Clinical Case Study Discussion: Maintenance in MM

Transcription

1 Evangelos Terpos, MD, PhD National & Kapodistrian University of Athens, School of Medicine, Athens, Greece Clinical Case Study Discussion: Maintenance in MM Disclosure of Conflict of Interest (List) Honoraria Celgene, Janssen-Cilag

2 61-year-old female presents with acute back pain that has persisted for 1 month Evaluations in the orthopedics clinic revealed A fracture in L4 DXA-scan T-score of the lumbar spine: -2.8 hemoglobin 10.5 g/dl serum protein electrophoresis: 25 g/l IgG-kappa Referral to the hematology clinic

3 Patient workup and diagnosis Evaluations in the hematology clinic revealed skeletal survey (WBXR): no osteolytic lesions, only diffuse osteoporosis, L4 fracture WBC 2.7 x 10 9 /L hemoglobin 10.6 g/dl platelets 175 x 10 9 /L creatinine 101 µmol/l (1.1 mg/dl) albumin 2.8 g/dl Kappa/lambda ratio: 8.4 Electrophoresis of the urine: 95% of k-light chains FISH analyses revealed t(4;14) translocation BM plasma cells: 35% plasma cells β 2 M 3.2 mg/l Patient diagnosed with multiple myeloma, IgGk, ISS-2

4 At this point would you treat the patient? A. The patient has asymptomatic myeloma (no CRAB) criteria and needs close follow-up B. The patients has symptomatic myeloma and requires immediate treatment C. The patient has an osteoporotic fracture and needs only bisphosphonate administration D. The patient has high-risk asymptomatic myeloma and needs treatment with RD (lenalidomide and dexamethasone)

5 Case continue An MRI of the spine was performed: several focal lesions were revealed 149 patients Focal lesions: 28% The presence of focal lesions was the strongest adverse prognostic factor for progression into symptomatic disease (p<0.001) Hillengass et al. J Clin Oncol 2010;28:

6 Algorithm for Imaging in our Center Soft tissue mass Suspected plasmacytoma or myeloma Suspected spinal cord compression CT scan and consider biopsy Radiological Skeletal Survey and WBCT Urgent MRI/CT scan and appropriate medical management Lytic Lesions Present? Yes No Risk for fracture? Whole Body CT/LS & pelvis MRI Yes Urgent orthodedic review; consider radiotherapy No Lytic Lesions >1 Diffuse pattern? Systemic Therapy 0-1 Focal Lesions 0-1 Lytic Lesions No Diffuse pattern Observation

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8 Case continue The patients was treated with VTD x 4, high dose melphalan with ASCT Zoledronica acid was also given She achieved a vgpr post-induction and CR post- ASCT: the M-component was present only in serum immunofixation Grade 2 painful peripheral neuropathy was present post-asct

9 Would you continue the treatment at this point? A. No, the patient has achieved a CR and does not need further anti-myeloma treatment; I will follow-up him every month with zoledronic acid administration only B. The patient has high-risk myeloma and I will give maintenance with thalidomide C. The patient has high-risk myeloma and I will give lenalidomide maintenance D. The patient has shown significant improvement with the given therapy and I will continue on VTD consolidation plus zoledronic acid with no maintenance afterwards E. The patient needs a second auto-transplant

10 Answer E: Single versus double ASCT in MM IFM94 trial VGPR after first ASCT Absence of VGPR after first ASCT P<0.001 P=0.7 Attal et al. N Engl J Med 2003;349:

11 Double vs single ASCT after bortezomib-based induction: Integrated analysis of phase European 3 studies Pts (n=606) Bortezomib-based induction Single (n=254) or double (n=352) ASCT Differentiation of 4 groups based on adverse prognostic variables: ISS 3, high-risk cytogenetics, failure to achieve CR after induction therapy Group 0 (13%): ISS 1-2, lack of high-risk cytogenetics, CR after induction Group 1 (61%): one adverse variable Group 2 (23%): two adverse variables Group 3 (3%): all three adverse variables Cavo et al. ASH 2013 (Abstract 767), oral presentation

12 Double vs single ASCT after bortezomib-based induction: Integrated analysis of phase European 3 studies Group 0 (no adverse variable) Group 1 (1 adverse variable) Group 2 (2 adverse variables) Group 3 (3 adverse variables) Median PFS 61 months 56 months 36 months 26 months Presence of 2 (P<0.001) or 3 (P<0.001) adverse prognostic variables associated with progressively shorter OS compared to lack of all 3 adverse variables Adverse variables: ISS 3, high-risk cytogenetics, failure to achieve CR after induction therapy Cavo et al. ASH 2013 (Abstract 767), oral presentation

