Multiple Myeloma Case studies UKMF Education Day November

Multiple Myeloma Case studies UKMF Education Day November 2011 Kwee Yong Cancer Institute University College London

Case 1 : Lynne • • • 36 year old business manager June 2010: fatigue & nosebleeds Hb 8. 8 g/d. L, WBC 2. 8 x 109/L, Neuts 0. 9, plts 198 Ig. G 79 g/L, pp = 61 Creatinine 109 umol/L, normal Ca++ Albumin 33 g/L, b 2 m 3. 7 mg/L (ISS Stage 2) BMT: 80% plasma cells, CD 56+, cyclin D 1+ FISH: t(11; 14) SS: no lytic lesions, MRI spine: no focal lesions

Case 1: Lynne Several karytopic abnormalities

Case 1: Lynne • July 2010: CTD & zometa (sibling match) – Neutropenia after one dose Cyclo – Thal/Dex – Poor tolerance: dizziness, bradycardia (45 -50/min) – Pp 46, then 53 What would you do now?

Case 1: Decision point 1 1. Continue with Dexamethasone alone 2. Switch to Velcade and Dexamethasone 3. Continue with Cyclophosphamide and dexamethasone with growth factor support 4. Stop treatment to allow bone marrow recovery

Case 1: Lynne • July 2010: CTD & zometa (sibling match) – Neutropenia after one dose Cyclo – Thal/Dex – Poor tolerance: dizziness, bradycardia (45 -50/min) – Pp 46, then 53 August 2010: Velcade/Dex 3 cycles Stable disease Grade 1 PN What would you do now?

Case 1: Decision point 2 1. Continue with Velcade and Dexamethasone for further 2 -3 cycles as tolerated 2. Switch to Revlimid and Dexamethasone 3. Add Revlimid to Velcade and Dexamethasone 4. Arrange mobilisation and PBSCH

Case 1 : Lynne • Revlimid 10 mg od days 1 -14, with velcade 1. 3 g/m 2 and dex • After 14 days, neutrophils 0. 6 • Prolonged neutropenia • Transfusions What would you do now?

Case 1: Decision point 3 1. Wait for bone marrow recovery and try again with RVD 2. Switch to Revlimid and Dexamethasone 3. ESHAP with PBSCH 4. Proceed to allogeneic transplant

Case 1: Lynne What would you do now?

Case 1: Decision point 4 1. 2. 3. 4. Salvage regimen prior to ASCT Proceed to allogeneic transplant Proceed to ASCT Clinical trial of new agent

Case 1: Lynne ASCT Jan 2011 (27 weeks after diagnosis): pp 42 ASCT 14. 01. 2011 5 week admission Fever day -1 Grade 3/4 mucositis: diarrhoea++, nausea, dehydrated • Hypokalaemia induced DI: polyuria, polydipsia • Neut engraftment day +12 • Discharged day +33 • • •

Case 1: Lynne BM 3% PC VGPR What would you do now?

Case 1: Decision point 5 1. Nothing 2. Reduced intensity sibling allograft (Lena. RIC study) 3. Maintenance with lenalidomide 4. Maintenance with thalidomide

Case 1: issues • Primary refractory MM • Discordance in prognostic information between FISH and karyotype • Sibling match – when to allograft? • Case for tandem sib RIC allo? • Poor tolerance of chemotherapy • Toxicity of conditioning

Case 2: Joanna • 49 year old charity worker • June 2010 – ‘blocked ear’ for 2 mo – Sudden onset diplopia and numbness R face 4 days • Right 6 th nerve palsy • MRI head: large irregular tumour arising from clivus and R sphenoid, invading cavernous sinus • CT scan: rib lesions, T 5 lesion invading canal, large sacral mass, sternal mass, L iliac lesion, breast lump

Case 2: Joanna R L

Case 2: Joanna • • Case 2: Joanna Immune paresis Urine protein: 2 g/24 hr SFLC: kappa 4720 mg/L BMT: 80% plasma cells, cyclin D 1+, CD 56 FISH: Ig. H split, 17 p loss in all cells CT-PET: FDG avid lesions manubrium, R iliac bone, R base of skull, T 5

