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Should We Treat Smoldering Myeloma?YES!
Lymphoma Myeloma 2014
Scottsdale, ArizonaScottsdale, Arizona Rochester, MinnesotaRochester, Minnesota Jacksonville, FloridaJacksonville, Florida
Joseph Mikhael, MD, MEd, FRCPC, FACPStaff Hematologist, Mayo Clinic Arizona
Additional Disclosures
• There is no such thing as Mikhael Oncology
• I am not incorporated
• I am just the average Joe…
James R. Berenson, MD
President and CEO - James R. Berenson, MD, Inc.Medical & Scientific Director - Institute for Myeloma & Bone Cancer Research (IMBCR)Chief Executive Officer - Oncotherapeutics
Background
• Remember Myeloma is a unique cancer – defined by the presence of organ damage – not just pathology
• Traditionally we wait until CRAB
• But does that really make sense? Do we have to wait until damage is present to intervene??
What if your friend is walking towards a cliff?
• Will you wait until they are falling to rescue them?
• What if they are running?
• What if they are enjoying the walk?
My Thesis – there are 3 groups within Smoldering Myeloma
• Group 1: “Ultra” High Risk• Plasmacytosis ≥ 60%• Involved/Uninvolved Light Chains ≥ 100• 1 or more focal lesions on MRI/PET TREAT AS IF TRUE MYELOMA
• Groups 2: High Risk (Defn to follow)DEBATE: To Treat or Not to Treat
• Group 3: Low Risk DON’T TREAT
Smoldering Multiple Myeloma
Low-risk SMM
5%/year
Ultra-High Risk
• >60% BMPC
• FLCr >100
• >1 MRI focal lesionsHigh-Risk SMM
25%/year
Ultra High Risk SMM = Active Myeloma
Not CRAB but now SLiM CRAB
•S (60%)
•Li (Light chains I/U >100)
•M (MRI 1 or more focal lesion)
•C (calcium elevation)
•R (renal insufficiency)
•A (anemia)
•B (bone disease)
>100
<100
FLC Ratio >100 and Risk of progression to myeloma
Larsen J, et al. Leukemia advance online publication 27 November 2012; doi: 10.1038/leu.2012.296
High Risk SMM = Median TTP ~2 years:
• Mayo: SMM with M protein ≥3 gm/dL and ≥10% PCs
• Spanish: ≥10% PCs, Absence (<5%) of normal PCs by immunophenotyping and Immunoparesis of ≥1 immunoglobulins
• Abnormal FLC ratio 8-100
• Deletion 17p, t4;14, 1q amp
• Evolving pattern
• IgA SMM
• SMM with M protein ≥4 gm/dL
• Increased circulating plasma cells
• Increased plasma cell proliferative rate
Rajkumar SV, Merlini G, San Miguel JF. Nat Rev Clin Oncol 2012
Management of High Risk SMM:
What does the data say? Do we believe the Spanish
Trial?
Recall – Randomized, Phase 3 Trial of high risk SMM pts
Lenalidomide – dexamethasone vs observation
1. Generalizability
– Mayo Criteria - BMPC ≥ 10% and M-protein ≥ 30 g/L
or
– Spanish Criteria BMPC ≥ 10% or M-protein ≥ 30 g/L and
– BM aPC/nPC > 95% and
– immunoparesis
– BUT note that 60% met Mayo Criteria!!
Issues with the Spanish Trial
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 PD
4 pts:symptomatic PD
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
aliv
e
Mateos. ASH 2012
3. Consequences
Spanish Trial Conclusions
• Early intervention in high risk SMM• Prolongs TTP• Improves OS• Does not result in appreciable toxicity
• Prevents irreversible damage to kidneys and bones that occur … “on our watch!”
Conclusions
• Don’t forget new criteria (SLiM CRAB) for myeloma (Ultra High Risk SMM = Myeloma)
• Low risk can be watched
• High risk is complex• Recall 50/50 in 2 years• Consider therapy these patients in an
individualized manner• Not limited to len-dex, but all active
therapy