1. Which bisphosphonate? How long do you give it for? What about Denosumab? What is the most effective method of preventing bone disease in patients with myeloma?

2. Which bisphosphonate? Meta-analysis and Cochrane review (20 randomised controlled trials incorporating 6692 patients) Mhaskar et al 2012 16 trials were bisphosphonate vs no bisphosphonate Great heterogeneity between trials and various bisphosphonates used ie ibandronate, etridronate not used in myeloma Reduced skeletal events, vertebral fractures and pain Zoledronate appeared to be superior to etidronate, clodronate and placebo. No trial of zoledronate vs pamidronate Phase III trial comparing denosumab to zoledronic acid in patients with at least 1 osteolytic lesion (Henry et al., 2011). Densumab is subcutaneous, has no need for renal monitoring, and without the burden of acute phase reactions

3. Denosumab 120mg subcutaneous denosumab and an intravenous placebo infusion every 4 weeks versus intravenous zoledronic acid 4mg and a subcutaneous placebo every 4 weeks. Massive study (Non-small cell lung cancer n=702, other tumours n=904). Myeloma n=180. For patients with myeloma: no difference in time to first on-study SRE However patients with myeloma on denosumab were found to have an decreased overall survival. These findings warrant further investigation and currently there is an ongoing phase 3 study specifically in myeloma patients (NCT01345019). The evidence

4. MRC Myeloma IX— Analysis Schematic for ZOL vs CLO Endpoints (ZOL vs CLO) Primary: PFS, OS, and Response Secondary: SREs (Time to first SRE, SRE incidence), Safety, and QoL N = 1,960 Patients with newly diagnosed MM (stage I, II, III) N = 1,960 Patients with newly diagnosed MM (stage I, II, III) Clodronate (1,600 mg/d PO) + intensive or non-intensive chemotherapy (n = 979) Zoledronic acid (4 mg a IV q 3-4 wk) + intensive or non-intensive chemotherapy (n = 981) Bisphosphonate treatment continued at least until disease progression 4

5. MRC Myeloma IX— gave zoledronate indefinitely ZOL Significantly  SREs vs CLO a in the Overall Population Abbreviations: CLO, clodronate; HR, hazard ratio; SRE, skeletal-related event; ZOL, zoledronic acid. a SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic bone lesions. Reprinted from Morgan G, et al. Lancet Oncol. 2011;12(8):743-752. 35.3% 27.0% ZOL reduced the risk of SREs by 26% vs CLO (HR = 0.74; P =.0004) 36423024181260 0 10 20 30 40 CLO ZOL Patients With an SRE, % Time From Randomisation, months 138 112 97 74 201 173 284 256 390 337 506 465 663 629 981 979 ZOL CLO Patients at risk, n Median follow-up = 3.7 years 5

6. MRC Myeloma IX— ZOL Significantly  OS vs CLO in Patients With Bone Disease at Baseline (n = 1,350) 50 60 70 80 90 100 40 30 Overall Survival, % 20 10 0 0123456 668 682 544 534 447 437 292 271 165 143 64 53 3 0 Time Since Initial Randomisation, years Clodronate (n = 682) Zoledronic acid (n = 668) P =.0107 HR = 0.82 (95% CI, 0.70-0.96) + Censored ZOL CLO Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; OS, overall survival; ZOL, zoledronic acid. Morgan GJ, et al. Lancet. 2010;376(9757):1989-1999. ∆ ~10 mo Median follow-up = 3.7 years 6

7. 061218243036424854606672 MRC Myeloma IX— ZOL ↓ SREs vs CLO Regardless of Baseline Bone Disease Abbreviations: CLO, clodronate; SRE, skeletal-related event; ZOL, zoledronic acid. a SREs were defined as vertebral fractures, other fractures, spinal cord compression, and the requirement for radiation or surgery to bone lesions or the appearance of new osteolytic bone lesions. Bone disease at baselineNo bone disease at baseline 0.5 0.4 0.3 0.2 0.1 0 Time from randomization, months Cumulative incidence function, SREs/patient 668 682 415 402 325 297 250 212 189 164 136 117 100 75 69 50 37 35 24 18 12 6464 0000 ZOL CLO Patients, n 061218243036424854606672 0.5 0.4 0.3 0.2 0.1 0 Time from randomization, months Cumulative incidence function, SREs/patient 302 276 241 212 185 159 135 118 92 91 63 56 38 37 28 24 18 11 12 8787 5454 0000 ZOL CLO Patients, n CLO ZOL CLO ZOL

