case 1: patient with high-risk smoldering myeloma – watch and wait or treat immediately? raymond...
TRANSCRIPT
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
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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