Case 2 : Decision point 1 How would you manage this patient? 1. Urgent DXT to base of skull 2. Treat with CTD 3. Use high grade NHL protocol with CNS treatment 4. Velcade and dexamethasone

Case 2: 1: Joanna Case 2: Joanna LP: no cells, methotrexate High dose dexamethasone Velcade, Idarubicin & Ara-C (June 2010) Clinical response, MRI improvement, KLC 79 mg/L • July 2010: Ida-Ara-C no. 2 with Velcade/dex • • – Neutropenic fever, klebsiella septicaemia – Hypoxia, severe mucositis

Case 2: Joanna • Velcade / dexamethasone no. 3 • Re-staging MRI: good response to treatment • PET-CT scan: new FDG-avid lesions in liver and spleen, previous lesions resolved • BM: CR, KLC 1. 7 mg/L, urine: IF neg for BJP

Case 2: Joanna • • • Biopsy liver lesions x 3!! Fibrosis with inflammatory cells Rx: posaconazole 3 mo Velcade / Dexamethasone no. 4 Cyclo-G-CSF prime and PBSC harvest Repeat CT scan: lesions unchanged What would you do now?

Case 2: Decision point 2 • Assume liver lesions disease and treat with Revlimid and dexamethasone • Attempt further biopsy of liver • Continue posaconazole and re-scan • Proceed with ASCT

Case 2: Joanna • 25 Feb 2011: Melphalan 140 / TBI – 12 Gy in 6 fractions • ASCT in ambulatory care • Fever day +8, resistant E Coli, PICC line out • Engrafted day +12, discharged day +15 • May 2011: BM clear, SFLC normal, – CT abdo: lesions smaller – MRI head

Case 2: repeat imaging What would you do now?

Case 2: Joanna 1. 2. 3. 4. Case 2: Decision point 3 Consolidation DXT to base of skull Do nothing Maintenance with thalidomide (lenalidomide) Search for donor (MUD RIC-allo, -Lena. RIC? ) 30 Gy DXT to base of skull in 15 fractions Watch and wait

Case 3: Lenny • 45 yr old warehouse supervisor • Aug 2011: Back pain since Dec 2010 – Anorexia and weight loss – Unsteady walking – “Numb balls” – Sluggish bowels, urinary hesitancy – Pain radiating down legs, walking with sticks

Case 3: Lenny

Case 3: Lenny MRI: extensive paravertebral mass T 11 -L 2, extending into soft tissues, and into the spinal canal at L 1 compressing the conus Biopsy at Stanmore: Plasma cell tumour

Case 3: Lenny • • • Case 3: Lenny Dexamethasone 4 mg qds BM clear FBC normal, renal function normal SEP small Ig. Ak pp, total Ig. A 9. 8 g/L SFLC SS, MRI spine: no other lesions Solitary plasmacytoma

Case 3: Decision point 1 How would you manage this patient? Case 3: Lenny • • Surgery and decompression Radiotherapy Treat with CTD Treat with velcade and dexamethasone

Case 3: Lenny • Velcade, cyclophosphamide & dexamethasone started within 24 hours • Radiotherapy review – on hold • Pain decreased, improved mobility • Postural drop beginning of cycle 2 – Lying 130/75, standing 107/70 – asymptomatic • Delay 1 week

Case 3: Lenny • MRI after 2 cycles CVD, marked improvement • Sensation in groins now normal, perineal parasthesiae persists but better • Bowels : grade 1 constipation • Bladder function normal • Ig. A reduced from 9. 8 to 1. 7 g/L What would you do now?

