Presentation on theme: "Myeloma 2013-What we know-What we don’t know and what we don’t know we don’t know. Sergio A. Giralt, MD Chief, Adult Bone Marrow Transplant Service Division."— Presentation transcript:
1 Myeloma 2013-What we know-What we don’t know and what we don’t know we don’t know. Sergio A. Giralt, MDChief, Adult Bone Marrow Transplant Service Division of Hematologic Oncology Department of Medicine Memorial Sloan-Kettering Cancer Center New York, New York
2 Disclosures Grant Support Honoraria Most important I am a transplanter CelgeneMilleniumOnyxHonorariaNovartisSanofi/GenzymeMost important I am a transplanter
3 Initial Presentation 45-year-old woman Presents with proteinuria. Normal PhysicalLaboratory findingsHemoglobin 11 gm/dl normal iron storesTotal proteinuria 5.82 g/dayBence Jones protein (BJP) 3.6 g/dayHypogammaglobulinemiaAlbumin 3.9 g/dLβ2-microglobulin 4.7 mg/LCreatinine 1.7 mg/dlNo paraprotein peak but kappa light chain with lambda light chain at 0.01Kappa/lambda ratio=
4 Bone marrow biopsyCellularity 80% with 25% plasma cellsCytogenetics 46, XX, inversion 9 (p11;q13)FISH no abnormalitiesSkeletal survey: extensive lytic bone disease with healing fractures of left 7th and the 8th ribsMRI of the spine: diffuse hyper-intense homogenous signal on STIR sequenceMRI of the pelvis: diffuse marrow infiltrative changes due to myelomaComorbidities: Diabetic on metformin, no history of coronary artery disease or other comorbidities
13 Novel Agents for Frontline Multiple Myeloma: A New Era of Efficacy Newly Diagnosed MMPhase II Study of Len, Bortezomib, and Dex (RVD) in Newly Diagnosed MM (Richardson et al)Pts35 enrolled in phase II; median age 59 (22-86) yrs;ISS Stage II/III 54%/11%DoseLenalidomide 25 mg/d, d 1-14 in 21 day cycleBortezomib 1.3 mg/m2 d 1, 4, 8, 11Dexamethasone 20 mg day of and after bortezomibAspirin and antiviral prophylaxisResultsAt 19 mos of follow-up, TTP, PFS,and OS have not been reachedMedian stem cell collection in 15/35patients: 4.4 x 106 CD34+ cells/kgResponse n = 35 evaluableCR/nCR52%< VGPR74%ORR (≥PR)100%SafetyGrade > 3 PN in 1 pt only, VTE in 2 pts, no rx related mortality
15 Stem Cell CollectionAfter 4 cycles of RVD she achieves a VGPR with kappa light chains reduced to 10 and lambda light chains recovered to 0.1.Her marrow reveals 4% kappa restricted plasma cells.MRI demonstrates significant resolution of infiltrative images.She agrees to proceed to stem-cell collection and transplantation.
16 Optimal mobilization strategy What we know…Optimal mobilization strategy
17 Effect of Lenalidomide Duration of Therapy on Stem Cell Collection Lenalidomide TherapyOther Induction TherapiesP value =P value=0.0025P value = 0.07P value =3594.550n=408n=40n=18845304073.525n=18n=403566302052.5n=16DaysPercentage25CD34+ Count (Cells µl-1)CD34+ Count (in Millions)15442031.510152210510.55Mean Peripheral BloodCD34+ CountTotal CD34+ Cellscollected(Mean x 106 cells Kg-1)Mean number ofdays of collectionPercentage of patientswho failedfirst collectionParipati H. Leukemia. 2008;22:
18 Overcoming the Negative Effects of Lenalidomide on Stem Cell Mobilization Utilizing Plerixafor Plerixafor + G-CSFN = 60 patients with myeloma frontline mobilization: 20 patients & CUP: 40 ptsMedian CD34 collected 5.6 x 106 CD34/kg87% collected ≥ 2 x 106 CD34/kg63% collected ≥ 5 x 106 CD34/kgUp front pts: 100% (≥ 2) & 95% (≥ 5)CUP pts: 80% (≥ 2) & 48% (≥ 5)Micallef I, et al. Haematologica. 2009;94(suppl 2):0718; Tarantolo S, et al. Biol Blood Marrow Transplant ;15(2 suppl 2):91.
19 What we don’t know Is VRD superior to VTD or CyBorD? Should the goal be ‘X” number of cycles and proceed to SCT or should patients continue induction until best response?Is “response adapted” therapy appropriate?Is there a role for carfilzomib based induction?Should anybody be chemomobilized in the era of plerixafor?
20 Stem Cell Transplantation She collects 10 million CD34 cells per kg over 3 days and is ready to be admitted for high dose melphalan and autologous stem cell transplantation.She asks what is it going to be like and does she really need a SCT?
