ASCT is dispensable in MM patients in the Era of …...ASCT is Dispensable in MM Patients in the Era of Novel Agents: Nyet Bart Barlogie Myeloma Institute for Research and Therapy

ASCT is Dispensable in MM Patients in the Era of Novel Agents: Nyet

Bart BarlogieMyeloma Institute for Research and

TherapyUAMS, Little Rock AR, USA

The issues • Consider progress made

– Remember 10‐year survival now accomplishable in up to and more than 50%

• TT1: 10% of 231 patients without relapse @ 18‐22+ years – plateau!!!

• 70% @ 9yr with GEP low risk

– Difficult to anticipate long‐term results with non‐ transplant up‐front therapy

• Nothing that works in medicine should be dispensable unless

– Danger to patient– Superseded by new treatments

• Usefulness of this recurring debate?– Show evidence of cure

ARK TT TRIALS v IFM & SWOG9321 median statistics

Overall Survival by Trial: UARK Total Therapy (TT) 1, TT2 and TT3,SWOG 9321 and IFM 90, IFM 94 and IFM 99

0%

20%

40%

60%

80%

100%

0 5 10 15 20 25Years from registration

IFM 90IFM 94IFM9902IFM9904S9321TT1TT2TT3

Deaths / N160 / 194303 / 402226 / 692114 / 197631 / 860189 / 231359 / 66794 / 303

Medianin Years

4.54.3NR3.94.05.78.8NR

Logrank P-value < .0001

Progression-Free Survival by Trial: UARK Total Therapy (TT) 1, TT2 and TT3,SWOG 9321 and IFM 90, IFM 94 and IFM 99

0%

20%

40%

60%

80%

100%

0 5 10 15 20 25Years from registration

IFM 90IFM 94IFM9902IFM9904S9321TT1TT2TT3

Events / N177 / 194367 / 402490 / 692169 / 197580 / 860207 / 231468 / 667119 / 303

Medianin Years

2.52.33.42.02.32.64.8NR


Improvement in long‐term outcomes with successive Total Therapy trials for multiple myeloma: are patients now being cured?

S Z Usmani1, J Crowley2, A Hoering2, A Mitchell2, S

Waheed1, B Nair1, Y AlSayed1, F vanRhee1

and B Barlogie1

• The concept of applying all active therapeutic agents in Total Therapy (TT) clinical

trials for newly diagnosed multiple myeloma was pursued with the

intent of

developing curative treatment. The results of TT1 (n=231), TT2 (n=668) without or

with thalidomide and TT3 with added bortezomib (n=303) have been reported. An

update with median follow‐up times of 17.1, 8.7 and 5.5 years, respectively, is

provided. Conditional overall survival (OS) analysis from a 4‐year landmark was

applied to account for earlier protocol failure owing to disease

aggressiveness and

toxicities. Cumulative relative survival was computed in the context of age‐

and

gender‐matched US population, and interval‐specific relative survival ratios were

estimated to determine times to normal survival expectation. Based on Cox

model‐adjusted statistics, OS, progression‐free survival and complete‐response

duration all improved with the transitions from TT1 to TT2 to TT3; improvement

was also evident from time‐to‐progression estimates, 4‐year conditional survival

data and cumulative relative survival. Interval‐specific relative survival normalized

progressively sooner, reaching near‐normal levels with TT3 in patients who

attained complete response. Thus, a strategy using all myeloma‐effective agents

up‐front seems effective at preventing, in progressively larger patient cohorts over

time, the outgrowth of resistant tumor cells that account for ongoing relapses.• Leukemia

advance online publication 13

July

2012; doi: 10.1038/leu.2012.160

Clinical outcomes overall – left; conditional 4‐yr ‐

right

Cumulative relapse rates overall – left; from CR ‐

right

Cumulative relative survival – left Interval‐specific relative survival ratios ‐

right

10% cure fraction in high‐risk MM

GEP‐70 Low Risk SubgroupUARK Total Therapy Protocols: Overall Survival

GEP-70 Low Risk Patients

0%

20%

40%

60%

80%

100%

0 5 10 15Years from Enrollment

TT2 No Thal (98-026)TT2 Thal (98-026)TT3a (2003-33)TT3b (2006-66)

Deaths / N81 / 15662 / 14960 / 23524 / 129

3-YearEstimate

87% (81, 92)85% (79, 90)87% (83, 92)88% (82, 93)

