“ pro cure” in multiple myeloma...multiple myeloma can achieve long term freedom from disease,...

““ Pro CurePro Cure”” in Multiple Myelomain Multiple Myeloma

Nicolaus KrNicolaus Krööger ger Dept. of Stem Cell TransplantationDept. of Stem Cell Transplantation

University Hospital HamburgUniversity Hospital HamburgHamburg, GermanyHamburg, Germany

Several hematological malignancies can be cured Several hematological malignancies can be cured by chemotherapy w/o SCT. Per definition cure by chemotherapy w/o SCT. Per definition cure means eradication of the disease (complete means eradication of the disease (complete remission) This has been shown for:remission) This has been shown for:

•• acute leukemiasacute leukemias•• high grade lymphomahigh grade lymphoma•• Low grade lymphoma (follicular lymphoma or CLL)Low grade lymphoma (follicular lymphoma or CLL)

In multiple myeloma achievement of CR has been In multiple myeloma achievement of CR has been observed rarely with conventional therapy and was observed rarely with conventional therapy and was obtained in the past only by autologous or obtained in the past only by autologous or allogeneic stem cell transplantation and more allogeneic stem cell transplantation and more recently by the novel agentsrecently by the novel agents

Pro Cure in Multiple MyelomaPro Cure in Multiple Myeloma

Kröger et al., BBMT 2010

German Study (DSMM) n=18TMI (9Gy)Busulfan (9-12 mg/kg)Cyclophosphamide (120 mg/kg)ATG FreseniusM. Myeloma (stage II/III)1998-2001

Long term follow upTRM: 17%12y PFS: 35%12y OS: 50%For those with CR:12y PFS/OS: 60%

Correlation between CR after ASCTCorrelation between CR after ASCTand OS/ PFSand OS/ PFS

Van de Velde H – Haematologica 2007

-- 10 prospective10 prospective-- 11 retrospective11 retrospective

-- Significant correlation between maximal Significant correlation between maximal response and outcomeresponse and outcomeprospective studies (<0.00001)prospective studies (<0.00001)retrospective studies (< 0.00001)retrospective studies (< 0.00001)

4990 pts4990 pts

Metaanalysis of 21 studiesMetaanalysis of 21 studies

CR less important inCR less important in•• patients with previous MGUS patients with previous MGUS (Pineda(Pineda--Roman 2007)Roman 2007)•• less aggressive disease e.g. ISS stage I less aggressive disease e.g. ISS stage I (Harousseau 2009)(Harousseau 2009)

•• Elderly and frial patientsElderly and frial patients•• Might also depend on the type of treatmentMight also depend on the type of treatment

(e.g. Vista trial:(e.g. Vista trial: CR after MPV, duration 24 monthsCR after MPV, duration 24 monthsCR after MP, duration only 12.8 monthsCR after MP, duration only 12.8 months

CR more important inCR more important in•• aggressive disease aggressive disease (Haessler 2007, Harousseau 2009)(Haessler 2007, Harousseau 2009)

Role of CR in Multiple MyelomaRole of CR in Multiple Myeloma

Impact of CR with regard to the biology of the diseaseImpact of CR with regard to the biology of the disease

Single HDSingle HDBjBjöörkstrand, 1994rkstrand, 1994 n = 130n = 130 CR vs. non CR: OS benefitCR vs. non CR: OS benefitLahuerta, 2000Lahuerta, 2000 n = 344n = 344 CR vs. non CR: OS benefitCR vs. non CR: OS benefitChild, 2003Child, 2003 n = 407n = 407 CR vs. PR: OS benefitCR vs. PR: OS benefitOO‘‘Shea, 2006Shea, 2006 n = 211n = 211 CR vs. PR: OS benefitCR vs. PR: OS benefitLenhoff, 2006Lenhoff, 2006 n = 247n = 247 CR vs. non CR: no OS benefitCR vs. non CR: no OS benefit

