (SEREX analysis)

• Disease stabilization in 70% of patients

Rosenblatt et al. Blood 2011; 117:393-402

• DC/MM fusions induce anti-MM immunity in vitro and inhibit MM cell growth in vivo in xenograft models

• Vasir et al. Brit J Hematol 2005; 129: 687-700

Background: MM/DC Vaccination following Autologous PBSCT for Myeloma

29%

54%

38%

25%

33% 13%

0%

10%

20%

30%

40%

50%

60%

70%

80%

90%

100%

100 Day Post-Transplant Post 100 Day (Best Response)

% P

artic

ipan

ts

CR/nCR VGPR PR

Rosenblatt et al., CCR 2013

PD-L1 Plays an Important Role in Dampening the Anti-tumor Immune Response

Stromal PD-L1 modulation of T cells

Immune cell modulation of T cells

PD-L1/PD-1-mediated Inhibition of

tumor cell killing

IFNg-mediated

up-regulation of tumor PD-

L1

Priming and Activation of T cells

PD-L2 mediated inhibition of TH-2 T cells

receptor

Chen DS, Irving BA, Hodi FS. Clin Cancer Res. 2012;18:6580.

PD-L1 expression in the tumor microenvironment can inhibit anti-tumor T cell activity:

1. PD-L1 expression by tumor infiltrating immune cells

2. PD-L1 expression by cancer cells

cancer cell

PD-L1

lymphocyte

Presence of intratumoral T-cells may lead to adaptive immune resistance

Combination Immunotherapy Posttransplant

• Anti PD-1 Ab administration in the early post-autologous transplant period is well tolerated

• Anti-PD1 results in the expansion of tumor reactive lymphocytes in the post-transplant period that persist at 6 months

• This provides a promising platform for combination with a tumor vaccine

• We have inititated enrollment into cohort 2, in which patients receive an autologous DC/myeloma fusion vaccine 1 week prior to each dose of Anti-PD-1Ab

Avigan et al.

20S20S

19S

19S

a b5, 5i1, 1i2, 2i

ATPases/Cdc48

PotentialTherapeutic Targets

26S PROTEASOME

ATP ADP

UB enzymes E1, E2 andE3-UB-Ligases

UbUb

Ub

Poly-ubiquitinated proteins (proteasome substrates)

Free for re-cycling

Six Proteaseactivities

Degraded proteinUb

Immunoproteasome

Proteasome: Present and Future Therapies

DeubiquitylatingEnzymes (DUBs)

Bortezomib, Carfilzomib, CEP-18770ONYX-0912MLN 2238

NPI-0052: 5, 1, 2

5

PR-924P5091 target USP-7

P5091 Specifically Target USP-7 and does not Alter Proteasome Activity

P5091 (µM) 2.5 5 7.5 10 12.5 Velcade (nM) 1 3 5 7 9

USP-7 Knockout Proteasome Activity Assay

Chauhan et al. Cancer Cell 2012;22: 345-58

P5091 Overcomes Bortezomib-Resistancein MM Cells

Chauhan et al. Cancer Cell 2012; 22: 345-58

MLN2238/9708 Decreases Cell Viability in MM Cells and Overcomes Bortezomib-

Resistance

24h 48h

Chauhan et al., Clin Cancer Res, 2011; 17: 5311-21.

Weekly MLN9708 in Relapsed/Refractory Multiple Myeloma: Phase I Study

• Single-agent oral MLN9708 MTD 2.97 mg/m2 on a weekly (days 1, 8, and 15 every 28 days) schedule

• Oral MLN9708 generally well tolerated– hematologic and gastrointestinal events generally

manageable, low rate of discontinuations – Infrequent PN, only 1 grade 3 PN

• Pharmacokinetic profile supports weekly oral dosing

• Relapsed and/or refractory MM patients (median 4 prior lines of therapy)– ORR (≥PR) of 18%, plus 2% MR and 30% SD, including

relapse post BortezomibKumar ASCO 2013

MLN9708 in Relapsed and/or Refractory MM: Expansion Cohorts of a Phase 1 Dose-

Escalation study• 46 pts evaluable for response

– 21 in dose-escalation cohorts

– 30 in expansion cohorts (including 6 from dose-escalation cohorts)

• 6 pts have achieved ≥PR

– 1 CR, confirmed by bone marrow (PI-naïve expansion cohort)

– 5 PRs (1 each at 1.2 and 2.23 mg/m2 in dose-escalation cohorts; 1 in RRMM and 2 in bortezomib-relapsed expansion cohorts)

• 1 pt achieved MR (bortezomib-relapsed expansion cohort; 40% M-protein reduction)