13 Double vs single ASCT after bortezomibbased induction PFS and OS in patients with 2 adverse variables Double ASCT Single ASCT P PFS 41 months 20 months OS 67 months 31.5 months <0.001 PFS and OS for pts with high-risk cytogenetics and who failed CR after bortezomib-based induction regimens PFS OS Cavo et al. ASH 2013 (Abstract 767), oral presentation

14 Answer D: VTD consolidation Study design (Gimema-MMY-3006) n=236 n=238 Randomization Induction (three 21-day cycles) Bortezomib-Thal-Dex (VTD) V 1.3 mg/m 2 d1, 4, 8, 11 T 200 mg daily D 320 mg/cycle Induction (three 21-day cycles) Thal-Dex (TD) T 200 mg daily D 320 mg/cycle Double ASCT Consolidation (two 35-day cycles) Bortezomib-Thal-Dex (VTD) V 1.3 mg/m 2 once-weekly T 100 mg/d through d 1 to 70 D 320 mg/cycle Consolidation (two 35-day cycles) Thal-Dex T 100 mg/d through d 1 to 70 D 320 mg/cycle Maintenance: Dex Cavo et al. Lancet 2010;376(9758): Cavo et al. Blood 2012;120(1):9-19 Cavo et al. ASH 2013 (Abstract 2090), poster presentation

15 VTD vs TD incorporated into double ASCT: Updated analysis of Phase 3 Gimema-MMY-3006 study PFS PFS for pts with t(4;14) and/or del(17p) PFS for pts with or without t(4;14) PFS from starting consolidation Cavo et al. ASH 2013 (Abstract 2090), poster presentation

16 Do we need a bisphosphonate together with VTD consolidation? N=42 VTD started on day 100 post- ASCT patients received 4 cycles of VTD (1 st block), were followed without treatment for 100 days and then received another 4 VTD cycles (2nd block) during this 12-month period, BPs were not administered. only one patient with PD developed a skeletal-related event (i.e. radiation to bone) Best response: CR 36%, CR 31%, vgpr 16.5%, PR 9.5%, PD 7% 33% and 47% of patients improved their status of response after the 1 st and 2 nd VTD block, respectively median TTP after ASCT was 34 months median TtNT was 40 months Terpos et al. Leukemia 2014;28:928-34

17 Phase 3 trial: Bortezomib monotherapy as consolidation (Nordic Myeloma Study Group [NMSG 15/05] trial) Induction (no bortezomib) + single or double ASCT (n=403) Randomization (3 months post-asct) (n=370) Bortezomib (n=187) 1.3 mg/m 2 IV Two 3-week cycles: days 1, 4, 8, 11 + Four 4-week cycles: days 1, 8, 15 (total 20 injections over 21 weeks) Observation (n=183) Primary objective: PFS Mellqvist et al. Blood 2013;121:

18 Bortezomib Monotherapy as Consolidation: Results Median follow-up: 38 months Bortezomib Control p value Improvement of response from PR to VGPR 57% 36% Median PFS 27 months 20 months 0.05 Incidence of neuropathy CTC III Neuropathic pain > grade 2 6% 1% < Sensory neuropathy > grade 2 5% 1% < 0.04 Beneficial effect of bortezomib consolidation on PFS only seen in patients not achieving at least VGPR after ASCT Mellqvist et al. Blood 2013;121:

19 Bortezomib Monotherapy as Consolidation: Results Median follow-up: 38 months Bortezomib Control p value Improvement of response from PR to VGPR 57% 36% Median PFS 27 months 20 months 0.05 Incidence of neuropathy CTC III Neuropathic pain > grade 2 6% 1% < Sensory neuropathy > grade 2 5% 1% < 0.04 Beneficial effect of bortezomib consolidation on PFS only seen in patients not achieving at least VGPR after ASCT Mellqvist et al. Blood 2013;121:

20 Bortezomib maintenance therapy Phase 3 HOVON/GMMG trial N VAD/HDM/Thalidomide PFS at 36 Mos, % OS at 36 Mos, % N PAD/HDM/Bortezomib PFS at 36 Mos, % OS at 36 Mos, % All /13q t(4;14) p P <.01 in univariate analysis All data FISH, -13/13q- also karyotype if available Sonneveld et al. J Clin Oncol 2012;30:3654

21 Cumulative percentage Bortezomib improves outcome in patients with intermediate/poor risk based on FISH/ISS Overall survival by risk group (FISH + ISS) VAD PAD good 75 good 50 intermediate 50 intermediate poor 25 0 good intermediate poor At risk: good intermediate poor N D poor months good intermediate poor Good Risk: no t(4;14)/del17p/add1q and ISS 1 Intermediate Risk: either t(4;14)/del17p/add1q and ISS 1 or no t(4;14)/del17p/add1q and ISS 2/3 Poor Risk: t(4;14)/del17p/add1q and ISS 2/ good intermediate poor At risk: N D months Sonneveld et al. ASH 2013 (Abstract 404), oral presentation; Neben et al. Blood 2012;119(4):940-8.

