Asymptomatic plasma cell dyscrasias –Smoldering myeloma & MGUS Aric Hall, MD Assistant Professor – UW Health

Objectives To discuss pathophysiology of plasma cell disorders To define and describe the asymptomatic plasma cell dyscrasias To discuss prognosis To discuss management Questions and further directions

Plasma cell origin and function Plasma Cells are terminally differentiated B cells whose function is the production of antibodies (=immunoglobulin = Ig) Immunoglobulin is a Y shaped protein that binds and helps neutralize pathogens This is the key portion of the adaptive immune system (part that recognizes stuff you’ve seen before) Immunoglobulins provide a major mechanism of durable immunity

Functionality requires flexibility Best “fit” variable region for pathogen Appropriate heavy chain for needed function / location

Flexibility requires physiologic DNA alteration Immune system needs to be ready for unknown unknowns Goal is to create most avid, least self reactive, most functional antibody possible Three points of physiologic double stranded breaks in DNA Presumed to be a point of trouble

Protein testing for clonality- what is a M-spike Normal  diverse plasma cell population, small amounts of many immunoglobulins Neoplastic transformation  specific plasma cell gains a growth and proliferation advantage (single clone of plasma cells predominating & secreting a single immunoglobulin) Clonal plasma cell ≠ Cancer One way we assess this clonality is by looking at the products of plasma cells  immunoglobulins in the blood Monoclonal protein (M-spike) indicator of a clonal plasma cell, unless you just make light chains

Protein Electrophoresis

SPEP Examples Normal Monoclonal gammopathy

Symptomatic multiple myeloma Presence of clonal plasma cell population + end organ damage. Organ damage is typically defined by CRAB HyperCalcemia Renal disease Anemia Bone Disease Or now just by a very high burden of clonal plasma cells with presumed near 100% risk of ultimately causing organ damage

What are we talking about – MGUS MGUS : “a clinically asymptomatic premalignant clonal plasma cell or lymphoplasmacytic proliferative disorder. It is defined by the presence of a serum monoclonal protein (M-protein) at a concentration <3 g/dL, a bone marrow with <10 percent monoclonal plasma cells, and absence of end-organ damage (lytic bone lesions, anemia, hypercalcemia, renal insufficiency, hyperviscosity) related to the proliferative process”

What are we talking about – Smoldering MM SMM: “a clinically asymptomatic premalignant clonal plasma cell or lymphoplasmacytic proliferative disorder. It is defined by the presence of a serum monoclonal protein (M-protein) at a concentration >3 g/dL or a bone marrow with >10 percent monoclonal plasma cells but <60%, and absence of end-organ damage related to the proliferative process and NOT involved/uninvolved light chains ration < 100:1 or > 2 bone lesions on advanced imaging > 5 mm in diameter

What we are NOT talking about… “Asymptomatic” symptomatic multiple myeloma: No bone lesions, no anemia, no hypercalcemia, no osteoporosis, no kidney issues but biomarker criteria for MM Solitary plasmacytoma, Plasmacytoma with minimal marrow involvement Dangerous small clone diseases – Low burden of plasma cells but clinically significant and causing organ injury AL amyloidosis, light chain and heavy chain deposition disease Monoclonal gammopathy of clinical significance

AL amyloidosis

Amyloid Manifestations If we can prove it, we should treat it

Monoclonal gammopathy of clinical significance “dangerous small B-cell clone” Low burden of abnormal plasma cells, low burden of monoclonal immunoglobulin Usually felt to be due to direct deposition and injury from immunoglobulin or immunologic activation Most common organs are kidneys, skin, peripheral nerves Likely all rare, but we don’t really know how rare If we can prove it, we should treat it Fermand et al. Blood. 2018.

Asymptomatic Plasma Cell Disorders- Very simple MGUS : A low number of abnormal plasma cells that we can detect on monoclonal protein testing SMM: More abnormal plasma cells that we can discuss on monoclonal protein testing but still short of the level where we think they are destined to get MM and there is no injury These are neoplasms (“new growths”) that are cells proliferating under own guidance; therefore they have the potential to become cancer but are not harmful yet Similar to polyps on colonoscopy or premalignant skin lesions

Epidemiology of asymptomatic plasma cell disorders MGUS Quite common – estimate about 3% of population > 50 years old Perhaps as high as 10% of octogenerians Main risks Age Male > Female African American Ethnicity Lower rates in East Asia Smoldering MM- likely much rarer < 1: 100, 000 Landgren et al. Leukemia 2014.