Logrank P-value = .02

UARK Total Therapy Protocols: Progression-Free SurvivalGEP-70 Low Risk Patients

0%

20%

40%

60%

80%

100%

0 5 10 15Years from Enrollment


Events / N123 / 15689 / 14991 / 23536 / 129

3-YearEstimate

65% (57, 72)76% (69, 83)83% (79, 88)81% (75, 88)


UARK Total Therapy Protocols: Cumulative Incidence of CRGEP-70 Low Risk Only

EBMT Response Criteria for TT2 & TT3a/b

0%

20%

40%

60%

80%

100%

0 24 48 72 96 120 144Years from Enrollment


Events / N68 / 15293 / 144149 / 23594 / 129

Medianin Months

NR21.415.411.1

UARK Total Therapy Protocols: Complete Response Duration from First CRGEP-70 Low Risk Patients

0%

20%

40%

60%

80%

100%

0 3 6 9 12Years from First CR


Events / N43 / 6847 / 93

37 / 14921 / 94

3-YearEstimate

68% (56, 79)73% (64, 82)88% (83, 93)85% (77, 92)


GEP‐70 High Risk Subgroup

UARK Total Therapy Protocols: Cumulative Incidence of CRGEP-70 High Risk Only

EBMT Response Criteria for TT2 & TT3a/b

0%

20%

40%

60%

80%

100%

0 12 24 36 48 60Years from Enrollment


Events / N8 / 2014 / 2623 / 4020 / 37

Medianin Months

NR17.913.713.8

UARK Total Therapy Protocols: Complete Response Duration from First CRGEP-70 High Risk Patients

0%

20%

40%

60%

80%

100%

0 2 4 6 8 10Years from First CR


Events / N7 / 8

10 / 1416 / 2311 / 20

3-YearEstimate

38% (7, 68)43% (18, 68)48% (28, 68)50% (27, 72)


UARK Total Therapy Protocols: Overall SurvivalGEP-70 High Risk Patients

0%

20%

40%

60%

80%

100%

0 3 6 9 12Years from Enrollment


Deaths / N19 / 2020 / 2631 / 4023 / 37

3-YearEstimate

40% (19, 61)39% (20, 57)53% (37, 68)46% (30, 62)


UARK Total Therapy Protocols: Progression-Free SurvivalGEP-70 High Risk Patients

0%

20%

40%

60%

80%

100%



Events / N19 / 2022 / 2632 / 4024 / 37

3-YearEstimate

20% (4, 36)31% (14, 48)40% (25, 55)41% (25, 56)


Induction-1 to Transplant-1

High vs Low risk p-values: TT2 P=.002, TT3 P=.008

0%

20%

40%

60%

80%

100%

0 2 3 5 6Months from Induction Cycle 1

TT2: High-risk 7 / 46

TT2: Low-risk 12 / 295



High vs Low risk p-values: TT2 P<.0001, TT3 P<.0001

0%

20%

40%

60%

80%

100%

0 3 6 9 12Months from Transplant 1





Transplant-1 to Transplant-2


0%

20%

40%

60%

80%

100%

0 3 6 9 12Months from Transplant 2

Transplant-2 to Consolidation-1TT2: High-risk 10 / 24





0%

20%

40%

60%

80%

100%

0 3 6 9 12Months from Consolidation

Consolidation-1 to Cons-2






0%

20%

40%

60%

80%

100%

0 3 6 9 12Months from Consolidation 2

Cons-2 to Maintenance-1TT2: High-risk 9 / 19




High vs Low risk p-values: TT2 P=.32, TT3 <.0001

0%

20%

40%

60%

80%

100%

0 9 18 27 36Months from Maintenance 1

From Maintenance OnwardTT2: High-risk 5 / 10 TT2: Low-risk 59 / 171

TT3: High-risk 18 / 39 TT3: Low-risk 36 / 274

TREATMENT FAILURE BY PROTOCOL PHASE AND GEP RISK

TT5 results vis‐à‐vis TT2 and TT3 in high‐risk myeloma

UARK Total Therapy Protocols: Complete Response Duration from First CRGEP-70 High Risk Patients

0%

20%

40%

60%

80%

100%


TT2 No Thal (98-026)TT2 Thal (98-026)TT3a (2003-33)TT3b (2006-66)TT5 (2008-02)

Events / N7 / 8

10 / 1416 / 2311 / 204 / 31

3-YearEstimate

38% (7, 68)43% (18, 68)48% (28, 68)50% (27, 72)80% (62, 98)


UARK Total Therapy Protocols: Overall SurvivalGEP-70 High Risk Patients

0%

20%

40%

60%

80%

100%



Deaths / N19 / 2020 / 2631 / 4023 / 375 / 56

3-YearEstimate

40% (19, 61)39% (20, 57)53% (37, 68)46% (30, 62)76% (58, 95)