Double HDDouble HDCavo, 2007Cavo, 2007 n = 321n = 321 CR vs. non CR: OS benefitCR vs. non CR: OS benefitSonneveld, 2007Sonneveld, 2007 n = 303n = 303 no benefit of CRno benefit of CRHarousseau, 2009Harousseau, 2009 n = 802n = 802 CR/VRPR vs. PR OS benefitCR/VRPR vs. PR OS benefitBarlogie, 1999Barlogie, 1999 n = 231n = 231 CR vs. PR: no OS benefitCR vs. PR: no OS benefit


Importance of CRImportance of CR


Martinez-Lopez J et al., Blood 2011;118:529-534

Autologous stem cell transplantation in 344 pts with Multiple Myeloma

AutoAuto--allo vs Auto in Myeloma (EBMTallo vs Auto in Myeloma (EBMT--trial)trial)

Auto+Allo

Auto only

Reduction of risk in time: p=0.0012 (Cox)

Auto (N=249) 194 123 96 58 27 8 2

Auto+allo (N=109) 80 57 46 34 19 11 3

At 60 mns: 35% (CI: 27% - 45%)

At 60 mns: 18% (CI: 13% - 24%)

Progression Free Survival since 1st transplant

AutoAuto--allo EBMT Study CR 50% allo EBMT Study CR 50% (allo) (allo) and 41% and 41% (auto)(auto)

1.1. Immunofixation (serum/urine): not Immunofixation (serum/urine): not qualitative, low sensitivity: 0.12 qualitative, low sensitivity: 0.12 –– 0.25 g/l 0.25 g/l (paraprotein)(paraprotein)

2.2. Free light chain assay (and Free light chain assay (and κκ//λλ ratio): ratio): necessary for stringent CR (sCR)necessary for stringent CR (sCR)

Methods to detect residual disease inMethods to detect residual disease inMultiple MyelomaMultiple Myeloma

VGPR or near CR (positive immunofixation)

n= 35

CR (negative immunofixation)

n = 52

free light chain ratio:abnormal: 37 %normal: 63 %

abnormal: 0 %normal: 100 %

Role of free light chain ration in 87 patients withRole of free light chain ration in 87 patients withat least VGPR after transplantationat least VGPR after transplantation

Kröger et al., Blood 2010



Moesbauer et al Haematologica 2009



3.3. Multiparameter flow: sensitivity 10Multiparameter flow: sensitivity 10--44

bone marrow samplesbone marrow samples


FlowFlow--cytometrycytometry

•• Flow cytometry has become an easy applicable Flow cytometry has become an easy applicable method to detect residual myeloma cellsmethod to detect residual myeloma cells

•• The European Myeloma Network recommends a The European Myeloma Network recommends a minimal panel including: CD19, CD56, CD20, minimal panel including: CD19, CD56, CD20, CD117, CD28 and CD27.CD117, CD28 and CD27.

•• Plasma cell gating should be based on CD38 vs. Plasma cell gating should be based on CD38 vs. CD138 expressionCD138 expression

•• This method has a sensitivity of 10This method has a sensitivity of 10--44

Rawstron, 2008Rawstron, 2008

CR after auto: Flow cytometry negative vs CR after auto: Flow cytometry negative vs Flow cytometry positiveFlow cytometry positive

Paiva et al., Blood, 2008

n = 295; MM: after autologous SCT day +100 after autologous SCT



3.3. Multiparameter flow: sensitivity 10Multiparameter flow: sensitivity 10--44

bone marrow samplesbone marrow samples

4.4. Allelic specific primer: high sensitivity: 10Allelic specific primer: high sensitivity: 10--5 5

toto 1010--66, cumbersome, bone marrow samples, cumbersome, bone marrow samples


Rate of molecular remission based on reRate of molecular remission based on re--arranged immunoglobulin heavy chain genesarranged immunoglobulin heavy chain genes

In CR:In CR: after allograft:after allograft: 50% molecular CR50% molecular CRafter autograft:after autograft: 7% molecular CR7% molecular CR

