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

References to Smoldering Multiple Myeloma

1974-1978 1979-1983 1984-1988 1989-1993 1994-1998 1999-2003 2004-2009 2010-20130

500

1000

1500

2000

2500

Hit

s: G

oo

gle

Sch

ola

r

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

Drug Cost ($)

Carfilzomib (BSA 1.8) 5,936 (cycle 1)8,013 (cycle 2)

Pomalidomide 10,437

Bortezomib (BSA 1.8) 4,106

Lenalidomide 8,673

Thalidomide 8,092

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, 2013 4:23 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. Lonial @ 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, 2013 5:19 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

Natureof the Clone

Organsat risk

Asymptomatic

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;24:1121Seminars Hematol 2011;48:4

BM PC >10% M-protein > 3 g/dL

Skewed sFLC ratio <0.125 or >8.0

PETHEMA Risk Factors for Progression

Blood 2007;110:2586Seminars 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 ortissue impairment

(end-organ damage, including

bone lesions) “CRAB”

BJH 2003;121:749Leukemia 2010;24:1121

Waiting for the

QuiReDex

High risk SMM*

Lenalidomide 25 mg/d D1-21Dexamethasone 20 mg/d

D1-4, 12-15Lenalidomide 10

mg/dD1-21 every 2 mos

Observation

Induction phase28d cycles x 9 cycles Maintenance

*High risk SMMBoth BMPC≥10% AND M-protein≥ 3 gm/dL

OR one of the above plus aPC >95% and immunoparesis

Mateos ASH 2011

50454035302520151050

1.0

0.8

0.6

0.4

0.2

0.0

Len-dex vs no treatment: TTP to active disease (n = 119) ITT analysis

Median follow-up: 32 months (range 12–49)

Lenalidomide +

dex

Median TTP: NR

9 Progressions

(15%)

5 pts:early disc

followed by DP

4 pts:symptomatic

DP

No treatment

Median TTP: 23m

37 Progressions (59%)

20 patients: bone disease

7 patients: renal failure

HR: 6.0; 95% IC (2.9–12.6); p < 0.0001

Time from inclusion

Pro

po

rtio

n o

f p

atie

nts

ali

ve

Len-dex vs no treatment: OS from inclusion(n = 119)

Median follow-up: 32 months (range 12–49)

Lenalidomide + Dex

No treatment

Lenalidomide + Dex: 93% at 3 yearsNo treatment: 76% at 3 years

Time from inclusion

Pro

po

rtio

n o

f p

ati

en

ts a

live

p=0.04

50454035302520151050

1.0

0.8

0.6

0.4

0.2

0.0

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;369:5BMJ 1999;307:1492

IMWG Guidelines for SMM

Preventive clinical trials need to be considered forpatients 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

NCT01441973 Elotuzumab

NCT01484275 Siltuximab

NCT01718899 Cancer vaccine

NCT01838369 CI-505

NCT01572480 CRd

NCT01660997 08/Dex(planned)

NCT01169337 ECOG Phase II/III

Definition of high-risk SMM

Time from diagnosis of SMM

Monthly Wholesale Acquisition Cost

Drug Cost ($)

Carfilzomib (BSA 1.8) 5,936 (cycle 1)8,013 (cycle 2)

Pomalidomide 10,437

Bortezomib (BSA 1.8) 4,106

Lenalidomide 8,673

Thalidomide 8,092

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 <0.125 or >8.0

• Within 12 months of diagnosis

• SS negative• Serum FLC monthly• GEP• MRI spine and pelvis

NEJM 2007;356:25Blood 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

http://static9.light-kr.com/documents/IMW2013/Landgren%20-%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