Post on 06-Jul-2020
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Smoldering Myeloma: Leave them alone!
D id H V l MD PhDDavid H. Vesole, MD, PhD
Co-Director, Myeloma Division
Director, Myeloma Research
John Theurer Cancer Center
Hackensack University Medical Center
Smoldering MM
• Prevalence• 1960‐2002
• 16% of MM (1000/6179)
• Progression rate• MGUS 1% per year
• SMM 10‐25% per year
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Progression to Symptomatic MM• MGUS: up to 2 percent of persons 50 years of age or older and about 3
percent of those older than 70 years
• For SMM, maximum risk in the first 5 years
• Risk factors: Higher M spike, higher plasma cell burden, type of M protein,Risk factors: Higher M spike, higher plasma cell burden, type of M protein, Abnormal free light chain ratio, circulating plasma cells
Kyle et al, NEJM, Volume 356:2582‐2590, June 21, 2007
Risk stratification based on bone marrow plasmacytosis, serum M protein, and serum immunoglobulin free‐light chain (FLC) ratio. Patients are assigned 1 point for meeting each of the following criteria: bone marrow clonal plasma cells 10%; serum M protein 3 g/dL; and serum immunoglobulin FLC ratio either less than 0.125 or > 8. The median times to progression for 1, 2, or 3 risk factors are 10, 5.1, and 1.9 years, respectively.
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Risk stratification schemes for SMM• Mayo Clinic for SMM patientsRisk factors: plasma cells >10%, M‐protein > 3 g/dL, FLC ratio < 0.125 or > 8N f i k f t N f ti t (%) 20 i % RRNo. of risk factors No. of patients (%) 20‐year progression, % RR
1 76 (28) 25 12 115 (42) 51 2.03 82 (30) 76 3.0Total 273 (100) 51 N/A
• Spanish study group for SMM patients• Spanish study group for SMM patientsRisk factors: 95% aPC, immunoparesis
0 28 (31) 4 11 22 (25) 46 11.52 39 (44) 72 18Total 89‡ (100) 46 N/A
Smoldering MM
Gr 1:TTP 1.9 y
Gr 2: TTP: 5 y
p < 0.001100
80 • PCsBM Infiltration ≥ 10%
No. of risk factors No. Rel risk
Gr 2: TTP: 5 y
Gr 3: TTP 10 y60
40
20
Pro
bab
ility
of
Pro
gre
ssio
n (
%)
• Serum M protein ≥ 3 g/dL
• Serum FLC ratio < 1/8 or > 8
Kyle RA, et al. N Engl J Med. 2007; 356:2582-90
Dispenzieri A, et al. Blood. 2008;111:785-9.
1 81 1
2 114 1.9 (1.2–2.9)
3 78 4.0 (2.6–6.1)00 5 10 15
Years
Mateos et al., Abstract #991
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Treatment of SMM
• Bisphosphonates
–Pamidronate (n =12) no direct anti‐tumor effect (Martin et al Br J Haematol 118:239–243, 2002)
–Pamidronate‐randomized triial: decrease SRE bu no prolongation of TTP or OS (Musto et
al Leukemia and Lymphoma 44:1545–1548, 2003)
Zoledronic acid randomized trial: decrease– Zoledronic acid‐randomized trial: decrease in SRE but no impact on TTP or OS (Musto et al
Cancer 113:1588–1595, 2008)
Treatment of SMM
• Alkylating Agents and Corticosteroids
– MP vs Obs (n = 50)‐no difference in response rate at time of PD, no difference in DOR or OS (Hjorth et a lEur J Haematol50:95–102, 1993)
– MP vs Obs (n = 44)‐median survival similar 54 vs 58 mo (Grignani et alBr J Cancer 73:1101–1107, 1996)( g , )
– MP vs Obs (n = 145)‐no difference in survival (Riccardi et al Br J Cancer 82:1254–1260, 2000)
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Treatment of SMM• Thalidomide
–Mayo Clinic (N =29): RR 34% (Rajkumar et al Leukemia
17:775–779, 2003))
Comparison (29 pts on thal study) with historical control (57 pts)• 2 year PFS: 47% (untreated) vs 63% (Thal)
–MD Anderson (n = 28): RR 36% (Weber et al J Clin Oncol21:16–19, 2003), )
– Arkansas (n = 74); RR42%, median time to progression 7 years; PN dose reduction 86%, DC’d 50% (200 mg/d) (Barlogie et al Blood 112:3122–3125, 2008)
63%(47% in historical controls)
Rajkumar SV. Leukemia 2003; 17:775-9
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Fig 3. (A) Event‐free survival was similar in patients with multiple myeloma (MM) evolved from monoclonal gammopathy of undetermined significance (MGUS)/SMM and other subgroups. (B) Overall survival was similar in patients with MM evolved from MGUS/SMM and other subgroups. Barlogie et al BJH 2007; 136: 393