In CR:In CR: after allograft:after allograft: 50% molecular CR50% molecular CRafter autograft:after autograft: 16% molecular CR16% molecular CR

Martinelli et al., JCO 2000

Corradini et al., JCO 1999

No. of ptsNo. of pts 1616 1919 1313

5 year cumulativ5 year cumulativrisk of relapserisk of relapse 0%0% 33%33% 100%100%

Minimal residual disease after Minimal residual disease after allogeneic stem cell transplantationallogeneic stem cell transplantation

Multiple Myeloma (EBMTMultiple Myeloma (EBMT--Studie): Pat with CRStudie): Pat with CR

PCR negPCR neg PCR mixedPCR mixed PCR posPCR pos

Corradini et al., Blood 2003Corradini et al., Blood 2003

Newly diagnosed multiple Myeloma II/IIINewly diagnosed multiple Myeloma II/III+ HLA+ HLA--compatible Donor (18 compatible Donor (18 -- 65 y.)65 y.)4x ID/AD/VAD/VCAP + 1x IEV/1xCy4x ID/AD/VAD/VCAP + 1x IEV/1xCy

Autologous PBSC Autologous PBSC

Melphalan 200 mg/mMelphalan 200 mg/m22

DLI persistent disease/relapseDLI persistent disease/relapse

Allogeneic PBSC Allogeneic PBSC

Fludarabin 5 x 30 mg/mFludarabin 5 x 30 mg/m22

Melphalan 140 mg/mMelphalan 140 mg/m22

ATG 3 x 10ATG 3 x 10--20 mg/kg KG20 mg/kg KG

KrKrööger et al., Blood 2002ger et al., Blood 2002

Molecular remissionMolecular remission

•• Overall, 68% achieved CR/nCR and 30 (46%) achieved a Overall, 68% achieved CR/nCR and 30 (46%) achieved a molecular CR, which was sustained negative in 15 pts molecular CR, which was sustained negative in 15 pts (21%). (21%).

•• 15 pts with residual disease received donor lymphocyte 15 pts with residual disease received donor lymphocyte infusion and 8 achieved molecular remission which was infusion and 8 achieved molecular remission which was mixed in 3 and sustained in 5 pts. In 3 of the responding pts mixed in 3 and sustained in 5 pts. In 3 of the responding pts molecular remission was associated with occurrence of molecular remission was associated with occurrence of graftgraft--versusversus--host disease.host disease.

ResultsResults

ResultsResults

del17p/(4;14)del17p/(4;14)n = 14n = 14

OthersOthersn = 43n = 43

Molecular Molecular remissionremission 8 (57%)8 (57%) 22 (52%)22 (52%) p = 0.5p = 0.5

Sustained Sustained molecular molecular remission (4 x)remission (4 x)

6 (43%)6 (43%) 9 (21%)9 (21%) p = 0.7p = 0.7

Relapse incidence according MRD after alloRelapse incidence according MRD after allo

ProgressionProgression--free survival free survival according MRD status post alloaccording MRD status post allo

MRD stable neg

MRD mixed

MRD pos

p<0.001

Overall survival Overall survival according MRD status after allo according MRD status after allo

MRD stable neg

MRD mixed

MRD posp<0.001

Kröger et al BBMT 2013

n = 39: 4 x VTD:n = 39: 4 x VTD:Bortezomib 1.6 mg/mBortezomib 1.6 mg/m²² day 1,8,15,22day 1,8,15,22Thal 50 mgThal 50 mgDex 20 mg day: 1Dex 20 mg day: 1--4,84,8--11,1511,15--1818after autologous SCTafter autologous SCT

CR: 15 % to 49 %CR: 15 % to 49 %Molecular remission: 3 Molecular remission: 3 -- 18 %18 %


Molecular remission after autologous SCTMolecular remission after autologous SCT

Ladetto et al., JCO 2010

Szenario of treatment of Multiple MyelomaSzenario of treatment of Multiple Myeloma