22 Spencer et al. J Clin Oncol 2009;27: ; Attal et al. Blood 2006;108: ; Barlogie et al. N Engl J Med 2006;354: ; Blood 2008;112: ;J Clin Oncol 2010;28: ; Lokhorst et al. Blood 2010; 115: ; Morgan et al. Clin Cancer Res 2013;19:6030-8; Stewart et al. Blood 2013;121: Answer 3: Thalidomide maintenance therapy Significant improvement in PFS with maintenance therapy Significant improvement in OS with maintenance therapy Survival after relapse Spencer Yes Yes (3 years follow up) Similar in all groups Attal Yes Yes (@ 39 m), but OS advantage disappeared with longer follow-up (5.7 years) Similar in all groups Barlogie Yes Yes (7.2 years follow-up) Reduced OS after thal exposure Lokhorst Yes No Morgan Yes No Stewart Yes No Reduced OS after thal exposure Reduced OS after thal exposure Reduced OS after thal exposure

23 ALLG MM6 study Updated results TP versus P: Survival benefit is durable Progression Free Survival Overall Survival TA CA TA CA Pts (n=243), newly diagnosed MM Treatment: Single ASCT Randomization: Thal/Pred (n=114) vs Pred (n=129) 5yr PFS: 27% vs 15% HR 0.16; 95% CI to yr OS: 66% vs 47% HR 0.12; 95% CI to Median follow-up: 5.4 years Kalff et al. HSANZ 2013 (oral presentation)

24 At least 8 months of thalidomide is required for PFS and OS benefit Progression Free Survival TA <8m TA 8-12m CA Overall Survival TA <8m TA 8-12m CA 8-12m vs CA p< m vs <8m p= m vs CA p< m vs <8m p=0.013 Kalff et al. HSANZ 2013 (oral presentati

25 Answer B: Lenalidomide maintenance (IFM ) Phase 3 randomized, placebo-controlled trial n= 614 patients, from 78 centers, enrolled between 7/2006 and 8/2008 Patients < 65 years, with non-progressive disease, 6 months after ASCT in first line Randomization: stratified according to Beta-2m, del13, VGPR Arm A= Placebo (n=307) until relapse Consolidation: Lenalidomide alone 25 mg/day p.o. days 1-21 of every 28 days for 2 months Arm B= Lenalidomide (n=307) mg/d until relapse Primary end-point: PFS. Secondary end-points: CR rate, TTP, OS, feasibility of long-term lenalidomide Attal et al. N Engl J Med 2012;366(19):

26 PFS and OS data IFM : Lenalidomide maintenance Median follow-up: 67 months (from randomization) Lenalidomide n=307 Placebo n=307 P PFS 46 months 24 months OS 82 months 81 months 0.8 Attal et al. ASH 2013 (Abstract 406), oral presentation

27 PFS according to Response Post-ASCT CR Not in CR Rev Rev p=0.021 p< Placebo Placebo Placebo Revlimid Placebo Revlimid HR= CI 95% [ ] HR= CI 95% [ ] Attal et al. N Engl J Med 2012;366:

28 Lenalidomide maintenance in high-risk cytogenetics Patients treated in trial: Vel/dex vs VAD Patients achieving PR post-transplantation enrolled in trial: 2 months consolidation with lenalidomide followed by lenalidomide maintenance or placebo Chromosomal data available for 488 patients: t(4;14) in 13.3% del(17p) in 6.6% Lenalidomide maintenance Placebo Median PFS for pts with t(4;14) 27 months 15 months Median PFS for pts with del(17p) 29 months 14 months Within lenalidomide arm, PFS comparison for patients with or without t(4;14) or del(17p) showed significant difference, in favor of no abnormality group: The median PFS of the total group of Len treated patients was 42m Avet-Loiseau et al. ASH 2010 (Abstract 1944)

