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

SMM Paradigm Shift

MGUS

SMM 10% per year x 5 years

~1% per year after 10 years

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)

Bone Marrow Plasma Cell ≥60%

Rajkumar SV et al. N Engl J Med 2011; N Engl J Med 2011; 365:474-475

>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

Rajkumar SV, Merlini G, San Miguel JF. Nat Rev Clin Oncol 2012

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

Mateos M et al. N Engl J Med 2013;369:438-447.

Len/Dex versus Observation in High Risk SMM: TTP

Mateos M et al. N Engl J Med 2013;369:438-447.

Len/Dex versus Observation in High Risk SMM: OS

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

Mateos M et al. N Engl J Med 2013;369:438-447.

2. Tolerability

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

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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

Don’t let your patients fall…