Choosing upfront and salvage therapy for myeloma in the ASEAN context

Choosing upfront and salvage therapy for myeloma in the ASEAN context Daryl Tan Consultant Department of Haematology Singapore General Hospital Adjunct Assistant Professor Duke-NUS Graduate Medical School

Overall Survival Impact of Novel Agents Up-front 1.0 0.8 0.6 0.4 0.2 1971-76 1977-82 1983-88 1989-94 1994-00 2001-06 0.0 0 20 40 60 80 100 120 140 mos. Kumar, S et al. Blood 111:2516, 2008.

ASEAN s Perspective?? Resources Access to drugs Access to good clinical trials Pharmaceutical representations

Evidence-Based Medicine

Choosing the optimal therapy for myeloma patients Ability to optimize available resources to achieve best outcomes for our patients

Questions??? Is risk stratification of myeloma necessary? What is the best induction regimen? Combination or Sequential? Is attaining CR important? Is HDT/ transplant still necessary? What is the best treatment at relapse?

Questions??? Is risk stratification of myeloma necessary? What is the best induction regimen? Combination or Sequential Certainly! Is attaining CR important? Prognostication Is HDT/ transplant still necessary? Research What is the best tx at relapse? Cross trials comparison Individualize treatment- Risk adapted

Risk Stratification ISS Stage PC Labelling Index Metaphase Karyotype Interphase FISH GEP B 2 MG Albumin $$$$ $

Frontline Treatment Bortezomib in del 13 : Jagannath, S et al. Leukemia 21:151, 2007 Bortezomib in t(14q32) : Sagaster, V et al. Leukemia 21:164, 2007. Bortezomib in del 13, t(4;14) and/or del 17p : IFM 2005/01 Trial and VISTA Trial 2008

Risk Stratification: Overall Survival by ISS SGH 2000-2007 (n=218) ISS Median OS(yrs)) I 8.6 II 3.6 III 2.5 p<0.001 Tan D et al. XII th IMW 2009 Abstract # 0286

Overall Survival by Metaphase Karyotype SGH 2000-2007 (n=213) Ploidy number Median OS(yrs) Normal diploid 8.7 Hyperdiploid 3.8 Non-hyperdiploid Hypodiploid 2.4 Pseudodiploid 2.6 Near-tetraploid not reached Near-tetraploid Normal diploid (51%) Non-hyperdiploid (27%) Hyperdiploid (22%) Pseudodiploid p<0.001 Hypodiploid Tan D et al. XII th IMW 2009 Abstract # 0286 Rajkumar et al. Cytogenetic abnormalities correlate with the plasma cell labelling index. Cancer Genet Cytogenet. 1999;113(1):73-7.

Overall survival by Metaphase Karyotyping and Interphase FISH Normal diploid with high-risk FISH t(4;14), t(14;16) & del17p Ploidy number Median OS(yrs) Ploidy Normal status diploid Median OS(yrs) 8.7 Normal Hyperdiploid 8.73.8 without Non-hyperdiploid high- risk FISH Hypodiploid 2.4 Hyperdiploid 3.8 Pseudodiploid 2.6 Non-hyperdiploid 2.6 Near-tetraploid not reached Normal diploid with 1.5 high-risk FISH Near-tetraploid Normal diploid (51%) Normal diploid Non-hyperdiploid (27%) Hyperdiploid (22%) Pseudodiploid Hyperdiploid p<0.001 p<0.001 Non-hyperdiploid Hypodiploid

Overall Survival by ISS Risk Group and Bortezomib Exposure Bortezomib- Naïve Bortezomib- Exposed ISS Median OS (yrs) High Risk I 8.6 14% II 3.2 25% III 1.5 25% ISS Median OS (yrs) High Risk I 4.3 36% II 5.6 44% III 4.7 35% ISS I ISS II ISS II p<0.001 ISS III p=0.4 ISS III ISS I p=0.04 Tan D et al. XII th IMW 2009 Abstract # 0286

Overall Survival by Metaphase Cytogenetics and Bortezomib Exposure Bortezomib- Naïve Bortezomib- Exposed Ploidy number Median OS(yrs) Normal Diploid 8.7 Hyperdiploid 2.9 Non-hyperdiploid 2.2 Ploidy number Median OS(yrs) Normal Diploid not reached Hyperdiploid 4.7 Non-hyperdiploid 2.7 p<0.001 p=0.002 Tan D et al. XII th IMW 2009 Abstract # 0286

Subjects without event (%) VISTA Trial: VMP vs MP then V 100 VMP 80 MP->V 60 MP 40 20 0 Group N Event VMP MP with bortezomib MP with no bortezomib 300 47 81 22 106 45 0 2 4 6 8 10 12 14 16 18 20 22 24 26 28 30 32 34 Time (months) San Miguel J, et al. N Engl J Med. 2008: 359:906-917.