UARK Total Therapy Protocols: Progression-Free SurvivalGEP-70 High Risk Patients

0%

20%

40%

60%

80%

100%



Events / N19 / 2022 / 2632 / 4024 / 376 / 56

3-YearEstimate

20% (4, 36)31% (14, 48)40% (25, 55)41% (25, 56)76% (58, 93)


UARK Total Therapy Protocols: Cumulative Incidence of CRGEP-70 High Risk Only

EBMT Response Criteria for TT2 & TT3a/bIMWG Response Criteria for TT5

0%

20%

40%

60%

80%

100%



Events / N8 / 2014 / 2623 / 4020 / 3731 / 56

Medianin Months

NR17.913.713.87.8

High‐risk myeloma – the place for discovery of novel strategies

• Median survival ~3yr, PFS ~2yr

• Finite cure rate of ~5%• Terminal event also in low‐risk MM after relapse

• Ideal scenario for exploration of novel concepts– TT5 dose‐dense and less dose‐intense– Consider cytokine storms with chemotherapy as

potentially harmful via providing MM growth signals

– Exciting data emerging with pomalidomide and carfilzomib

Let’s unite and quit debating the obvious

• International effort on high‐risk MM– Agree on high‐risk criteria

• Look at several approaches concurrently– Dose‐dense chemo‐novo‐therapy– Cytokine‐storm‐avoiding therapies

• New agents• Metronomic therapy• Oncolytic‐viral therapy• Expanded NK cyto‐therapy• RIC allo‐Tx

Incidence of any MDS-CAby protocol at first transplant

0%

5%

10%

15%

20%

25%

0 5 10 15Years from first autotransplantation

TT2+ThalTT2-ThalTT3aTT3b

Events / N20 / 27018 / 28322 / 27911 / 162

10-YearEstimate

9.1%8.4%

13.0%8.5%

Incidence of any persistent MDS-CAby protocol at first transplant

0%

5%

10%

15%

20%

25%

0 5 10 15Years from first autotransplantation

TT2+ThalTT2-ThalTT3aTT3b

Events / N9 / 2707 / 283

10 / 2797 / 162

10-YearEstimate

4.2%3.7%6.4%7.9%

Cumulative incidence of MDS-CA and persistent MDS-CA by protocol

Pairwise log-rank comparisons: Pairwise log-rank comparisons:TT3b vs. TT3a: p-value = 0.0206 TT3b vs. TT3a: p-value = 0.0207TT3b vs. TT2-Thal: p-value = 0.0134 TT3b vs. TT2-Thal: p-value = 0.0045TT3b vs. TT2+Thal: p-value = 0.0178 TT3b vs. TT2+Thal: p-value = 0.0002TT3a vs. TT2-Thal: p-value = 0.1502 TT3a vs. TT2-Thal: p-value = 0.1283TT3a vs. TT2+Thal: p-value = 0.3134 TT3a vs. TT2+Thal: p-value = 0.2090TT2-Thal vs. TT2+Thal: p-value = 0.8863 TT2-Thal vs. TT2+Thal: p-value = 0.7490

Thank you

On behalf of our suffering patients!

Examples

• Anti‐CD20 in AMM

– 40 y/o WM with AMM

– Observed with high SFLC

– Achieved almost CR with

rituximab alone

• Pomalidomide in PCL

• Overall

• VTD‐PACE

• Nagen

Lambda Light Chain SMM, asymptomatic; Slight progression in 6/08, collected stem cells•Dx – Jan ‘08: •Feb ‘08: Gene Array low‐risk 70/80 with CD‐2 molecular subtype with CD20 expression of 5400 and High Levels

of

VPREB3; no cyclin D1 spike nor cyclin D3 spike. •Feb ‘08: Cytogenetics 46 XY [17] with del 6, q15 [3]•Aug ‘10: Observation•May ‘11: Consider designation of LPL/WM of non‐IgM variety due to CD20 & VPREB3 •LLC at 213 and Urine M 1766•started on Rituximab 750mg/m2/d x 5, weekly x 4, monthly•May ‘12: LLC at 9.3; Urine M only trace