Diagnostic work - up Full paraprotein evaluation (blood and urine labs) Assess for anemia / high calcium / renal failure If low risk MGUS (M-spike < 1.5 g/dL, Nl light chain ratio, IgG M-spike) and no evidence of lab abnormalities above can stop and watch without any further work up If not, bone marrow biopsy to determine if smoldering myeloma vs MGUS (i.e. are there 10% plasma cells or less)

Further work up… Smoldering MM – Need skeletal imaging, start with skeletal survey and if negative move on to advanced cross sectional imaging to exclude bone disease (CT-PET, MRI total spine and pelvis, whole body CT) If weird organ dysfunction you can’t otherwise explain (i.e. heart failure, kidney injury, skin lesions) consider biopsy of target organ as this will be usually necessary to look for amyloid or monoclonal gammopathy of clinical significance

Cross Sectional Imaging

Risk Stratification

Risk of developing MM from MGUS – Very low Historic cohort followed at Mayo Clinic 241 patients with at least 5 years of follow up where nothing bad had happened (no MM or WM) Amount of monoclonal protein corresponded to risk of progression Kyle, R. Am J Med 1978: 815

Holds up over time… 22 years follow up There are a few more progressions But… Rate of progression reduces with time Young patients are likely harder to predict

MGUS - Stratification When we break down MGUS even clearer Risk factors Non-IgG subtype Abnormal FLC ratio M-spike > 1.5 g/dL Stratify based on 1,2, or 3 risks Rajkumar et al. Blood. 2005.

Risk with SMM is MUCH, MUCH Higher These are series of fewer patients, however, that are contaminated with patients we would now call symptomatic MM Still, huge difference Kyle et al. NEJM. 2007.

Risk Stratification SMM- Old Mayo Model Risk factors- Marrow > 10% infiltrated M-spike > 3 gm/dL FLC ratio abnormal Kyle et al. Leukemia. 2010.

Risk Stratification MM- Spanish Model 2 risk factors >95% “aberrant” plasma cells Immunoparesis (Low “good” immunoglobulins)

Risk Stratification MM-Newer model? Mayo 20-20-201: reviewed 421 SMM pts for factors that correlate with TTP to symptomatic myeloma Bone marrow plasma cells >20% (HR 2.28 CI 1.63-3.20) M spike >2.0 g/dl at time of diagnosis (HR 1.56 CI 1.11-2.20) FLC ratio>20 (HR 2.13, CI 1.55-2.93) 0 factors-110 months 1 factor 68 months > 2 factors 29 months

“Other” High risk Features High risk CG including t(4:14), -17p, and +1q More urine protein rather than less Rapidly increasing M-spike Abnormal cross-sectional imaging even if not sufficient for diagnosis of symptomatic MM Less clear how this predicts on its own (i.e. if I have otherwise low risk SMM and have high risk CG)

Difficulties with current risk stratification Unfortunately, concordance between risk factors is not great As definitions are shifting rapidly, the cohort we are diagnosing people in now will probably do differently than those we defined Biggest strength is probably targeting high risk patients for potential intervention

Asymptomatic Plasma cell disorders- Management

MGUS – no interest in medical treatment Standard of care remains periodic follow up SEER data indicates that F/U is beneficial to avoid morbidity and death No indication (yet) that early intervention will improve outcomes Go et al. Clin Lymph Myelo. 2015.

Non-pharmacologic interventions? Unfortunately, not a lot of things we have to offer There are small analyses that suggest obesity is a risk factor for early progression after transplant and remission and for MGUS  MM This could actually represent many patterns of causality, there is no evidence any natural product prevents /slows progression

Smoldering MM- Interest in treating for a long time Ref Intervention N PFS OS 1 Mel-Pred: early vs delayed 50 12 mo ND 2,3 145 ~12mo 64mo vs 71 mo 4,5 Pamidronate vs Obs 174 5yr 53%; SRE 74% vs 39% (p<.01) 46 vs 48 mo 6 Zol vs Obs 169 67 vs 59 m, p=NS SRE 55% vs 78% (p<.05) 7 Thal-Zol vs Zol 68 29m vs 14m (p<.01) 6 yr>70% 8 Silituximab vs Obs 85 1 yr PFS 84.5% vs 74.4% Not reached 1.Horth M, EJH 1993. 50:95-102. 2. Riccardi A BJC 1994. 70:1203-10 3. Riccardi A BJC 2000. 84: 1254-60 4. Musto P Leuk Lymph 44: 1545-8 5. D’Arena G. Leuk Lymph 2011 52: 771 6. Musto P Cancer 2008. 113:88 7. Witzig T Leukemia 2013 27:220 8. Brighton B Clin Canc Res 2019 ePub

Targeting High Risk SMM Now MM People above the line are those still at risk of developing MM Trying to target and help the group in the green box is probably highest value Kyle et al. NEJM. 2007.

1st Successful Phase III trial - QuiReDex 125 high risk patients in Spain or Portugal Randomized to Lenalidomide (Revlimid)/ Dexamethasone X 9 mos then lenalidomide versus observation High risk defined by Spanish system (unclear how mirrors our patients) Surprising Results Unsurprising Results Mateos et al. Lancet Onc. 2016.