8. MRC Myeloma IX— ZOL Significantly  OS vs CLO in Patients With Bone Disease at Baseline (n = 1,350) 50 60 70 80 90 100 40 30 Overall Survival, % 20 10 0 0123456 668 682 544 534 447 437 292 271 165 143 64 53 3 0 Time Since Initial Randomisation, years Clodronate (n = 682) Zoledronic acid (n = 668) P =.0107 HR = 0.82 (95% CI, 0.70-0.96) + Censored ZOL CLO Abbreviations: CI, confidence interval; CLO, clodronate; HR, hazard ratio; OS, overall survival; ZOL, zoledronic acid. Morgan GJ, et al. Lancet. 2010;376(9757):1989-1999. ∆ ~10 mo Median follow-up = 3.7 years 8

9. Zoledronate is the better than clodronate Unclear if zoledronate is better than pamidronate but quicker to give ONJ rate less than 5% probably BUT much less if good dental care immediately from diagnosis and awareness of ONJ. Stop zoledronate or pamidronate around dental procedures Be aware of renal function and hypocalcaemia

10. Future research Duration and frequency of zoledronate Rate of skeletal events after 2 years in a patient with stable disease is very low (but MMIX) Randomised trial needed: zoledronate monthly indefinitely vs reduced frequency or stopping after fixed time if stable disease Data on using bone biomarkers to assess duration and frequency Randomised trial needed: zoledronate monthly indefinitely vs stopping or reducing based on bone biomarkers Data on new bone agents vs bishophosphonates Ongoing tial of denosumab vs zoledronate. Other newer agents around

11. Role of imaging in Myeloma and MGUS in 2015 As a diagnostic tool (especially new definition by IMWG) In evaluating spinal disease for management (conservative vs surgery, vertebro/kyphoplasty, radiotherapy) In evaluating non-spinal disease for management (conservative, radiotherapy, surgery) Baseline for monitoring especially non-secretory, oligo-secretory, plasmacytoma, extramedullary disease Could identify potential complications Prognostic information

12. Skeletal survey, whole body MRI, whole body low dose CT scan, FDG-PET Skeletal survey (=£100). Standard of care for decades. Numerous plain radiographs Requires patient to move in various positions. Takes time. Lacks sensitivity compared to newer techniques Cannot distinguish cause of vertebral wedge fractures and osteopenia Whole body MRI (=£200) Limited capacity and limited experience in most units. Takes time The best in terms of sensitivity –picks up infiltrative disease as well as focal disease. Presence of infiltrative disease – can be difficult to assess. Does not alter management currently Picks up extramedullary disease No radiation Some patients not suitable (unbale to lie still, pacemaker, claustrophobia) Not very useful for follow up or assessment of response Newer techniques = Diffusion weighted MRI (see Messiou and Kaiser, BJH 2015)

13. Whole body low dose CT scan (£150) ?Probably more capacity Will pick up focal disease ?as good as MRI but not good for infiltrative disease Picks up extramedullary disease Some radiation Not useful for follow up or assessment of response FDG-PET in myeloma (£650) Less experience, still need to confirm if positive lesion an osteolytic lesion on the CT portion. Radiation, capacity Better for monitoring especially non-secretory or oligosecretory disease or major extramedullary disease For detection of focal disease IMWG has not specified which cross sectional imaging technique to use Focal lesion >5mm so all techniques (?PET especially) may pick up equivocal activity Skeletal survey, whole body MRI, whole body low dose CT scan, FDG-PET

14. Where is cross sectional imaging most likely to be most useful or Cost effective Patients with suspected smouldering myeloma (because of new IMWG recommendations greater than one FOCAL lesion due to myeloma is an indication for treatment IMWG 2014) Patients with symptomatic spinal disease where myeloma is a possible or known diagnosis Patients with symptomatic non-spinal disease where cross sectional imaging may provide useful information for management (i.e. when plain radiography negative or ambiguous) As mandatory work up for solitary plasmacytoma For non-secretory or oligo-secretory disease or significant extrameduallry disease, PET is useful for monitoring IN THESE CASES IT MAY BE COST EFFECTIVE TO NOT DO A SKELETAL SURVEY AND GO STRAIGHT TO CROSS SECTIONAL IMAGING

15. Where is cross sectional imaging most likely to be least useful or cost effective LEAST USEFUL For asymptomatic patients with suspected MGUS? NO. Capacity is an issue with MRI so not recommended to order cross- sectional imaging Assess risk of MGUS and avoid radiology if low risk and perhaps intermediate risk unless unexplained bony symptoms More controversial: Newly diagnosed patients with little in the way of bony disease and no bony symptoms Why – currently cross sectional imaging techniques have limited value in follow up so limited value at diagnosis?

