Amyloidosis- What does it have to do with Myeloma? Anita D Souza, MD, MS Froedtert & MCW Cancer Center Milwaukee, WI

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1 Amyloidosis- What does it have to do with Myeloma? Anita D Souza, MD, MS Froedtert & MCW Cancer Center Milwaukee, WI

2 Objectives Types of amyloidosis How does amyloidosis form? How is amyloidosis diagnosed? Treatment of amyloidosis Definitive Supportive care Research- new drugs on the horizon

3 What is amyloidosis? Disorder in which a protein-like material builds up in organs Not degraded Symptoms depend on organ where amyloid builds up Several types of amyloidosis, according to the protein of origin

4 Common types of systemic amyloidosis AL/Light chain- most common, ~65% ATTR Wild type (age-related) Hereditary/familial Other hereditary types Secondary (AA)

5 AL Amyloidosis Bone marrow plasma cell clone clonal free light chains misfolded light chains (AL) organ AL deposition leading to dysfunction Myeloma >10% plasma cells CRAB

6 Diagnosis- patient and caregiver experience Lousada, I et al. Adv Ther 2015

7 Suspecting amyloidosis in the diagnosis Multisystem disease Fatigue Swelling in legs, around eyes Frothy urine Dizziness with activity Big tongue Enlarged liver Periorbital bruising

8 Tissue diagnosis Diagnosis Fat pad and bone marrow Involved organ Subtype amyloid deposits Critical step before starting treatment Mass spectrometry

9 Stage of disease Prognosis Difference in free light chains NT probnp Troponin T Blood pressure Renal failure Functional status Plasma cell clone

10 Symptoms/Signs- Heart Amyloid in heart Stiff heart Heart failure Rhythm problems Symptoms, Signs Fatigue Shortness of breath Swelling Unable to lie down (from shortness of breath) Wake up gasping for breath Cough, often at night Tests Echo MRI PYP scan Blood tests (troponin, NTproBNP)

11 Symptoms/Signs- Kidney Amyloid in kidneys Nephrotic syndrome Kidney failure Symptoms, Signs Swelling in legs Puffiness around the eyes Frothy urine Tests Urine tests (24 h urine protein, urine protein/creatinine ratio Low albumin High cholesterol

12 Symptoms/Signs- Neuropathy Peripheral neuropathy Ascending numbness Muscle weakness Gait Muscle atrophy Autonomic neuropathy Dry eyes, mouth Altered sweating Dizziness Diarrhea/ constipation Bladder dysfunction Erectile dysfunction Carpal tunnel Syndrome

13 Amyloid Treatment Strategies Prevent protein misfolding Suppress amyloidogenic protein production Destabilize amyloid deposits

14 Bone marrow plasma cell clone clonal free light chains misfolded light chains (AL) organ AL deposition leading to dysfunction Effective Chemotherapy available Needs time for endogenous clearance Chemotherapy can worsen e.g. fluid retention, cardiotoxicity, neuropathy Need for clinical trials with fibrildirected therapies

15 Chemotherapy Melphalan/Dexamethasone Bortezomib (Velcade), CyBorD Lenalidomide (Revlimid) Pomalidomide (Pomalyst) Ixazomib (Ninlaro)

16 Autologous stem cell transplant Long standing responses and excellent outcomes from single centers Clinical trial showed high transplant-related mortality, 24% Jaccard, et al. NEJM 2007;357:1083

17 Real-world US/Canada data, N=1536 D Souza, A et al. J Clin Oncol 2015

18 To transplant or not to transplant? Patient selection is critical NT probnp >5000, TnT >0.06 Center experience also key Centers 4 AL transplants/year Induction treatment pre-transplant? CyBorD can convert transplant ineligible to eligible May test ability of patients to tolerate treatment BMPC >10% Gertz, et al. BMT 2013; 48:557 D Souza, et al. JCO 2015; 33:3741 Hwa, et al. AJH 2016;91:984

19 Supportive Care-heart Low salt diet Diuretics for swelling Individualized treatment (beta blockers, ACE-inhibitors, anti-arrhythmic) Blood thinners

20 Diuretics Supportive care-kidneys Albumin infusions ACE-Inhibitors Avoid nephrotoxic medications (pain medications like ibuprofen)

21 Supportive care-neuropathy Topical medication Lidoderm patch, Anesthetic cream, Capsacin Neurotropic medications Lyrica, Neurontin Cymbalta, Elavil Pain medications Anti-inflammatory (aspirin, NSAIDs) Narcotics (patch or extended release)

22 Supportive care- autonomic dysfunction Dry eyes and mouth- tear and saliva supplements Lightheadedness when standingmidodrine Diarrhea- Lomotil, loperamide, tincture opium Constipation- stool softeners Bladder dysfunction Erectile dysfunction

23 Foot care- if you can t feel your feet, you can t feel cuts or sores Foot care tips Look between and under your toes every day Wear soft, well-fitting shoes Do not walk barefoot, particularly outside Keep feet soft and well moisturized Have nails filed rather than cut A podiatrist can help

24 Carpal tunnel syndrome Ergonomic adjustment Wrist brace Local steroid injection Surgery

25 Supplements? Multivitamin supplement EGCG (green tea) Curcumin- interesting data in lab, no data in humans except case reports,?dose Known neurotoxins Cut down on alcohol (directly toxic to nerves) Stop smoking (damages blood vessels)

26 Doxycycline- old antibiotic Forloni, G, et al. FEBS Letter 2001 Ward, J, et al. Blood 2011

27 Retrospective clinical data Survival advantage for AL patients who received doxycycline prophylaxis after transplant. Kumar, S et al. ASH 2012 Case (N=16)- Control (N=22) Advanced AL: Stage 3 (N=3)/Stage 4 (N=35) Treated with chemotherapy Lowered mortality with doxycycline Wechalekar, A et al. ASH 2014, ASH 2015

28 Amyloid busters Monoclonal antibodies targeting amyloid fibrils NEOD001 (VITAL, PRONTO trials) Anti-SAP + CPHPC 11-1F4

29 NEOD001 binds AL oligomers and fibrils λ λ κ λ λ λ λ κ λ λ λ κ λ κ MonocyteMacrophage Clearance Slide courtesy: Prothena

30 Anti-CD38 antibody: Daratumumab

31 Froedtert & Medical College of Wisconsin Cancer Amyloidosis Support Groups