Multivariate analysis of factors predicting for complete response, event‐free survival and overall survival – all patients
All patients Factor % HR (95% CI) P-value
Complete response (n = 637) Prior MGUS/SMM 7 0·45 (0·25,0·81) 0·007
Thalidomide arm 49 1·54 (1·24,1·91) <0·001
LDH > upper normal limit 27 1 28 (1 00 1 62) 0 045LDH > upper normal limit 27 1·28 (1·00,1·62) 0·045
Event-free survival (n = 654) Prior MGUS/SMM 7 1·12 (0·71,1·76) 0·637
Thalidomide arm 49 0·75 (0·59,0·95) 0·016
LDH > upper normal limit 27 1·51 (1·17,1·96) 0·002
Cytogenetic abnormalities
30 1·55 (1·22,1·98) <0·001
Albumin < 35 g/l 18 1·52 (1·14,2·02) 0·004
B2M ≥ 35 mg/l 36 1·47 (1·14,1·88) 0·003
IgA isotype 24 1·45 (1·12,1·89) 0·006
CR (time dependent) 52 0·64 (0·49,0·83) 0·001
Overall survival (n = 654) Prior MGUS/SMM 7 1·04 (0·59,1·81) 0·900
LDH > upper normal limit 27 1·66 (1·22,2·25) 0·001
Cytogenetic abnormalities
30 1·88 (1·41,2·52) <0·001
Albumin < 35 g/l 18 1·85 (1·33,2·56) <0·001
CR (time dependent) 52 0·52 (0·37,0·72) <0·001
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QuiRedex: Study Design
• Multicenter, open‐label, randomized phase III trial– Evaluated new treatment regimen for smoldering MM vs currentEvaluated new treatment regimen for smoldering MM vs current
standard of care
Patients with high‐risk
smoldering MM
Lenalidomide 25 mg/day on Days 1‐21 +
Dexamethasone 20 mg/day on Days 1‐4, 12‐15
Lenalidomide10 mg/day on Days 1‐21(Low‐dose dexamethasone
added at time ofbiologic progression)
Induction9 x 28‐day cycles
Maintenance28‐day cycles
2 yrs
Mateos MV, et al. ASH 2011. Abstract 991.
smoldering MM
(N = 126)No Treatment No Treatment
Primary endpoint: TTP to symptomatic MMSecondary endpoints: response, duration of response, safety and tolerability, PFS, OS
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QuiRedex: Response• Majority of patients responded to lenalidomide plus
dexamethasone
– Responses improved with maintenance
Response, %
ITT Population With Median of 9 Induction Cycles
(Range: 1-9)(n = 57)
After Completion of
9 Induction Cycles(n = 51)
After Median of 15 Maintenance
Cycles(Range: 2-31)
(n = 50)
ORR 86 96 96
Stringent
• 12 of 14 patients either improved to PR or had SD after receiving low‐dose dexamethasone during lenalidomide maintenance
Mateos MV, et al. ASH 2011. Abstract 991.
Stringent CR
7 8 16
CR 7 8 12
VGPR 11 12 16
PR 61 68 52
SD 14 4 4
QuiRedex: Safety• 3 cases of second primary malignancies reported in treatment arm
Adverse Event, % Lenalidomide + Dexamethasone(n = 57)
No Treatment(n = 62)
Grade 1/2 Grade 3 Grade 1/2
Anemia 28 2 --
Neutropenia 20 5 --
Thrombocytopenia 13 2 --
Asthenia 20 7 11
Constipation 18 -- 2
Mateos MV, et al. ASH 2011. Abstract 991.
Diarrhea 24 2 4
Rash 33 4 --
Paresthesias 5 -- --
Tremor 13 -- 2
Infection 46 6 26
Deep vein thrombosis 5 --
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1 0
Len‐dex vs no treatment: TTP to active disease (n = 119)
ITT analysis
Median follow-up: 32 months (range 12–49)
Lenalidomide + dex
[Len 25*21 d + dex 20*4*2]q28 *9 then len 10 q21
1.0
0.8
0.6
0.4
Lenalidomide + dex
Median TTP: NR
9 Progressions (15%)
5 pts:early disc then DP
4 pts:symptomatic DP
No treatment
on of patients alive
454035302520151050
0.2
0.0
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
Proportio
Mateos et al., Abstract #991
QuiRedex: TTP to Symptomatic MM and OS• Significant increase in TTP with vs without treatment
1 0
Median TTPLenalidomide + dexamethasone: NR
No treatment: 23 mosHR: 6.0 (95% CI: 2.9‐12.6; P < .0001)
Median follow‐up: 32 mos (range: 12‐49)
1.0
0.8
0.6
0.4
0.2
0
Proportion of
Patien
ts Alive
0 0 20 2 30 3 0
Lenalidomide + dexamethasoneNo treatment
• Significantly prolonged OS with vs without treatment
– Median 3‐yr OS (from study inclusion): 93% vs 76%; P = .04
– Median 5‐yr OS (from diagnosis): 94% vs 79%; P = .03
Mateos MV, et al. ASH 2011. Abstract 991.
