PRECURSOR MULTIPLE MYELOMA

Transcription

1 PREURSOR MULTIPLE MYELOMA PRESENTED BY: Irene Ghobrial, MD Associate Professor of Medicine Harvard Medical School Dana Farber ancer Institute Boston, MA April 16, 2016

2 Monoclonal Gammopathies Lymphoproliferative 3% (1,358) Amyloidosis 9% (4,102) Multiple myeloma 18% (7,668) N=48,853 SMM 4% (1,643) Solitary or extramedullary 2% (843) Macro 2.5% (1,075) Other 4% (1,733) MGUS 57.5% (25,004) Mayo linic

3 History of Myeloma Kyle et al, Blood 2008

4 MGUS Monoclonal Gammopathy of Undermined Significance Light chain MGUS 3 times more common in AA More common in familial cases 0.8% of general population >50 years Dispenzieri A, et al. Lancet; : % of general population >50 years, 1.7% in 50-59, >5% in over 70 Kyle RA et al. N Engl J Med 2006; Volume 354:

5 lonal Hematopoiesis of Indeterminate Potential (HIP) Jaiswal et al., NEJM 2014

6 Prevalence of MGUS in the US (NHANES) n=12,482 African Americans aucasians Hispanics Landgren O. et.al. Leukemia 2014

7 SMM Smoldering Myeloma 2014 Dana-Farber ancer Institute Inc. All Rights Reserved.

8 IMWG 2010 Diagnostic riteria for Smoldering Myeloma Plasma ell disorder Disease Definition Smoldering multiple myeloma (SMM) Both criteria must be met: 1. Serum monoclonal protein (IgG or IgA) >3 g/dl and/or clonal bone marrow plasma cells >10% 2. Absence of end-organ damage such as hypercalcemia, renal insufficiency, anemia, and bone lesions that can be attributed to the plasma cell proliferative disorder Kyle et al. Int l Myeloma Working Group, Leukemia 2010

9 High-risk Patients Median Time to MM is <2 Years Mayo linic (n=273) No. of risk factors No. of patients, n (%) Progression at 5 years 1 76 (28) 25% (42) 51% 3 82 (30) 76% Risk factors: Ps >10% M-protein >3 g/dl FL-ratio <0.125 or >8 PETHEMA Study Group (n=89) No. of risk factors No. of patients, n (%) Progression at 5 years 0 28 (31) 4% 1 22 (25) 46% 2 39 (44) 72% Risk factors: 95% abnormal plasma cells* Immunoparesis *Incl decreased D38 expression, expression of D56, and absence of D19 and/or D45 Dispenzieri et al. Blood 2008 Pérez-Persona et al. Blood 2007

10 Nationwide PLO prospective cancer screening study by NI 77,465 cancer-free men & women (55-74 years) 71 developed multiple myeloma at mean age 70 (58-81) years Blood draw annually up to 6 years Landgren et al. Blood 2009

11 Germinalcenter B-cell MGUS SMM MM Stored samples (years before multiple myeloma) n/n MGUS % (95% I) 2 27/ (87 100) 3 57/58 98 (91 100) 4 47/48 98 (89 100) 5 35/37 95 (82 99) 6 25/ (86 100) 7 14/15 93 (68 100) >8 14/17 82 (57 96) Landgren et al. Blood 2009

12 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

13 Smoldering Multiple Myeloma High-Risk SMM 25%/year Low-risk SMM 5%/year Ultra-High Risk >60% P FLr >100 >1 MRI focal lesions

14 SMM Paradigm Shift SMM 10% per year x 5 years MGUS ~1% per year after 10 years

15 Focal bone marrow infiltration in smoldering myeloma Focal bone marrow infiltration Smoldering myeloma Multiple myeloma Minimal Diffuse Focal 46% 26% 28%* 8% 28% 64%* * *15% had a mixed bone marrow infiltration (i.e. both focal and diffuse); **14% had a mixed bone marrow infiltration Hillengass et al. Leuk & Lymphoma 2013

16 Progression-free survival Focal bone marrow infiltration in smoldering myeloma Log-rank P<0.001 <1 lesion 2 or more lesions Time Since MRI (months) Median TTP: NR Median TTP: 13 mo Hillengass et al. J lin Oncol 2010

17 Plasma cell infiltration and risk of progression SMM myeloma <60% Ps >60% Ps Progression to myeloma occurred within 2 years of the diagnosis in 95% of the patients >60% bone marrow plasma cells, with a median time to progression of 7 months Rajkumar et al. New Engl J Medicine 2011

