Myeloma and renal failure Future directions. Karthik Ramasamy

Transcription

1 Myeloma and renal failure Future directions Karthik Ramasamy

2 Overview Historical perspective & Background Drug interventions & trials OPTIMAL Trial Future directions

3 Burden of disease Upto 40% of newly diagnosed myeloma patients have atleast mild renal impairment At diagnosis 8% of patients require renal replacement therapy They belong to 1% of chronic dialysis pool

4 Treatment Options have improved survival in Myeloma Proportion of Patients Survival (Months) Kumar SK, et al. Blood. 2008;111:

5 Impact of therapeutics Median: 7.3 yrs Proportion Surviving Yr Survival by Age, % 65 Yrs > 65 Yrs Follow-up From Diagnosis (Yrs) 10 Kumar SK, et al. ASH Abstract 3972.

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7 Early mortality NDMM MRC trials JCO Vol 22;36, 2008

8 Early mortality : MM 10% of patients die <60 days of diagnosis with MM Most important predictors of early death: Beta-2-microglobulin Performance status Age (median age at presentation years) Infection (45%) Bone pain (thoracic) Delay in presenting to medical care Neutropaenia: only in 11/135 deaths from infection Renal failure (28%) Light chain MM (48%) Hypercalcemia (72%) Dehydration NSAIDs

9 NDT 2010: 25:

10 Lack of real progress Lack of active agents ( rapid tumour control) Supportive care Plasma exchange, Haemodialysis Poor risk group ( ISS stage III, GEP or ifish defined high risk) Late presentation/ lack of immediate attention Absence of a tangible biomarker

11 Improved Response rates - Its the combinations..

12 Improved PFS in Transplant Ineligible patients PFS 3 Year OS

13 Major Phase III trials in last 5 years- Exclusion of renal MM patients Phase III trials MM IX CTD vs CVAD/MP n=1883 Bologna study VTD vs TD n=480 VISTA trial VMP vs MP n=663 IFM VD vs VAD n=483 FIRST trial MPT vs Len/Dex n=1623 Exclusion criteria Dialysis dependent >176umol/L >176umol/L >176umol/L Dialysis dependent

14 TRIALS IN RENAL MYELOMA

15 Plasma Exchange When Myeloma Presents as Acute Renal Failure A Randomized, Controlled Trial. Clark et al: Ann Intern Med. 2005;143:

16 MERIT TRIAL Treatment as per local protocol (after 100 days) Newly diagnosed myeloma and acute renal failure Randomised Chemotherapy only Chemotherapy & Plasma exchange (PE x ) Dexamethasone 40mg (days 1-4, 9-12) Dexamethasone 40mg (days 1-4, 9-12) & 7 PE x treatments* (days 1-14; 4 in days 1-7) * by cytocentrifugation or plasma filtration 4 cycles VAD Or, since protocol amendment April 2006:Chemotherapy chosen by the local clinician up to Day 100 (first cycle beginning day 17)

17 Age at randomisation (years) MERIT TRIAL Treatment group Mean Median SD SE Min Max N Plasma Exchange No Plasma Exchange All Patients requiring dialysis at baseline Patients Requiring Dialysis Treatment group Yes No Total Plasma Exchange 22 (57.9%) 16 (42.1%) 38 No Plasma Exchange 25 (62.5%) 15 (37.5%) 40 Total 47 (60.3%) 31 (39.7%) 78 Behrens et al IMW 2011

18 MERIT TRIAL Primary End point Proportion alive and dialysis independent 100 days after randomisation Treatment group Alive and Dialysis- Independent Dead Dialysis-dependent Missing N Plasma Exchange 11 (28.9%) 7 (18.4%) 17 (44.7%) 3 (7.9%) 38 No Plasma Exchange 10 (25.0%) 5 (12.5%) 22 (55.0%) 3 (7.5%) 40 Total 21 (26.9%) 12 (15.4%) 39 (50.0%) 6 (7.7%) 78 Behrens et al IMW 2011

19 MERIT TRIAL OVERALL SURVIVAL Behrens et al IMW 2011

20 MERIT TRIAL Serum FLC levels were reduced from baseline to day 15 (p<0.0001) The 18 patients who were alive and dialysis independent at 100 days had lower FLC levels (p=0.019) than the 34 patients who were dialysis dependent and the 7 who died Behrens et al IMW 2011