21 Role of sct in the era of imids and proteosome inhibition What we don’t know…Role of sct in the era of imids and proteosome inhibition
23 Early-vs-Late SCT Study? OptimalinductionregimenCOLLECTHD THERAPY + SCTAAAMaintenanceAAAmmmHARVEST AND HOLDSCT UPON RELAPSERisk profile
24 IFM/DFCI 2009 Study Newly Diagnosed MM Pts (SCT candidates) Randomize, stratification ISS & FISHVRD x 3InductionVRD x 3CY (3g/m2) MOBILIZATIONGoal: 5 x106 cells/kgCY (3g/m2)MOBILIZATIONGoal: 5 x106 cells/kgCollectionMelphalan 200mg/m2* + ASCTVRD x 5ConsolidationVRD x 2MaintenanceLenalidomide 12 mosLenalidomide 12 mosSCT at relapseMEL 200 mg/m2 if <65 yrs,≥65 yrs 140mg/m2
25 stem cells mobilized with cyclophosphamide + G-CSF Melphalan/Prednisone/Lenalidomide (MPR) vs MEL200/ASCT Following Lenalidomide/Dexamethasone (Ld) InductionConsolidationn=402<65 yearsRANDOMIZERANDOMIZEMPR (n=202)Melphalan: 0.18 mg/kg/d, days 1–4Prednisone: 2 mg/kg/d, days 1–4 Lenalidomide: 10 mg/d, days 1–21q 28 days ×6NomaintenanceLenalidomide:25 mg, days 1–21Low-dose Dex:40 mg, days 1, 8,15, 22 q 28 days ×4Tandem MEL200ASCTstem cells mobilized withcyclophosphamide + G-CSFMaintenancelenalidomide:10 mg/d, Days 1–21q 28 days until relapsePrimary end point: PFSPalumbo A et al. Blood. 2009;114:Abstract 350.25
27 Conclusions MPR MEL200 P value CR 20% 25% P=0.55 24 months % % P=0.0002OS @ 24 months % % P=0.19Less G3-4 hematologic toxicity in MPR arm (P<0.001)Less mucositis and infections in MPR arm (P<0.001)No difference in term of early deathsSignificantly longer PFS after ASCT (P<0.001)Longer follow up is needed to assess OSMPR, melphalan-prednisone-lenalidomide; MEL200, melphalan 200 mg/m2; CR, complete response; PFS, progression-free survival; OS, overall survival; ASCT, autologus stem cell transplantation
28 E4A03: Landmark Analysis at Median Follow-up of 36 mo 431 patients aliveat 4 cyclesOff therapyn=183Primary therapybeyond 4 cyclesn=248no transplantN=93(median age 68)Transplantn=90(median age 57)Ldn=140(median age 66)LDn=108(median age 65)Rajkumar SV et al. The Lancet Oncology, Volume 11, Issue 1, Pages , January 20102828
29 Outcomes in pts Age <65 Progression Free SurvivalOverall Survival
30 What we don’t know Should everybody be collected upfront? How much? Who should undergo upfront SCT?All patients?Only those with suboptimal response?What is suboptimal?PRVGPRNear CRWho is truly transplant ineligible?What about low risk patients in CR?What role does risk stratification play in deciding therapies?
37 In my humble opinionHigh dose melphalan is one of the most active agents in myeloma today30-40% CR24 months median remission duration without maintenanceName another agent with similar single agent activityIt is also cost-effectiveWith stem cell support it can be given safely to older patients with comorbidities.Thus not planning for it’s use upfront is similar to telling a patient I am never going to use bortezomib or lenalidomide during your disease course because “I don’t like it” or I don’t believe in it”.Whether early or late, once twice or more times it remains an active agent that can be extremely effective in all stages of the patients disease journey.
39 Both have a 10/10 sibling donor available. Tales of Two CasesCase 155-year-old female presents with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/LWorkup reveals30% plasma cellsCytogenetic diploidIgA kappa peak of 3.2β2M of 3.0Receives 4 cycles of Bz/Thal/DexFollowed by Auto SCT on day 60 documented stringent CRCase 255-year-old female presents with asymptomatic anemia of 10 gm/dL and total serum protein 10 gm/LWorkup reveals30% plasma cellsCytogenetic t(4;14)IgA kappa peak of 3.2β2M of 3.0Receives 4 cycles of Bz/Thal/DexFollowed by Auto SCT on day 60 documented paraprotein peak of 0.4 g/dLBoth have a 10/10 sibling donor available.
40 PRIMARY ENDPOINT : 3yr Progression Free Survival BMT CTN 0102 Study SchemaMultiple Myelomameetingeligibility criteriaHLA typing of all patientswith siblings*Biologic assignment occurred when HLA-typing results were available after enrollment.High-dose melphalan (200 mg/m2)+ autologous PBSC transplantBiologic assignment*Eligible HLA-matchedsibling donorNo eligible HLA-matchedsibling donor60 to 120 daysNon-myeloablative conditioningTBI 200 cGYallogeneic PBSC transplantHigh-dose melphalan (200 mg/m2)+ autologous PBSC transplantRandomization†† Randomization occurred once patients were assigned to auto-autoObservationThalidomideDexamethasonex12 months.PRIMARY ENDPOINT : 3yr Progression Free Survival40
41 1st Autologous Transplant N=710 No Sibling DonorAuto-AutoN=484Sibling DonorAuto-AlloN=226HighRiskN=48StandardN=189N=436N=37Main groups compared
42 Number of Myeloma Cells Rate of molecular CR with HDT is 5% Monitoring Disease CR Definition Does Matter With Regards to Depth of Remission1 × 1012At diagnosisNumber of Myeloma CellsPartial response – 50% reduction in M proteinNear complete remission – immunofixation positive onlyComplete remission – immunofixation negativeNonquantitative ASO-PCR1 × 108Quantitative ASO-PCR flow cytometry1 × 106MRD1 × 104Rate of molecular CR with HDT is 5%
43 SummaryHigh dose melphalan with autologous stem cell support remains the standard of care for consolidation therapy for patients with chemosensitive diseaseCurrent therapy with high dose melphalan followed by maintenance therapy results in more than 70% major responses and median remission durations of around years.Moving forward minimizing toxicities, developing more effective conditioning regimens and better risk stratification will allow us to provide each patient with the best chance of a long life with myeloma control, good quality of life with the least treatment burden