• All 7 pts remain in response, with duration of disease control of up to 15.9 months

• 28 pts have achieved SD

– 14 in dose-escalation cohorts

– 9, 5, and 2 in RRMM, bortezomib-relapsed, and PI-naïve expansion cohorts

– Durable, with disease stabilization for up to 12.9 months

Richardson et al. ASH 2011

• Phase I clinical trials ongoing

In Vitro Anti-MM Activity of Oral Chymotryptic Inhibitor ONX 0912 (Opromazib)

Myeloma Cell Lines Patient Tumor Cells

Chauhan et al. Blood. 2010;116:490614

Marizomib: A Non-Peptide Proteasome Inhibitor Induces Rapid, Broad and Prolonged Inhibition

Chauhan et al., Cancer Cell 2005; 8: 407-19

• Exhibits high levels of proteasome inhibition

without toxicities associated with bortezomib

• Active in bortezomib and IMiD resistant myeloma preclinically

Marizomib (NPI-0052)

HN

O

O

O

CH3

OH

Cl

H

H

H

Responses to Marizomib +/- Dexamethasone in Evaluable Pts at Full Dose [ >0.4 mg/m2 ]* Twice Weekly (n=21**)

All PtsEBMT ≥ SD 11/20 55%MR + PR 3/20 15%

Uniform Criteria ≥ SD 12/21 57%PR + VGPR 4/21 19%

Pts Exposed to Bortezomib EBMT ≥ SD 11/19 58%MR + PR 3/19 16%

Uniform Criteria ≥ SD 11/19 58%PR + VGPR 3/19 16%

*As of 05 Dec 11

• Response criteria defined with baseline SPEP ≥ 0.5 g/dL or UPEP ≥ 200 mg/24h with at least 2 assessments after treatment Day 1 for EBMT ; also by free lite for UC**.

• Refractory defined as having PD during or within 60 days of last regimen.

Pts Refractory to BortezomibEBMT ≥ SD 8/12 67%MR + PR 2/12 17%

Uniform Criteria ≥ SD 8/12 67%PR + VGPR 2/12 17%

Pts Refractory to LenalidomideEBMT ≥ SD 8/13 62%MR + PR 3/13 23%

Uniform Criteria ≥ SD 9/14 64%PR + VGPR 4/14 29%

Median Duration of Response (all Pts) = 133 days (~ 5 mos)

Richardson et al. ASH 2011

MM

Functional Sequelae of Btk Inhibition by PCI-32765 in the MM BM milieu

Osteoclast precursors Osteoclast

M-CSF, IL-6, MCP-1

PCI32765

IL-6SDF-1MIP-1MIP-1M-CSFMCP-1

PCI-32765

M-CSF

TRAP5bSDF-1IL-8Activin AAPRILMIP-1MIP-1TGF1RANTESBAFF

Stromal cellsfms

RANK Boneresorption

Tumor microenvironment

Adhesion MigrationHoming

PCI32765

MM Stem Cell

Btk activation by IL-6, SDF-1

Colony formation

MIP-1, MIP-1, IL-8, TGF1RANTES, BAFF, TRAF2, CXCR4, LAT, PLC2, MYD88, NFATc1

Tai et al. Blood2012; 120: 1877-87.

Delmore JE., Issa GC, et al. Cell 2011; 146:904.

BET Bromodomain Inhibition Suppresses c-myc Expression and Function and Triggers Anti-MM

Activity

Additional Targeted Therapies in Development

KSP inhibitors (Array 520)

AKT inhibitor (GSK agent)

Nuclear transport inhibitors (KPT)

CDK inhibitors

Protein

protein aggregates(toxic)

UbUb

UbUb

26S proteasome

UbUb

Ub Ub

Ub

Aggresome

Panibinostat,Vorinostat, ACY1215

dynein

UbUb

dynein

MicrotubuleAutophagy

Bortezomib, Carfilzomib, NPI0052, MLN9708, ONX 0912

Ub Ub

Ub

Lysosome

HDAC6

HDAC6

HDAC6

Ub

Ub

Development of Rationally-based Combination Therapies (HDAC and Proteasome Inhibitors)

Hideshima et al. Clin Cancer Res. 2005;11:8530.Catley et al. Blood. 2006;108:3441-9.