21 EuLITE study 90 Patient recruitment target Randomisation Control Arm HD 45 Patients Standard high-flux HD Research Arm HD 45 Patients Extended HD on HCO 1100 Modified PAD regimen Chemotherapy (P) VELCADE (bortezomib) iv 1.0 mg/m 2 (A) Adriamycin (Doxorubicin) iv 9.0 mg/m 2 (D) Dexamethasone oral 40 mg primary outcome = independence of dialysis at 3 months

22 MYRE trial Primary endpoint: Dialysis independence egfr > 40ml/min/1.73m2

23 Choice of drugs ImiD based combination Proteasome inhibitor based combination Alkylating agent vs anthracycline

24 Phase III Trial of PAD vs VAD as Induction/ Maintenance in Newly Diagnosed Myeloma Patients aged yrs with newly diagnosed stage II/III MM PAD x 3 cycles Bortezomib 1.3 mg/m 2 on Days 1, 4, 8, 11 + Doxorubicin 9 mg/m 2 on Days Dexamethasone 40 mg on Days 1-4, 9-12, (n = 371) Stem cell collection and Transplantation* Bortezomib 1.3 mg/m 2 every 2 wks 2 yrs (N = 744) VAD x 3 cycles Vincristine 0.4 mg on Days Doxorubicin 9 mg/m 2 on Days Dexamethasone 40 mg on Days 1-4, 9-12, (n = 373) Stem cell collection and Transplantation* Thalidomide 50 mg daily Primary endpoint: PFS Secondary endpoints: response, OS, toxicity Sonneveld P, et al. ASH Abstract 40. *ASCT + melphalan 200 mg/m 2 ; allogenic SCT with no maintenance offered when possible; German patients enrolled through GMMG underwent 2 ASCTs.

25 Increased incidence of High risk genetic features in renal MM

26 Improved OS/ PFS in Bortezomib arm

27 Renal response correlates with Haematological response Modified PAD in a phase II study

28 Carfilzomib in renal MM Leukemia (2013) 27,

29 Carfilzomib in renal MM

30 Ixazomib in Patients With RRMM Not Refractory to Bortezomib Phase II Trial N = 32 Ixazomib 5.5 mg Days 1, 8, day cycle 2-4 cycles < MR by 2 cycles or < PR by 4 cycles or PD anytime MR by 2 cycles or PR by 4 cycles Add 40 mg/wk dexamethasone Continue treatment until progression Continue treatment until progression Patients receive standard supportive care, including antiemitics Key exclusions: grade 3 neuropathy (or grade 2 with pain); previous proteasome inhibitor therapy except bortezomib Kumar SK, et al. ASH Abstract 1944.

31 Responses to Ixazomib With or Without Dexamethasone Response Category, n Single-Agent Response Upgraded Response With Dex PR 5 11 MR 8 13 scr CR VGPR PR 3 6 (2 MR, 4 SD)* 9 MR 3 3 (2 SD, 1 PD)* 4 SD PD 4 3 NA 4 4 *Responses in parentheses prior to adding dexamethasone. Kumar SK, et al. ASH Abstract Reproduced with permission. ORR

32 Adverse Events With Ixazomib Plus Dexamethasone Thrombocytopenia Fatigue Nausea Diarrhea Constipation Vomiting PSN Neutropenia Cognitive disturbance Rash Lymphopenia Anemia Leukopenia Edema, Limbs Insomnia Creatinine Increased Grade 1 Grade 2 Grade 3 Grade Patients, % (N = 32) Kumar SK, et al. ASH Abstract Reproduced with permission.

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35 Thalidomide studies in renal MM Matsue et al ( 2010) 12 Dialysis dependent 12 Newly Diagnosed 75% ORR (8/12 dialysis independent)

36 Lenalidomide studies in renal MM

37 Bendamustine Bifunctional chemotherapeutic agent alkylating agent and antimetabolite PK both hepatic and renal excretion, clearance not significantly affected in patients with renal impairment Ramasamy et al - Nine patients who received a combination of bendamustine (120 mg intravenously, day 1) with thalidomide (100 mg/d) and low dose dexamethasone (20 mg, days 1, 8, 15, and 22 of a 28-d cycle) in both newly diagnosed and relapsed myeloma patients with renal impairment ( egfr < 30ml/min). Haematological ORR 55% ( > PR) and dialysis independence in 3/ 4 ( 75%) patients Ponisch et al -18 patients with egfr < 35ml/min treated with Bendamustine (60 mg/m2) was given as a 30 min infusion on days 1 and 2 in combination with prednisone (100 mg) given orally on days 1, 2, 4, 8, and 11, and bortezomib (1.3 mg/m2) as an intravenously push on days 1, 4, 8, and 11 (BBD) Haematological ORR 83% with 4/8 patients ( 50%) dialysis independent