29 Lenalidomide maintenance therapy: CALGB Update at IMW 2013 Lenalidomide arm Placebo arm P Median EFS 47 months 27 months <0.001 Events: PD, death, SPM Cumulative incidence of second primary cancers greater in lenalidomide group (P=0.034) Cumulative incidence of risk of PD (P=0.004) and death (P<0.001) greater in placebo group McCarthy P. IMW 2013, oral presentation (S15 Consolidation / Maintenance)

30 Phase 3: MPR vs tandem ASCT, Len maintenance vs no treatment Pts (n=402) with newly diagnosed MM <65 years Gay et al. ASH 2013 (Abstract 2089), poster presentation

31 PFS PFS and OS: Len maintenance vs no treatment R maintenance No maintenance Median PFS: Len maintenance 42.7 mos No maintenance 17.5 mos OS No maintenance R maintenance 4-year OS: Len maintenance 80% No maintenance 62% Gay et al. ASH 2013 (Abstract 2089), poster presentation

32 Lenalidomide maintenance: Meta-analysis of randomized trials 4 phase 3 trials (3 publications and 1 abstract) (n= 1935): IFM 05-02, CALGB , RV-MM-PI209 (transplant setting) MM-015 (non-transplant setting) Analysis of entire treatment package (not only maintenance) Findings Len maintenance is associated with improvement in PFS trend towards improved OS increased risk of grade 3-4 AEs and SPMs Subset of pts benefiting from Len maintenance not yet defined Careful discussion with patient required Singh et al. ASH 2013 (Abstract 407), oral presentation

33 Who might benefit from continued therapy?

34 Implications of continued response after ASCT Retrospective analysis Pts (n=430) who underwent ASCT within 12 months of diagnosis Excluded: pts in CR at day 100 or who had received maintenance Comparison of patients with and without continued response after day 100 without additional therapy Results Continued response (n=167) No continued response (n=263) P PFS 35 months 13 months <0.001 TTNT 43 months 16 months <0.001 OS 96 months 57 months <0.001 Multivariate analysis: lack of continued response predicted for worse PFS and OS Conclusions Continued response post-asct is prognostic Possible clinical implications on the use of post-transplant therapy Gonsalves et al. Blood 2013;122(10):

35 Who might benefit from post-asct therapy? High-risk disease by FISH and GEP associated with poor OS Chng et al. Leukemia 2013 Aug 26 [Epub ahead of print] Avet-Loiseau et al, Blood 2007;109: Shaughnessy et al. Blood 2007;109: Decaux et al. J Clin Oncol 2008;26: Dickens et al. Clin Cancer Res 2010;16(6); Moreaux et al. Haematologica 2011;96(4): Broyl et al. Blood 2010;116(14): ISS 3, high LDH and t(4;14) and/or del(17p) as a prognostic index for OS Scoring system to identify pts with very high-risk disease and short survival due to PD Moreau et al. IMW 2013 (Abstract O-13), oral presentation

36 Who might benefit from post-asct therapy? High serum-free light chain levels and their rapid reduction in response to therapy define an aggressive MM subtype with poor prognosis SFLC baseline levels higher than 75 mg/dl identified pts with higher ncr to induction therapy, yet inferior EFS and OS Van Rhee et al. Blood. 2007; 110: Early responder myeloma: kinetic studies identify patient subgroup characterized by poor prognosis Early response associated with high plasma cell proliferative activity is a poor prognostic factor Boccadoro et al. J Clin Oncol 1989;7(1): Shorter remission duration and OS in pts who had an initially rapid response to therapy Belch et al. Br J Cancer 1988;57(1):94-9

37 Who might benefit from post-asct therapy? Sustained CR independent favorable post-treatment variable associated with prolonged OS Loss of CR associated with adverse prognosis Barlogie et al. Cancer 2008;113:355 9 Hoering et al. Blood 2009; 114(7): Long-term survival despite absence of CR Persistent small levels of M-protein and minimal marrow plasmacytosis (likely regression to an MGUS phase) Fassas et al. Bone Marrow Transplant 2005;35(3):215-24

38 Study case continue. The patient received lenalidomide maintenance for 5 years Achieve scr Suddenly a dramatic reduction in FBC values RAEB-II was diagnosed Currently on Vidaza (acatydidine) 75 mg/m2 seven days per month MDS in PR

39 Summary / Conclusions Consolidated data confirm PFS and OS benefit of bortezomib-based induction therapy Consolidation with VTD improves depth of response and PFS Maintenance therapy: Thalidomide: improvement in PFS and OS Lenalidomide: improvement in PFS (2 studies) and OS (1 study), but reduced OS post-relapse (1 study) Bortezomib: improvement in OS We need further studies to better define the subgroups of patients who will be benefited for a post-asct continuous therapy strategy