18 New definition of overt myeloma requiring therapy Not RAB but now RAB +MDE (calcium elevation) R (renal insufficiency) A (anemia) B (bone disease) MDE criteria Bone marrow (60%) Light chains (Light chains I/U >100) MRI (MRI 1 or more focal lesion)

19 Independent cytogenetic predictors for SMM myeloma t(4;14) del(17p13) 1q21 Hyperdiploidy Neben et al. J lin Oncol 2013; Rajkumar et al. Leukemia 2013

20 New definition of high risk SMM Mayo: SMM with M protein 3 gm/dl and 10% Ps Spanish: 10% Ps, Absence (<5%) of normal Ps by immunophenotyping and Immunoparesis of 1 immunoglobulins IgA SMM Immunoparesis with reduction of two uninvolved immunoglobulin isotypes Serum involved/uninvolved free light chain ratio 8 (but less than 100) Progressive increase in M protein level (Evolving type of SMM) Bone marrow clonal plasma cells 50-60% t(4;14) or del 17p or 1q gain Increased circulating plasma cells MRI with diffuse abnormalities or 1 focal lesion PET-T with focal lesion with increased uptake without underlying osteolytic bone destruction Abnormal FL ratio Rajkumar SV, Blood 2013

21 an we cure precursor HM by early therapeutic intervention? Ductal arcinoma in Situ Metastatic breast cancer Treat as early as possible URE Watch and wait until end organ damage NO URE MGUS URRENT approach... WATH & WAIT Multiple Myeloma

22 Who really needs to be treated? 2014 Dana-Farber ancer Institute Inc. All Rights Reserved.

23 Treatment goals for high-risk smoldering myeloma Landgren et al, lin ancer Research 2011

24 Randomization of high-risk * smoldering MM patients: Lenalidomide 25 mg/day, D1-21 Dexamethasone 20 mg D1-D4 and D12-D15 Induction: 9 28-day cycles Therapeutic abstention Lenalidomide 10 mg/day, D1-21 (28 day cycle) for 2 yrs Maintenance: until progression Therapeutic abstention Primary endpoint: time to progression to symptomatic MM Secondary endpoints: response rates, duration of response, progression-free survival, overall survival, and safety and tolerability * Ps 10% plus M-protein 30 g/l or Ps 10% or M-protein 30 g/l but ap/np > 95% plus immunoparesis. ap, abnormal plasma cell; MM, multiple myeloma; np, normal plasma cell; P plasma cell. Mateos M, et al. NEJM 2013

25 Len/Dex versus Observation in High Risk SMM: TTP Mateos M et al. N Engl J Med 2013;369:

26 Len/Dex versus Observation in High Risk SMM: OS Mateos M et al. N Engl J Med 2013;369:

27 SD or better? Phase II trial for high-risk SMM: carfilzomib/revlimid/dex 8 cycles Rd ombination Therapy arfilzomib 20/36 mg/m 2, day 1, 2, 8, 9, 15, 16 Lenalidomide 25 mg/day, day 1-21 Dexamethasone 20/10 mg day 1, 2, 8, 9, 15, 16, 22, cycles Rev Extended Dosing Lenalidomide 10 mg/day, day 1-21 Each cycle is 28 days Stem cell harvest after >4 cycles Rd for patients aged <70-75 y 1D1/2 arfilzomib dose is 20 mg/m Dex dose is 20 mg, 5-8 Dex dose is 10 mg Landgren, et al. ASH abstract #1939: Sat, Dec 7, 2013: 5:30 PM-7:30 PM, Hall G

28 Mean M-spike (d/dl) nr/r/sr 8% 58% 83% 100% 11/12 (92%) are MRD negative by 8-color flow cytometry of the bone marrow Landgren, et al. ASH abstract #1939: Sat, Dec 7, 2013: 5:30 PM-7:30 PM, Hall G

29 Vaccine PVX rev or Nivolumab in SMM Elotuzumab/Len/Dex for high risk SMM Open to accrual Daratumumab for intermediate/high risk SMM Daratumumab 8 doses for high risk MGUS and low risk SMM Ixazomib/rev/dex for high risk SMM Nivolumab/Len/Dex for high risk SMM Approved and submitted

30 ell autonomous regulation: Darwinian evolution from MGUS myeloma Walker et al. Nature Reviews ancer 2012

31 Permissive microenvironment

32 Model of progression in MGUS/SMM

33 enter for Prevention of Progression of Blood ancers PROWD Retrospective Studies Biology Therapeutic Screening