38 Aims and Hypothesis The aim of this study is to establish the optimal therapy for increasing the rate of renal recovery and overall survival in patients presenting with myeloma and renal failure. We hypothesise: 1) A significant difference in achieving a reduction in sflc levels during the first two cycles of therapy when comparing thalidomide versus bortezomib in combination with bendamustine and dexamethasone 2) Light chain response at end of two cycles predicts response to four cycles of therapy allowing early identification of poor responders who may benefit from alternative therapy

39 Randomised (n= 120) N=60 Bortezomib, Bendamustine and Dexamethasone (BBD) (In older, frail patients the dose of dexamethasone will be reduced from 40 to 20mg daily) Days 1, 4, 8 and 11 Bortezomib 1.3 mg/m2 sub cutaneously Days 1, 8 Bendamustine 60mg/m2 intravenous infusion Days 1-2, 4-5, 8-9 and Dexamethasone 40mg daily orally 21 day cycle 4 cycles Bortezomib vs Thalidomide N=60 Thalidomide, Bendamustine and Dexamethasone (BTD) (In older, frail patients the dose of dexamethasone will be reduced from 40 to 20mg daily) Continuously Thalidomide 100mg daily p.o. Days 1, 8 Bendamustine 60mg/m2 intravenous infusion Days 1-2, 4-5, 8-9 and Dexamethasone 40mg daily orally 21 day cycle 4 cycles PBSC Collection after 4 cycles CO-PRIMARY ENDPOINTS: SERUM FLC RESPONSE AT 6 WEEKS RENAL RESPONSE AT END OF 12 WEEKS Standard response assessments Blood/ urine /BM will be performed Dose reduction As per SmPC SECONDARY ENDPOINTS Serum free light chain response and prediction of overall response, Renal response at end of 2 nd and 4 th Cycles, Toxicity, Overall Survival, QOL

40 Summary First randomised trial comparing activity of Bortezomib vs Thalidomide induction therapy in myeloma patients Results from this trial would help inform a phase III design in this group of patients Renal biopsies not required for inclusion, as primary end point sflc reduction Correlation between sflc reduction and renal response Early identification of non responders Develop sflc as biomarker for early response to evaluate in phase III studies

41 Future directions Early diagnosis Improved Diagnostics Biomarkers Non drug therapy interventions Optimal therapy - Early switch of non responders Maintaining response prevent LC injury and renoprotective effects

42 Near Patient Testing MT Drayson et al Journal of Immunological Methods Volume 391, Issues 1 2, 31 May 2013, Pages 1 13

43 HR23B Candidate biomarker for proteasome activation Cancer Cell 15, 57 66, January 6, 2009

44 HR23B

45 Comprehensive Clinical Nephrology (Johnson & Feehally); p238

46 Tamm Horsfall protein

47 CDR in light chains - VL

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51 Rapid renal scarring in Myeloma Kidney Presentation Biopsy Repeat Biopsy 6 weeks Basnayake et al: J Clin Pathol 2010;63:

52 PACAP 38 Pituitary adenylate cyclase activating polypeptide PACAP38 belongs to family of VIP, neuropeptide secreted from hypothalamus VPAC and PAC1 receptors for PACAP 38 expressed on proximal tubular epithelial cells and myeloma cells Blood Jan 15;107(2): Epub 2005 Oct 4

53 PACAP38 Uromodulin ( TH protein) over expression/ mutation leading to cast nephropathy? Under investigation

54 Bortezomib is renoprotective

55 Conclusions Early confirmation of myeloma Renal Myeloma is a medical emergency Optimal initial therapy Early recognition of poor responders Maintenance with oral drugs ( future trials)

56 Acknowledgements Kings College London Prof Stephen Schey University of Birmingham Prof Mark Drayson University of Warwick Prof Janet Dunn