1010--11

1010--22

1010--33

1010--44

1010--55

1010--66

1010--77

11 22 33 44 5 years5 years

Tumor cellsTumor cells

Conv. treatmentConv. treatmentHDHD--therapytherapy

AutoAuto--allo therapyallo therapy

Clinical CRClinical CR

Molecular CRMolecular CR

CureCure

LongLong--termtermremissionremission

Target CR posttransplantTarget CR posttransplant

CRCREBMT: n = 8 (27%)EBMT: n = 8 (27%)FACS: n = 7FACS: n = 7Molec.: n = 7Molec.: n = 7

plus one or two novel agentplus one or two novel agentthalidomide / bortezomib or thalidomide / bortezomib or lenalidomidelenalidomide

CRCREBMT: n = 11EBMT: n = 11FACS: n = 10 FACS: n = 10 Molec: n = 8Molec: n = 8

Patients with nonPatients with non--complete remissioncomplete remissionafter allogeneic SCT (n = 32)after allogeneic SCT (n = 32)

(evaluable for response: according EBMT criteria: n = 32, (evaluable for response: according EBMT criteria: n = 32, FACS: n = 27, molecular methods: n = 30)FACS: n = 27, molecular methods: n = 30)

escalating DLI (n = 30), median: 2 DLIsescalating DLI (n = 30), median: 2 DLIsThalidomide (n = 1) Bortezomib (n = 1) Thalidomide (n = 1) Bortezomib (n = 1) (due to cGvH)(due to cGvH)

PDPDn = 2n = 2

non CRnon CRn = 24n = 24

Overall: CR (EBMT): n=19 (59%); FACS: n=17 (63%); molecular: n= Overall: CR (EBMT): n=19 (59%); FACS: n=17 (63%); molecular: n= 15 (50%)15 (50%)

CRCR

non CRnon CR

DLI +/DLI +/-- new agents after allonew agents after allo--SCT forSCT forpatients with PR/VGPRpatients with PR/VGPR

p=0.03

According EBMT criteria: 5 year PFS

58%

35%

mCRmCR

non mCRnon mCR

DLI +/DLI +/-- new agents after allonew agents after allo--SCT forSCT forpatients with PR/VGPRpatients with PR/VGPR

p=0.001

81%

According to molecular methods(sensitivity 10-5 to 10-6)

38%

Kröger et al., Exp Hem 2009

ConclusionsConclusions

•• The available studies suggest that some patients with The available studies suggest that some patients with multiple myeloma can achieve long term freedom from multiple myeloma can achieve long term freedom from disease, which can be regarded as curedisease, which can be regarded as cure

•• Long term PFS survival can be observed after Long term PFS survival can be observed after autologous (10autologous (10--20%)and to a higher degree after 20%)and to a higher degree after allogeneic (20allogeneic (20--30%) stem cell transplantation30%) stem cell transplantation

•• Achievement of complete remission increases the Achievement of complete remission increases the probability of long term PFSprobability of long term PFS

•• Increasing number of studies suggest that the depth of Increasing number of studies suggest that the depth of complete remission is of importance for long term PFScomplete remission is of importance for long term PFS

•• Primary aim of prospective studies should target Primary aim of prospective studies should target molecular remission molecular remission

AcknowledgementAcknowledgement

F. AyukF. AyukT. StT. StüübigbigC. WolschkeC. WolschkeU. BacherU. BacherH. AlchalbyH. AlchalbyJ. PanseJ. PanseF. BernhardF. BernhardH. LellekH. LellekA.R. ZanderA.R. Zander

B. FehseB. FehseA. BadbaranA. BadbaranM. ZagrivnajaM. ZagrivnajaC. LangeC. LangeG. SchillingG. SchillingM. LioznovM. LioznovT. BinderT. BinderT. ZabelinaT. ZabelinaD. AtanackovicD. Atanackovic

Dept of Stem Cell Transplantation at the University Dept of Stem Cell Transplantation at the University Medical Center Hamburg/GermanyMedical Center Hamburg/Germany

“ pro cure” in multiple myeloma...multiple myeloma can achieve long term freedom from disease,...

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