How Should High Risk AMM be treated? Treat Now Sagar Lonial, MD Professor, Winship Cancer Institute Director of Translational Research, B-cell Malignancy Program

Real Case 52 year old healthy surgeon presents with knee pain MRI done shows marrow infiltration, no bone disease. Has extensive workup that shows no m protein, normal renal and chemistries, CBC shows Hgb of 11.3. Freelight ratio of >100, UPEP ufix only. PET and MRI shows no lytic disease Marrow shows 40% plasma cells, normal cyto, negative FISH panel

Additional details Hgb 1 month ago was 14 B2M is 2.2, albumin is 3.9 Would you treat this patient? What are you waiting to happen before you treat him? Does something bad have to happen before you start treatment? Why???

Our ‘Case’ Male with no anemia, >10% plasma cells, and m protein of >3gm/dl What does this mean in terms of his risk of progression?

Criteria for Diagnosis of Myeloma SMM ≥ 3 g M spike ≥ 10% plasma cells Active MM ≥ 10% plasma cells M spike + AND MGUS < 3 g M spike < 10% plasma cells AND No anemia, bone lesions, normal calcium, and kidney function Anemia, bone lesions, high calcium, or abnormal kidney function MGUS = monoclonal gammopathy of unknown significance; SMM = smoldering multiple myeloma. Kyle et al, 2009.

We were not given specifics on risk SMM “Conversion” Clearly not all patients are the same with SMM Is there a way to identify ‘Some’ of the patients such that… “Should patients with high risk Asymptomatic or Smoldering MM (AMM) receive treatment as routine care?” We were not given specifics on risk

Smoldering Multiple Myeloma 27% will convert in 15 years Roughly 2% per year Kyle R et al. N Engl J Med 2007;356:2582-2590

Initial Risk Stratification 2 yr 19 yr 8 yr Patients with >10% plasma cells and >3gm/dl M protein are at higher risk Kyle R et al. N Engl J Med 2007;356:2582-2590

Free Light is Useful for Risk Assessment in AMM Dispenzeri et al Blood 2008

This is all well and good, but can we know more? How can we differentiate from those just stopping by AMM on their way to MM vs those who really have AMM? Mayo team suggests patients with freelight ratio >100 or >60% plasma cells have a much higher risk and should be treated No prospective data to support this analysis

Freelight Ratio >100 predicts risk Larsen et al, Leukemia 2013

There are patients with higher risk of progression to MM These patients can be defined by the use of simple testing There is a subset of high risk AMM patients that progress to MM on average within 2 years. Can we change the natural history of their disease for these patients?

Trials with old treatments Use of MP was tested in 3 small trials in the past No improvement in outcomes was noted Risk of MDS among early treated patients.

The use of Thalidomide in SMM 3 trials have been done to date (MDACC, Mayo, UAMS) 2 showed longer TTP for responders to thal, UAMS trial showed shorter TTP for responders to thal. No improvement in OS

What was the Price of Early Therapy Toxicity of therapy was significant Significant PN was noted Median duration of thal was short in Mayo study “Despite our results and those reported by others, we do not recommend the use of thalidomide for SMM.” Detweiler-Short et al, AMJ 2010

Smoldering multiple myeloma: aberrant PCs by immunophenotype plus immunoparesis 1.0 p = 0.003 >95% aPC/BMPC + paresis n = 39 (28 progr.) Median 23 months 0.8 82% > 95% aPC/BMPC or paresis n = 22 (10 progr.) 0.6 Median 73 months TTP (%) 42% No adverse factors n = 28 (1 progr.) 0.4 0.2 Median not reached 8% 0.0 24 48 72 96 120 Months Perez-Persona E, et al. Blood. 2007;110:2586-92.

Schedule of therapy (n:126 pts) Treatment arm (n = 60) Control arm (n = 66) Lenalidomide 25 mg/daily during 21d every 28 d Dexamethasone 20 mg D1-D4 and D12-D15 every 28 d Induction Nine 4-week cycles Therapeutic abstention Lenalidomide 10 mg/daily during 21 d every month* Therapeutic abstention Maintenance Ammendment on August 2011: Stop treatment at 2 years of treatment * Low-dose Dex will be added at the moment of biological progression

PFS for Early treatment Mateos et al, NEJM 2013

Len-dex: toxicity profile during induction (n:57) Anemia 15 (28%) 1(2%) Neutropenia 11 (20%) 3 (5%) Thrombocytopenia 7 (13%) 1 (2%) Asthenia 4 (7%) Constipation 10 (18%) - Diarrhea 13 (24%) Rash 18 (33%) 2 (4%) Parestesias Tremor Infection* 25 (46%) 4 (6%) DVT** One infection was Grade 4 **DVT prophylaxis with Aspirin (100mg) in 1 pt, oral anticoagulation in 1 pt with low INR levels and no px in the other one

OS from study entry Mateos et al, NEJM 2013

Initial Review of the data Very impressive effect of a novel treatment approach Treatment with modest toxicity Preliminary encouraging data demonstrates a change in the natural history for early treatment If we presume the patient has high risk AMM, then this data supports early intervention.

Treat or not to Treat? For low risk AMM, observation is reasonable For patients with concerns for high risk disease, what are you waiting for? For intermediate risk, may be able to alter the natural history of disease For all cases, close follow up and tempo of disease is critical

ECOG/SWOG: Phase III – Asymptomatic Myeloma*(PI: SL) Lenalidomide vs. observation No Dex to isolate the effect of len Observation Lenalidomide CR/PR/ Stable Prog. anytime Continue therapy till prog. or toxicity Off Rx RANDOMIZATION Control/standard arm

So Where does that Leave us? Preliminary data looks encouraging. This patient meets criteria for high risk AMM and thus should be treated before irreversible toxicity sets in

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