Case 3: Lenny • • Case 3: Decision point 2 Stop CVD and give radical DXT Continue with CVD Switch to CTD Surgery to stabilise spine

Spinal plasmacytoma: Radiotherapy, surgical decompression/fixation or systemic treatment? • Level of tumour – Cervical, thoracic, T-L jn, lumbo-sacral • • • Spinal cord issues: bony or tumour Spinal stability: (bracing? ) Presence of disease elsewhere Stage of disease (diagnosis, relapse) Access (clinical oncologists, surgical colleagues)

Solitary bone plasmacytoma • Most (>70%) progress to MM, majority within 2 -4 years • Risk of progression assoc with persistence of M-band, abnormal SFLC ratio • PET-CT scanning may be useful to identify occult disease • Relatively indolent disease even after progression, OS 5 -10 years

Case 4: Michael • 55 yr old schoolteacher • March 2010: back pain (previous L 4/5 vertebrectomy) • Hb 6. 6 g/dl, WBC 2. 4, neuts 1. 2, Plats 34 • SEP: pp 2 g/L, UTP 9 g/L • b 2 microglobulin 9. 3 mg/L • SFLC lambda 5270 mg/L • Calcium and Renal function normal

Case 4: Michael • BM 90% cyclin D 1+ PC, FISH ? Partial p 53 loss • MRI: diffuse abn BM signal, extraosseus tumour left 6 th rib, paravertebral mass at T 11/12 • No spinal cord issues, neurologically intact

Case 4: Decision point 1 How would you treat this patient? 1. CTD 2. Velcade and dexamethasone 3. Urgent radiotherapy to paravertebral mass 4. VAD/Idarubicin & Dex (Myeloma XI, PADIMAC)

Case 4: Michael BM FISH: t(11; 14) single fusion TP 53: deleted in 88% What would you do now?

Case 4: Decision point 2 1. Add Cyclophosphamide to Revlimid /Dex 2. Proceed with mobilising stem cells 3. ESHAP-type regimen 4. Palliate

Case 4: Michael What would you do now?

Case 4: Decision point 3 1. 2. 3. 4. Do nothing Search for donor for RIC allo Maintenance with thalidomide Consolidation - ? VTD consolidation

Summary of novel agent induction trials (randomized studies) ≥ VGPR rates post-induction and post-transplant Post-induction Post-transplant 44 -50% 45 -55% 57% 79% 71% 49% * 1516% 3035% 39% 42% VAD TD VD RD 33% 45% TAD PAD 62% VTD *Post-transplant data not available Harousseau et al. ASH/ASCO symposium during ASH 2008 Rajkumar et al. ASCO 2008 (Abstract 8504); ASH/ASCO symposium during ASH 2008 Lokhorst et al. Haematologica 2008; 93: 124– 7 Sonneveld et al. ASH 2008 (abstract 653); IMW (abstract 152) Cavo et al. ASH 2008 (abstract 158); IMW 2009 (abstract 451)

17 p- disease in MM • 9 -10% at presentation • Progression event • Associated with Light chain only disease, high ISS stage • Prognostic only if in ≥ 50% plasma cells • Very poor outlook • IFM study of Vel/Dex, EFS 14 mo vs 36 mo

(A) Event-free survival (EFS) and (B) overall survival (OS) in patients with del(17 p) (n = 54) or without del(17 p) (n = 453) treated with bortezomib-dexamethasone induction (EFS and OS in years; P <. 001 for EFS and OS). © 2010 by American Society of Clinical Oncology Avet-Loiseau H et al. JCO 2010; 28: 4630 -4634

Case 5: John • • • 63 year old aircraft engineer Presented with anaemia Diagnosed with Ig. Gk MM Initial treatment with VAMP, minor response CDT x 5 ASCT

Case 5: John ?

Case 5: Decision point 1 1. Palliate 2. Cyclophosphamide and dexamethasone 3. Thalidomide regimen 4. Re-treat with velcade on NHS

Case 5: John

Case 5: Decision point 2 • • Palliate Thalidomide Cyclophosphamide and dexamethasone Clinical trial

Clinical trials for relapsed MM • Bortezomib trials (± HDACi, ±hsp 90 i, ±m. Ab) – Usually IV velcade – 1 -3 prior lines • Lenalidomide trials (±carfilzomib, ±CS 1 m. Ab) • Pomalidomide trials • MUK Clinical Trials Network early phase studies – Less restriction in no of prior lines • Other, eg carfilzomib