Case 1: Patient with high-risk smoldering myeloma – watch and wait or treat immediately? Raymond L. Comenzo, MD Professor of Medicine and Pathology Tufts University School of Medicine Boston, Massachusetts

Disclosures Research support: Takeda/Millennium, Prothena, Teva Consultant: Takeda/Millennium, Prothena

Smoldering Myeloma Kyle NEJM 1980 (6 cases): We believe that a patient whose illness fulfills the criteria for the diagnosis of multiple myeloma should be observed off therapy if there is no anemia, bone lesions, hypercalcemia, or renal insufficiency... Therapy may lead to leukopenia... [And] unnecessary chemotherapy causes unnecessary expense, and it is a source of concern to the patient. NEJM 1980;302:1347

Monthly Wholesale Acquisition Cost DrugCost ($) Carfilzomib (BSA 1.8)5,936 (cycle 1) 8,013 (cycle 2) Pomalidomide10,437 Bortezomib (BSA 1.8)4,106 Lenalidomide8,673 Thalidomide8,092

Asymptomatic Myeloma Blood 1980;56:521 Alexanian Blood 1980 (20 cases): Since asymptomatic patients with higher tumor mass grades... are even less common... chemotherapy should not be withheld in those rare asymptomatic patients with intermediate or high tumor mass. Also, the presence of an IgA myeloma protein or the excretion of more than 200 mg/day of Bence Jones protein favored the need for early chemotherapy... Serial assessments of myeloma protein level provided a useful index of changing tumor load and the need for chemotherapy.

Blood 2000;96:2037 Progression of Asymptomatic Myeloma

Two Patterns of Changes in M-Ig Level During Progression to MM Blood 2009;113:5418

Traditional Elements Traditional variables –Monoclonal protein status –Bone marrow plasmacytosis –Symptoms –Time Traditional clinical philosophies –Minimalists vs Intensivists –Palliation –Prolong survival

Modern Elements Translational science –Serum free light chains –New platforms for clonal genetics –New metrics of organ damage Modern clinical philosophy –Incurable but treatable –Safety of high-dose melphalan –Effective le$$ toxic new drug$ Patient involvement and advocacy Changing view of risk

Would you consider treatment for High Risk Smoldering multiple myeloma? PostPosted: Thu Feb 28, :23 pm by DanaH I would welcome the community's thoughts on early treatment of High Risk Smoldering multiple myeloma (high risk for progression to active disease) in the clinical trial setting. I am aware of early clinical trial intervention studies with [lenalidomide] w/ Dex (Spanish study group as well as some centers in the US, I believe Dr. Emory ) and carfilzomib, [lenalidomide] w/ Dex (NIH w/ Dr. Landgren). Have any smolderers considered this and actually participate(d) in these trials? Or would anyone currently under treatment for active multiple myeloma have or had considered this option prior to commencing treatment once their multiple myeloma became active, had you known you were at high risk for progression ? All opinions will be very much appreciated.

Re: Would you consider treatment for High Risk Smoldering mu PostPosted: Thu Feb 28, :19 pm by mrsv118 Dana H, I am in the NIH trial. I went to the NIH and had all the testing done planning to enter the natural history study. My testing showed that i was a high risk smolderer according to the both the italian and spanish study protocol. Dr Landgren felt that I had a 75% chance of converting to active myeloma in the next two years. They had introduced the CRD for smolderers at a previous visit so I was already considering it and those odds were not for me. I didn't want to wait to be symptomatic before starting to fight it. They are having great results thus far! You need to meet them and have an evaluation before you think too much about this. Nothing wrong with standard therapy. Lots involved in making a decision like this besides the labs. Can you get there easily, (its an eight month treatment, almost weekly). You may or may not be able to work depending on your response to the meds and what kind of job you have. Expenses are not totally covered. Your comfort level with the docs. Good luck with your eval and your decision.

Symptomatic Nature of the Clone Organs at risk

Signs and Syndromes Anemia Renal insufficiency Hypercalcemia Bone lesions Infections with hypogammaglobulinemia Painful extramedullary disease Paraprotein-related neuropathy

Conditional Models Time to Event Risk of Event Predictive Tests

Progression From a pre-symptomatic state Increased cell mass –Proliferation –M protein Genetic events? –Primary –Secondary Risk of organ damage

Mayo Clinic Risk Factors for Progression Leukemia 2010;24:1121 Seminars Hematol 2011;48:4 BM PC >10% M-protein > 3 g/dL Skewed sFLC ratio 8.0

PETHEMA Risk Factors for Progression Blood 2007;110:2586 Seminars Hematol 2011;48:4 aBMPC > 95% Immunoparesis