Why didn’t Lenalidomide / Dex become standard of care? They did not do cross sectional imaging did not have biochemical criteria for disease, concern contaminated with “real” MM Median PFS in control arm 23 mos, shorter than even really high-risk people in Mayo risk or Spanish risk papers Unclear need for dexamethasone – Hated by patients Aberrant plasma cell testing not usually standard in US

US study to look at high risk smoldering MM E3A06: Phase III – Asymptomatic Myeloma*(PI: Sagar Lonial) Lenalidomide vs. observation: Does dexamethasone make a difference? Observation Lenalidomide CR/PR/ Stable Prog. anytime Continue therapy till prog. or toxicity Off Rx RANDOMI ZAT ION N=226 pts 10/23 ACTION LETTER DSMB: PFS favors lenalidomide group! ASCO Sunday June 3, 2019 – PFS at 3 years 91% vs 66%

EA306 Results – Still questions 66% PFS at 3 years is still pretty good, puts the control arm between low and intermediate on the old Mayo hierarchy (is this what we see with “real” smoldering where we’ve ruled out the people we’d now call MM) No survival advantage (wouldn’t expect to see yet) Lenalidomide is expensive, and there are toxicities Alongside these efforts there is a new idea…. “cure” of smoldering MM

KRD/R maintenance for high-risk SMM* *FLC ratio >8; or<0.125 Korde N JAMA Onc 2015 1: 746

GEM-CESAR (Curativo Estrategia Smouldering Alto Riesgo): Phase II Study Design Multicenter, open-label trial Consolidation 2 x 28-day cycles Maintenance 24 x 28-day cycles Induction 6 x 28-day cycles Carfilzomib IV 20/36 mg/m2 Days 1, 2, 8, 9, 15, 16 Lenalidomide 25 mg Days 1-21 Dexamethasone 40 mg Days 1, 8, 15, 22 High-dose Melphalan 200 mg/m2 followed by ASCT Carfilzomib IV 20/36 mg/m2 Days 1, 2, 8, 9, 15, 16 Lenalidomide 25 mg Days 1-21 Dexamethasone 40 mg Days 1, 8, 15, 22 Lenalidomide 10 mg Days 1-21 Dexamethasone 20 mg Days 1, 8, 15, 22 Patients with high-risk* smoldering MM (N = 90) ASCT, autologous stem cell transplantation; MM, multiple myeloma; MRD, minimal residual disease; sCR, stringent CR; TTP, time to progression. Primary endpoint: MRD negative rate (by flow cytometry) after induction, ASCT, consolidation/maintenance, and 3 and 5 yrs after maintenance Secondary endpoints: response, TTP, PFS, OS, safety *High risk defined per Mayo and/or Spanish models (pre-2014 diagnostic criteria) Pts with both BM PCs ≥ 10% and serum M- protein ≥ 3g/dL, or 1 plus > 95% aberrant BM PCs by immunophenotyping plus immunoparesis Pts w/ bone disease on CT or PET/CT at screening excluded Mateos MV, et al. ASH 2017. Abstract 402.

GEM-CESAR: PFS and OS Median follow-up: 10 mos (range: 1-28) PFS OS 1.0 1.0 0.8 0.8 0.6 0.6 Proportion Remaining Alive Proportion Without Progression 0.4 0.4 0.2 0.2 94% PFS at 28 mos 98% OS at 28 mos 5 10 15 20 25 30 10 20 30 Mos Mos 2 deaths: 1 due to progression after relapse from CR, 1 due to ischemic stroke during induction 2 pts relapsed from CR during induction, proceeded to subsequent therapy Mateos MV, et al. ASH 2017. Abstract 402.

EA173: Phase III –Daratumumab to Enhance Therapeutic Effectiveness of Revlimid in Smoldering Myeloma (DETER-SMM)(PI: NC) Lenalidomide + Dex Daratumumab + Lenalidomide CR/PR/ Stable Prog. anytime Continue therapy For 2 years Off Rx RANDOMI ZAT ION N = 288 PI: Natalie Callander (Activated – just s starting)

Summary – MGUS MGUS is a common condition associated with age in which the majority of patients will never develop a plasma cell cancer Higher or non IgG M-spike as well as abnormal free light chain ratio are main indicators of risk of progression Regular surveillance of paraprotein (at least yearly) seems to be associated with better outcomes

Summary - SMM The actual prevalence of smoldering myeloma is unknown and given shifts in diagnosis it is somewhat unclear how high the risk of progression is Bone marrow plasma cell burden >20%, M-spike > 2 gm/dL, and FLC ratio >200 are all associated with worse risks of progression Studies of treatment of high-risk SMM have had mixed results but lenalidomide with or without dexamethasone seem to be associated with a progression free survival advantage though overall survival unclear

Summary - General The best therapeutic management of high-risk SMM at the moment is a clinical trial Patients may choose between lower intensity type protocols to prolong time to progression vs “nuclear option” type trials to attempt cure Clinical suspicion and curiosity as well as possible biopsy of target organ are the major paths to finding pathologic small clone diseases