Response of AMM to Rituximab

Presented with IgGƛ+ƛ•Dx –

11/15/10: •Some response to cyclophosphamide 50mg with added Revlimid 25mg Dex 12/22/10; last dose 1/12/10•Data from Royal Marsden in London with CD20 expression co‐expressed with CD138•1/18/11: GEP – CD2 molecular subtype, without spiked expression of cyclin D1 or cyclin D3•Bone Marrow with 50% aspirate/60% biopsy and 70% cellularity; CD138 and in situ hybridization studies:

predominantly of lambda expression cells.•CD20 expressed in quartile 4 at 7700. VPREB3, another B‐cell marker was quartile 2. Apparently WM signature.•Uniquely

hyper‐expresses

EBI

2,

which

is

an orphan

7‐transmembrane

receptor

with

constitutive

activity.•1/28/12: Rituximab initiated at 750mg/m2/day x 5, then q 1 week x 4, then monthly

Rituximab

ƛ

109

Rituximab

SC collection

Ongoing response to Rituximab in patient with WM‐like myeloma

Plasma Cell Leukemia IgGƛ

isotype, relapsed and started Pomalidomide on June 28, 2012.•Dx ‐

1/25/12: HiRisk subgroup MS GEP 70 1.24 GEP 80 3.59 •2007: VD with remission•Maintenance with Revlimid and Zometa until 4/2011•Kirin Trial with Velcade PR until 12/11•Genetic analysis with monosomy 13 and FGFR3 translocation•January 2012: leukocytosis of 15k with 80% granulocytes; referred.•Treated like TT6: MEL‐10 VEL 1.0 DTPACE/MEL80+VRDPACE with cells 3/27/12•MEL80VRDPACE 3/27/12 tx. •Intertx #1 M20VDTPACE 5/15/12•Pomalidomide 6/28/12

Tx #1M80

VDRPACE

InductionVM10DTPACE

InterTx #1M20VDTPACEv

relapse

Collection 20 mil CD34/kg

44~45,X,X,der(1;?12)(q10;q10)dup(1)(q12q4

4),del(3)(p14),der(7)t(1;7)(q12;p22),del(11)(

q13q23),+?12,13,14,+?19,del(22)(q11.2),inc[

cp4]/78~83,idemx2,inc[5]/46,XX[cp12]

InterTx #1M20VDTPACE

Striking response to Pomalidomide in case of secondary PCL

Total Therapy as an example of extending survival toward curability

UARK Total Therapy Protocols: Overall Survival

0%

20%

40%

60%

80%

100%


TT1 (89-001)TT2 No Thal (98-026)TT2 Thal (98-026)TT3a (2003-33)TT3b (2006-66)

Deaths / N192 / 231209 / 345161 / 32399 / 30349 / 177

3-YearEstimate

71% (66, 77)79% (75, 83)79% (74, 83)82% (77, 86)79% (73, 85)


UARK Total Therapy Protocols: Progression-Free Survival

0%

20%

40%

60%

80%

100%



Events / N208 / 231269 / 345205 / 323132 / 30364 / 177

3-YearEstimate

42% (36, 48)60% (55, 65)69% (64, 74)77% (72, 82)73% (66, 79)


UARK Total Therapy Protocols: Cumulative Incidence of CREBMT Response Criteria for TT1, TT2 & TT3a/b

0%

20%

40%

60%

80%

100%

0 24 48 72 96 120 144 168Years from Enrollment


Events / N94 / 231146 / 336201 / 314189 / 303120 / 176

Medianin Months

NRNR22.614.811.9

UARK Total Therapy Protocols: Complete Response Duration from First CR

0%

20%

40%

60%

80%

100%



Events / N74 / 87

95 / 146106 / 20155 / 18933 / 120

3-YearEstimate

43% (33, 53)66% (59, 74)73% (67, 79)84% (78, 89)79% (71, 86)


TOTAL THERAPIES 2, 3 FOR UNTREATED MM GEP HIGH-RISK – DATA AS OF JUNE 10, 2010

0%

20%

40%

60%

80%

100%


Overall Survival

TT3b: 18 / 37TT3: 27 / 40

TT2+: 18 / 26

TT2-: 17 / 200%

20%

40%

60%

80%

100%


TT3b: 20 / 37

TT3: 30 / 40TT2+: 21 / 26

TT2-: 18 / 20

Event-free Survival

0%

20%

40%

60%

80%

100%


TT3b: 20 / 37 TT3: 23 / 40

TT2+: 14 / 26

TT2-: 8 / 200%

20%

40%

60%

80%

100%

0 2 4 6 8Years from Date of 1st CR

TT3b: 8 / 20TT3: 14 / 23

TT2+: 9 / 14

TT2-: 6 / 8

Cumulative CR Rate CR Duration

Documents

ASCT is dispensable in MM patients in the Era of …...ASCT is Dispensable in MM Patients in the Era of Novel Agents: Nyet Bart Barlogie Myeloma Institute for Research and Therapy