Risk Stratification for Induction Therapy (SGH) ISS III / Non-hyperdiploidy Clinical trial if available Bortezomib-Combination Bortezomib if reimbursement permits VTD >TD (Cavo et al) TD >VAD (Cavo et al 2005) Bort/Dex >VAD (IFM 2005/01) VMP >MP (VISTA trial) VMPT >VMP weekly (Palumbo et al 09) >Dex (ECOG 2004) MPT >MP (Palumbo et al, Facon et al, Hulin et al) Rd >RD pending approval in frontline use (Rajkumar et al)

MRD Monitoring: What is CR? BM plasma cells <5% M-band Immunofixation Free Light Chains Immunophenotype PCR exposed surface Kappa hidden surface hinge region Previously hidden surface carbohydrate Lambda Intact Immunoglobulin Free Light Chain Bradwell, Serum free light chain assay PR VGPR Stringent CR CR Immunophenotypic CR Molecular CR Tumor Burden $$$$ $

Depth of Response Treatment initiation Progression? MR PR VGPR ncr CR scr IP/mCR Time Depth of response is related to TTP

Cumulative Proportion Surviving OS by Induction Response 1,0 0,9 0,8 0,7 CR 0,6 0,5 ncr PR 0,4 0,3 0,2 P= 0.01 PD 0 12 24 36 48 60 72 84 96 Months from diagnosis Lahuerta et al. JCO. 2008;10:5775 Harousseau et al. J Clin Oncol 2009; 27: 5720

Patients without event (%) VMP : CRs Have Superior TTP 100 TTP 80 60 40 20 Group N Event Median CR 102 18 NA PR 136 41 21.7 <PR 106 24 17.1 CR PR <PR 0 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (months) CR associated with significantly longer TTP vs. PR (HR 0.45, P=0.004) Significant benefit also seen for CR + PR vs. <PR Harousseau, JL et al. 2008 ASH Abstract 2778.

Attainment of VGPR after induction is an important surrogate of longer survival. Tan D et al. Bone Marrow Transplant. 2010 Feb15 [epub ]

Attainment of VGPR after induction is an important surrogate of longer survival. PFS OS 1-yr landmark Tan D et al. Bone Marrow Transplant. 2010 Feb 15 [epub]

OS of patients achieving VGPR by transplant status HDT/ASCT (n) Median OS (yrs)) Yes (42) 8.1 No (25) not reached HDT/ASCT VAD 57% Thal/Dex or MPT 26% Bort Combi 10% No HDT 7% 57% 30% P=0.76 P=0.76 Tan D et al. Bone Marrow Transplant. 2010 Feb 15 [epub]

How Long To Treat? Niesvizky et al. Blood 2008;111:11019

YES! NO! CR Post-ASCT Important in High-risk MM? Source Chang et al Br J Haem. 2004;25:64 Chang et al Blood 2005.105:358 Gertz et al Blood.2005;106:2837 Cavo et al. J Clin Oncol. 2006;20;24 Study The t(4;14) is associated with poor prognosis in myeloma patients undergoing autologous stem cell transplant p53 gene deletion detected by fluorescence in situ hybridization is an adverse prognostic factor for patients with multiple myeloma following autologous stem cell transplantation Clinical implications of t(11;14)(q13;q32), t(4;14)(p16.3;q32), and -17p13 in myeloma patients treated with high-dose therapy Poor outcome with front-line autologous transplantation in t(4;14) multiple myeloma: low complete remission rate and short duration of remission Source Harousseau et al. J Clin Oncol. 2009;114:3139 Study Achievement of at least very good partial response is a simple and robust prognostic factor in patients with multiple myeloma treated with high-dose therapy. t(4;14)(p16.3;q32), and -17p13 Haessler J et al. Clin Cancer Res 2007; 13(23):7073-7079. Benefit of complete response in multiple myeloma limited to high-risk subgroup identified by gene expression profiling.

An Abnormal Non-Hyperdiploid Karyotype Predicts for an Adverse Outcome After HDT/ASCT (N=77) PFS OS Ploidy No. PFS (yrs) Diploid 4.0 Hyperdiploid 2.3 Non-hyperdiploid 2.2 Normal Diploid Ploidy No. PFS (yrs) Diploid NR Hyperdiploid 6.3 Non-hyperdiploid 2.8 Normal Diploid Hyperdiploid Non-hyperdiploid P=0.02 Hyperdiploid P<0.001 Non-hyperdiploid Tan D et al. 36 th EBMT Meeting 2010. Abstract #896

Study Design Primary analysis: post-induction response in VAD (A1+A2) vs. Bort/Dex (B1+B2) Randomization; Stratified by b 2 -microglobulin level (>3 mg/l vs 3 mg/l) and presence of chromosome 13 abnormalities (by FISH) A1 A2 B1 B2 VAD x 4 VAD x 4 Induction Bort/Dex x 4 Bort/Dex x 4 DCEP x 2 Consolidation DCEP x 2 Melphalan 200 mg/m 2 + ASCT Melphalan 200 mg/m 2 + ASCT Transplant 1 Melphalan 200 mg/m 2 + ASCT Second ASCT or RIC allo if <vgpr Melphalan 200 mg/m 2 + ASCT Harrouseau et al. ASH 2009. Abstract 353