16. Early relapse after autologous stem cell transplant 20% of patients relapse within a year of first auto-SCT Median overall survival for this group is around 20-26 months from diagnosis (Kumar et al; Jimenez-Zepeda et al 2015) and probably only a year after relapse Various “risk” factors (few papers on this) Failure to achieve CR pre-transplant More than one induction regimen High B2M More likely to have high risk genetics - >1 high risk genetic abnormality/poor gene expression profile/plasma cell leukaemia EARLY RELAPSE <12 MONTHS POST AUTO = “ULTRA” HIGH RISK DISEASE as outlook so poor (<1-2 years) UNMET NEED

17. Patients will have already had exposure to at least one novel agent during induction most likely bortezomib Conventional strategies unlikely to lead to survival >1 year Therefore experimental approaches warranted (if patient wants) = clinical trials Current concepts of treating high risk disease (based on little evidence) would suggest continuous therapy approach with a maintenance strategy Combination of IMID + newer proteasome inhibitor+ antibody +/- steroid /cyclophosphamide Daratumumab, Pomalidomide, Carfilzomib/Ixazomib, new agents Allogeneic transplantation/immunotherapy

18. DARATUMUMAB anti CD38 monoclonal antibody CD38 also present on CLL, AML, ALL and B cell lymphomas (mantle, follicular, DLBL) Phase I/II single agent in relapsed refractory MM 20 relapsed and/or refractory patients (who had received an average of four prior treatments) given 16mg/kg doses of daratumumab in a Phase II clinical trial, 35% responded, of which 10% achieved a complete response The most commonly observed side-effects of daratumumab occur within three to four hours of receiving the intravenous infusion. These include fever, chills, cough, nausea, changes in blood pressure, flushing, rash and fatigue. Other side-effects reported include: thrombocytopenia, anaemia and elevated liver enzymes Give weekly to start – various schedules but one example = weekly for a 8 weeks, then fortnightly for 16 weeks (also given 3 weekly with bortezomib regimens) then 4 weekly until progression ie as a MAINTENANCE as well

19. DARATUMUMAB anti CD38 monoclonal antibody Single agents studies = 36% PFS 6 months Relapsed patients Daratumumab + lenalidomide + dexamethasone. Early data = 75-100% response rate. Well tolerated Newly diagnosed Daratumumab + bortezomib based regimens bortezomib-dexamethasone (VD), bortezomib- thalidomide-dexamethasone (VTD), bortezomib- melphalan-prednisone (VMP) Daratumumab + pomalidomide-dexamethasone All early days but very well tolerated, fast response, PBSCH successful Isatuximab/SAR 650984, a Therapeutic Anti-CD38 Monoclonal Antibody (SANOFI) A Phase Ib Dose Escalation Trial of SAR650984 (Anti-CD-38 mAb) in Combination with Lenalidomide and Dexamethasone in Relapsed/Refractory Multiple Myeloma In heavily treated patients 64.5% response rate and VGPR of 23% - note 74% refractory to lenalidomide, 48% prior carfilzomib

21. 396 PATIENTS IN EACH ARM PFS was significantly improved by 8.7 months with KRd (HR, 0.69; P<0.0001) An unprecedented median PFS of 26.3 months with KRd Interim OS analysis: trend in OS favouring the KRd group; Kaplan-Meier 24-month OS rates 73.3% (KRd) versus 65.0% (Rd) ORR was higher with KRd (87.1% vs 66.7%); significantly more patients achieved ≥CR (31.8% vs 9.3%) ASPIRE TRIAL

22. ASPIRE study Guess which arm???

23. Allogeneic stem cell transplantation Controversial high TRM of 10-20% with reduced intensity conditioning. Timing important as less effective and higher toxicity with later relapses –i.e not so good in this setting Need for graft versus myeloma effect but this is linked with GVHD. Disappointing PFS at 5 years ?around 20% Conflicting data in various studies versus tandem auto studies However some patients do get long term disease control “Selected” patients who understand risk of procedure