Criteria for Diagnosis MGUS <3 g M-protein <10% PC Smoldering MM  3 g M-protein or  10% PC Symptomatic MM M-protein  10% PC No related organ or tissue impairment (no end-organ damage including bone lesions) or no symptoms Related organ or tissue impairment (end-organ damage, including bone lesions) “CRAB” BJH 2003;121:749 Leukemia 2010;24:1121

Waiting for the

QuiReDex High risk SMM* Lenalidomide 25 mg/d D1-21 Dexamethasone 20 mg/d D1-4, Lenalidomide 10 mg/d D1-21 every 2 mos Observation Induction phase 28d cycles x 9 cycles Maintenance *High risk SMM Both BMPC≥10% AND M-protein≥ 3 gm/dL OR one of the above plus aPC >95% and immunoparesis Mateos ASH 2011

QuiReDex SMM within the past 5 years –Stratified Combined Mayo/PETHEMA high risk –But no serum FLC Asymptomatic Skeletal survey at screening –Repeated only with symptoms –No MRI

QuiReDex Absolute risk reductions at 3 years –Progression 82% –Death 69% Overall survival at 3 years –94% with LenDex –80% with observation Number needed to treat –Two to prevent 1 progression –Seven to prevent 1 death NEJM 2013;369:5 BMJ 1999;307:1492

IMWG Guidelines for SMM Preventive clinical trials need to be considered for patients with high risk smoldering myeloma. Patients with smoldering myeloma with FLC ratio <0.125 or > 8 plus > 10% plasma cells in the marrow are at high risk of progression in the first 2 years following recognition. These patients should be considered candidates for chemoprevention trials. However, off-study, observation is still the standard even in this group. Leukemia 2010;24:1121

Numerous SMM Trials

Monthly Wholesale Acquisition Cost DrugCost ($) Carfilzomib (BSA 1.8)5,936 (cycle 1) 8,013 (cycle 2) Pomalidomide10,437 Bortezomib (BSA 1.8)4,106 Lenalidomide8,673 Thalidomide8,092

New Patient 52 year-old woman, asymptomatic Elevated total protein –IgGλ M-protein 3.6g/dL –FLC λ 123mg/L, Ratio 0.08 –190mg BJP 30% PCs, standard risk cyto/FISH Hemoglobin 11.8g/dL SS and spinal MRI negative GFR and creatinine normal NTX:Creat 102 units

Wb-MRI in SMM “End organ damage currently is the most important factor for the classification and the decision to treat systemically in monoclonal plasma cell disease. Therefore, serum calcium, renal damage, anemia, and bone destruction (ie, osteoporosis or focal lytic bone lesions) are the most important parameters (ie, CRAB criteria).” JCO 2010;28:1606

NTX:Creatinine Ratio Leukemia 2010;24:1700

Tests for Response and Progression Trends M-protein, free light chains Biomarkers –NT-proBNP, troponin –Albuminuria Cytogenetics/FISH/GEP? Imaging studies? –MRI –PET/CT

QuiReDex CD138-FISH abnormal in 91/123 (74%) –41% gain 1q –42% del 13q –9% del 17p –17% t(11;14) –12% t(4;14), 6% t(14;16) –8% 14q32 with unknown partner No group or grouping predicted POD –11 before and at progression Suggestive GEP Haematologica 2012;97:1439

E3A06 Groups 1 and 2 if the FLC ratio is 8.0 Within 12 months of diagnosis SS negative Serum FLC monthly GEP MRI spine and pelvis NEJM 2007;356:25 Blood 2008; 111:785

CRd at NIH for High-risk SMM Pilot study 8 cycles of CRd then 12 cycles lenalidomide extended dosing Stem cell harvest after > 4 cycles Primary objective is response rate Correlative studies: GEP, proteasome activity, MRD by flow, FDG PET-CT %20CRd%20Smoldering%20Myeloma.pdf

During screening for the trial many SMM patients had bone lesions detectable by CT or PET-CT; these patients were ineligible for the trial (due to multiple myeloma) Among SMM without bone lesions, about 30% had increased PET uptake in the bone marrow Depending on the extent of imaging, SMM for E3A06 but MM for CRd? CRd at NIH for High-risk SMM

Who and When to Treat Newly diagnosed patients with no evidence of evolving organ damage –Vaccinate –Observe at 3 month intervals –Offer E3A06 Follow clonal proliferation based on increasing M-protein or FLC Follow for trends in organ damage Marrow, kidneys, skeletal system

Should all high risk SMM patients be treated immediately? Not as standard of care Determine what the patient wants –Offer E3A06 or NIH CRd trial Use best metrics for clone and organ damage –Follow trends Image appropriately –MRI, PET/CT

Changing Landscape Updated IMWG guidelines needed –for SMM clinical trials How rational are our definitions? How radically should they be changed? Should we –redefine myeloma needing treatment? –regroup plasma cell diseases? risk from clone and organ damage We cannot overlook the urgency of relapsed/refractory status as a major driver