VANTAGE 088: An International, Multicenter, Randomized, Double-Blind Study of Vorinostat

or Placebo with Bortezomib in Relapsed MM

• The combination of vorinostat + bortezomib is active in patients with relapsed and refractory MM– Significant improvement in response rate– ORR 54% vs 41% (P<0.0001); CBR 71% vs 53% (P<0.0001)

• PFS and TTP were prolonged in the combination arm compared with bortezomib alonePFS hazard ratio reduction of 23% (P=0.01); 7.63 months (6.9–8.4)

versus 6.83 months (5.7–7.7)

• Diarrhea, fatigue, and thrombocytopenia limited tolerability

Dimopoulos et al. ASH 2011, Lancet Oncology, in press

Bench to Bedside Translation of HDAC 6 Selective Inhibitor ACY 1215

• Orally bioavailable, highly potent, selective • inhibitor of HDAC 6 synthesized in fall 2009

• Synergistic MM cytotoxicity with Bortezomib • in vitro and in vivo

• Favorable PK/PD, toxicity profile

•Phase Ia/Ib/II clinical trials of ACY1215, alone and with Bortezomib and with lenalidomide/dexamethasone, ongoing; trials with pomalidomide and carfilzomib this year.

Santo et al. Blood 2012;119:2579-89

Mutations in Myeloma19 Patients Each With

Newly Diagnosed and Relapsed MM

• Protein homeostasis: 42% including FAM46C, RPL10, RPS6KA1, EIF3B, XBP1, LRRK2

• NF-kB signaling: 10 point mutations, 4 additional structural re-arrangements affecting codingConfers bortezomib sensitivity

• Histone methylating enzymes: WHSC1, UTX, MLL

• BRAF: 4% activating : Single patient MM response Andrulis et al Cancer Discovery 2013; 3: 862-9.

• PSMB5 b5 proteasome subunit mutation confers proteasome inhibitor resistance in laboratory, not identified in clinic

Lichter et al Blood 2012: 120: 4513-16.

Chapman et al. Nature 2011; 471: 467-72.

EARLY

LATE

PRAMEF12

NRAS

USH2A

ASXL2

NCKAP5PLS1

ACOT12

PCDHB6

CDKAL1

COL9A1

TIAM2

LRRC69

TRPM3

0

0.2

0.4

0.6

0.8

1

1.2

PD4301

%MutLate%MutEarly

Early mutationnot in late sample

New mutations in late sample

Early Tumor Late Tumor

Whole Genome Sequencing Identifies Acquisition of New Changes in MM: 71 Patient Study

(Munshi et al, ASH 2011 Abstract 276)

Early Tumor Late Tumor

1. Lenalidomide dexamethasone, bortezomib, and pegylated doxorubicin are approved regimens for relapsed MM.

2. Pomalidomide/dex and carfilzomib are newly FDA approved options.

3. There are many promising protocols of novel immune and targeted agents which show promise, alone and in combination.

4. Genomic analyses are both defining the basis for evolution underlying relapse and identifying new targets.

Relapsed Refractory Myeloma

United Nations Against Myeloma:

Bench to Bedside Research TeamKenneth AndersonNikhil MunshiPaul RichardsonRobert SchlossmanIrene GhobrialSteven TreonJacob LaubachDeborah DossKathleen ColsonMary McKenneyKim NoonanTina FlahertyKathleen Finn Muriel GannonStacey ChumaJanet KunsmanDiane WarrenCarolyn RevtaAndrea FreemanAlexis FieldsAndrea KolligianJohn FeatherFarzana MasoodNora LoughneyHeather GoddardTiffany PoonNicole StavitzskiRanjit BanwaitShawna CormanHeather GoddardMeghan Marie LeahyCaitlin O’GallagherChristina TripsasKarin AndersonShannon VieraKatherine RedmanAmber WalshSamir AminWanling XieParantu ShahHolly BartelLisa PopitzJeffrey Sorrell

Teru HideshimaConstantine MitsiadesDharminder ChauhanNoopur RajeYu-Tzu TaiRuben CarrascoJames BradnerGullu GorgunJooeun BaeFrancesca CottiniMichele CeaAntonia CagnettaTeresa CalimeriEdie WellerAjita SinghZe TianDiana CirsteaYiguo HuNaoya MimuraJiro MinamiSun-Yung KongWeihua SongDouglas McMillinCatriona HayesSteffen KlippelJana JakubikovaPanisinee LawasutNiels van de DonkEugen DhimoleaJake DelmoreHannah JacobsMasood ShammasMariateresa FulcinitiJianhong LinJagannath PalSamantha PozziLoredana SantoClaire FabreAnuj MahindraRao PrabhalaJake DelmorePuru NanjappaMichael SellitoAvani Vaishnav

USA

UK

India

Italy

Japan

Canada

Germany

China

Greece

Taiwan

Australia

IrelandIsrael

Turkey

Austria