Study Design R E G I S T R A T I O N Thalidomide + Dex T 200 mg po days 1-21 / D 40 mg days 1, 2, 4, 5, 8, 9, 11, 12 q21 x 3 cycles Bortezomib + T + D B 1.3 mg/m 2 days 1, 4, 8, 11 q21 x 3 cycles Double ASCT Melphalan 200 mg/m 2 TD Consolidation VTD Consolidation Cavo et al. ASH 2008. abstract #158

Conclusions of IFM and GIMEMA Studies A better induction regimen pre-transplant improves the outcomes post-transplant. Earlier use of novel agents improves response rates, which translate to improving long-term outcomes as well

Treatment Options for Relapsed Myeloma No definitive data on optimal sequence Factors to consider : Prior tx and response duration Toxicities from prior tx Organ function Patients preference All pts should be encouraged to paticipate in clin trials Always keep in mind future therapies

2009 NCCN Guidelines Repeat primary therapy (if relapse at > 6 mos.) Bortezomib (Category 1) Bortezomib/liposomal doxorubicin (1) Lenalidomide/dex (1) Bendamustine (2B) Bortezomib/dex Lenalidomide Hi dose cyclophosphamide, or Cy-VAD Thalidomide, or thalidomide/dex Dex, or DCEP, or DT-PACE 1 year

Survival Impact of Novel Agents at Relapse 1.0 0.8 0.6 Relapsed before 1998 Relapsed 1998 1999 Relapsed 2000 2001 Relapsed 2002 2003 Relapsed 2004 2005 0.4 0.2 P<0.001 0.0 0 20 40 60 80 100 Time (months) Kumar, S et al. Blood 111:2516, 2008.

Supportive Care of Myeloma in the Asian Context

Myeloma Myths in Asia Incidence of DVT lower in Asians on IMIDs? Asians are more vulnerable to bortezomib induced neuropathy? Why are they only producing 3.5 mgvials??

360 pts Retrospective 25 Centres Incidence in Singapore General Hospital: 12/150 (8%)

Myeloma Myths in Asia Incidence of DVT lower in Asians on IMIDs? Asians are more vulnerable to bortezomib induced neuropathy? Why are they only producing 3.5 mgvials??

Incidence of PN in Bortezomib front-line trials in elderly patients Study VISTA 1 VMP 14% MP 0% PETHEMA/G VMP 15% EM 2 VTP 9% GIMEMA 3 Grade 3/4 PN VMP Biweekly: 14% VMPT Biweekly: 24% Italian study 4 PAD-ASCT(MEL100) 11% Once weekly: 3% Once weekly: 9% Asian Incidence?? 1. San Miguel et al. ASH 2008 (abstract 650) 2. Mateos et al. ASH 2008 (abstract 651) 3. Palumbo et al. ASH 2008 (abstract 652) 4. Palumbo et al. ASH 2008 (abstract 159)

Bortezomib dose modification for the management of PN Severity of PN signs/symptoms Grade 1 (paresthesia and/or loss of reflexes without pain or loss of function) Grade 1 with pain or Grade 2 (interfering with function but not with ADL) Grade 2 with pain or Grade 3 (interfering with ADL) Grade 4 (permanent sensory loss interfering with function) Modification of dose and regimen No action Reduce bortezomib to 1.0 mg/m 2 Withhold bortezomib until toxicity resolves then reinitiate at 0.7 mg/m 2 and administer once per week Discontinue bortezomib ADL, activities of daily living

Myeloma Myths in Asia Incidence of DCT lower in Asians on IMIDs Asians are more vulnerable to bortezomib induced neuropathy? Why are they only producing 3.5 mgvials??

Risk of Hepatitis B Virus (HBV) Reactivation and the Role of Anti-Viral Prophylaxis in Multiple Myeloma Patients with HBV Infection in the Era of Novel Therapies. Hep B reactivation during immune reconstitution post-transplant Role of imids? Emerging incidence of mutant strains Mya et al ASH 2009. Abstract #3882

Conclusions Is risk stratification of myeloma necessary? Yes! What is the best induction regimen? Earlier use of novel agents improves RR and long-term outcomes Combination outperforms sequencing Is attaining CR important? Yes! Excellent predictors of long-term benefit for myeloma patients in the up-front setting Pushing for a CR pre-transplant appears to be improving the outcome after transplant Is HDT/ transplant still necessary? Yes

Prognosis of Myeloma in SE Asia Overall Survival 1.0 0.8 0.6 0.4 > 2000 0.2 0.0 0 1960-2000 20 40 60 80 100 120 140 mos.

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