Mos From Inclusion
0 455 10 15 20 25 30 35 40
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Len‐dex vs no treatment: OS from inclusion(n = 119)
Median follow-up: 32 months (range 12–49)
Lenalidomide + Dex1.0
No treatment
tion of patients alive
p=0.04
0.8
0.6
0.4
Lenalidomide + Dex: 93% at 3 yearsNo treatment: 76% at 3 years
Time from inclusion
Proport
50454035302520151050
0.2
0.0
Mateos et al., Abstract #991
QuiRedex: Conclusions• Improved outcomes with lenalidomide and dexamethasone induction
plus maintenance lenalidomide vs no treatment in smoldering MM[1]
– Significantly prolonged TTP OS– Significantly prolonged TTP, OS
• Addition of low‐dose dexamethasone to maintenance lenalidomide maintained disease stabilization in most cases of biologic progression[1]
• Well tolerated, with most adverse events grade 1/2[1]
– Drug‐related toxicities should be considered when evaluating risk/benefitrisk/benefit
• Question remains regarding effect of treatment at this disease stage
– Delay progression only or alter natural history also
• Ongoing phase II/III ECOG trial evaluating single‐agent lenalidomide vs observation in smoldering MM; suspended in December 2011[2]
1. Mateos MV, et al. ASH 2011. Abstract 991. 2. ClinicalTrials.gov. NCT01169337.
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E3A06: Eligibility
•Diagnosis asymptomatic high‐risk disease•No immediate need for chemotherapy
•No lytic lesions on skeletal surveys and no hypercalcemia (i e ≥ 11 mg/dL)No lytic lesions on skeletal surveys and no hypercalcemia (i.e., ≥ 11 mg/dL)
•Bone marrow plasmacytosis with ≥ 10% plasma cells or sheet of plasma cells by bone marrow aspiration and/or biopsy
•Abnormal serum free‐light chain (FLC) ratio (< 0.125 or > 8.0) bby serum FLC assay
•Measurable monoclonal protein in the serum ≥ 1.0 g/dL or urine ≥ 200 mg/24 hrs
E3A06: Objectives
Primary• Study the risk of grade 3‐4 non‐hematologic adverse events in patients with asymptomatic high‐risk
smoldering multiple myeloma treated with lenalidomide. (Phase II)• Compare the progression‐free survival (PFS) of patients with asymptomatic high‐risk smoldering
multiple myeloma treated with lenalidomide versus observation alone. (Phase III)
Secondary• Assess the response of patients treated with lenalidomide. (Phase II) • Describe the gene expression profile (GEP) and cytogenetic risk classification and evaluate baseline
immune and MRI parameters in these patients. (Phase II)• Determine and compare the response rate, time to progression, 1‐year PFS probability, and the
overall survival of patients treated with lenalidomide versus observation alone. (Phase III)• Estimate the incidence of adverse events of these regimens in these patients. (Phase III)• Evaluate the impact of therapy within GEP‐defined risk groups and GEP as a prognostic marker.
(Phase III)• Study the effects of lenalidomide on laboratory markers of immune function. (Phase III)• Study the prognostic value of MRI‐detected asymptomatic bone disease on clinical outcome. (Phase
III)• Evaluate the prognostic effect of baseline high‐risk cytogenetic abnormalities on clinical outcome.
(Phase III)• Compare the quality of life of patients treated with these regimens. (Phase III)
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Diagnosis & Managementof High‐Risk SMM
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What are the best risk factors today toidentify patients with high risk SMM?
Goal
• To identify patients with high‐risk SMM with ≥ 90%
chance to develop symptomatic MM at 2 years in order to:
• ‐ prevent end‐organ damagep g g
• ‐ possibly extend survival
• ‐ avoid unnecessary treatment in low‐risk SMM
What are potential new risk factors that weshould look for?
• Bone imaging (wbMRI, PET‐CT)
• Changes in dFLC and e GFR
• Total concentration FLC (i.e. > 1000 mg/L)
• BMPCs (i.e.≥ 60%)
• Number of circulating plasma cells
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Should we treat some patients with SMM?
• Len‐dex is a promising and attractive option
• All efforts to plan an early treatment in asymptomatic MM patients should be focused on high‐risk patients
• Long term follow‐up is required to actually confirm the benefit, especially in OS
• Results of other trials that they are being conducted are needed
In the near future, we could offer early treatment to a selected high‐risk of patients with the confidence that they are going to obtain a significant benefit
Does the survival benefit seen in the Spanish trialoutweigh the risks? Should we change practice?
• The present data of the QuiRedex trial do not support change of practice!
• High risk patients are encouraged to enroll into clinical trials
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Conclusions
• Treatment of SMM should only be considered in the context of a clinical
Consensus opinion of IMWG– Consensus opinion of IMWG
• No proven survival advantage with conventional Rx OR transplant
• Short and Long‐term toxicities need to be delineated
• ? Second malignancies
• We need to better define ‘High Risk’ SMM
• The use of bisphosphonates is not clear, especially in light of the MRC data