34 pcrowd.dana-farber.org/

35 Non DFI/H Patients DFI/H Patients PROWD Pipeline Identify Accrue Register ollect Sample Process & Store Annotate I.T. Resources REPORT FAX REPORT OBTAIN DATA ONLINE, 93 PRINT LABELS WEBSITE LETTER WEBSITE UPDATE ONSENT REPORT REPORT UPDATE OBTAIN DATA* OBTAIN DATA* Knowledge, Design & User Experience (KDUX) MAIL, 74 MD, 231 LOATION MEDIAL PROVIDER MEDIAL PROVIDER UPDATE ORDER SAMPLE ANNOTATE LOAL I.T. SYSTEM REPORT FAX REPORT PRINT LABELS OBTAIN DATA Plasmacytoma, 4 LETTER REPORT OBTAIN DATA WEBSITE OBTAIN DATA* MEDIAL PROVIDER WEBSITE MEDIAL PROVIDER UPDATE ONSENT UPDATE REPORT SHIP KIT UPDATE LOATION OBTAIN DATA* ANNOTATE SMM/SWM, 148 MGUS, 246 Need IT Integrative Platform

36 Progressors Mutational landscape Bone marrow biopsy linical impact Non-progressors Liquid biopsy cfdna, Ts lonal heterogeneity lonal evolution

37 MM413 MM461 noncoding nonsilent null silent E T T MM413 MM431 MM434 MM447 MM448 MM453 MM457 MM461 A:T transitions A:T transitions percentage 100% :G GEN transitions :G GEN transversions pggen transitions A:T transversions 75% :G transitions 50% :G transversions 25% pg transitions 0% pg transversions pg transversions GEN T T T T A GEN GEN GEN MM448 MM453 MM457 MM461 GEN GEN GEN T GEN GEN GEN Allele fraction a % 75% 50% MM413 90% MM431 MM434 MM447 MM453 MM457 MM461 b A 25% 0.25!s=0.96! MM 31 M4!s=0.91!M 34 M4 M!s=1.0! 47 M4 M!s=1.8! 48 M4 M!s=0.92! 3 45 MM 57 M4 61 M4!s=0.79! M!s=0.86!M!s=0.97! % of variants found in T % of T variants found in c 1 43 MM 4 43 MM 7 44 MM Purity: 0.16, Ploidy: MM 3 45 MM 7 45 MM MM!drivers! (Significant)! (Near!Significance)! Pan!cancer!drivers! d 1 46 MM X 14174_1066.ctDNA.Q.F Purity: 0.083, Ploidy: 1.71 NVs!idenDfied!in!MM453! 2 1 MM!drivers! 259! 971! 2 Allele fraction in T 3 41 MM (1230)! 14174_129.ctDNA.Q.F ! 0% 25% T!! % of variants found in T (1506)! 2 % of T variants found in 50% 0% GEN MM448 75% opy Number (log2 ratio) B GEN MM447 Log2 Ratio 0 silent opy Number (log2 ratio) 2 null Log2 Ratio 4 nonsilent 25% Allele fraction in 6 MM % variants MM431 Log2 Ratio T T T Number of mutations GEN00 GEN00 GEN00 GEN00 GEN00 GEN00 Density GEN00 GEN00 GEN00 MM GEN A:T transversions T 100 noncoding 50% 0% GEN T MM461 75% T T 9 MM457 T 6 MM453 T 5 T T 4 T T 400 Somatic non-silent c mutations 0 2 MM413 MM431 MM434 MM447 MM448 MM453 MM457 MM461 0 B 100 T T T T counts b 1 MM448 T MM447 T 200 D MM434 T A MM % T MM457 T MM453 T MM448 T MM447 T MM434 T MM431 % variants MM percentage counts a X % of mutant allele (repeat 2) B Allelic Frac on in cfdna from duplicate samples % of mutant allele (repeat 1) D6 3 D nm #1 #2 #3 #4 #5 #6 #7 #8 #9 #10 #11 #12 #13 #14 #15 #16 T B T B T B T B T B T B T B T B T B T B T B T B T B T B T B T B KRAS NRAS FAM153A HSP90AB1 FAM153B IDH1 HIST1H1E ZFHX4 NF

38 Should we screen for MGUS? JAMA Oncol. 2015;1(2): If 4% >65 years have MGUS= 1.6 million Potential for MM at 10 years (10%)= 160,000 myeloma cases Higher risk with high risk MGUS and smoldering MM More % with African-American and familial cases

39 AKNOWLEDGMENT Aldo Roccaro Antonio Sacco Salomon Manier Adriana Perilla-Glen Karma Salem Yawara Kawano Patrick Henrick Kim Noonan Kaitlen Reyes Yuji Mishima Michele Moschetta Sioban Glavey Daisy Huynh Jiantao Shi Jihye Park Juliette Bouyssou Shokichi Tsukamoto ourtney Hamilton Diane Warren Joe appuccio Aaron aola Emily Lai Jessica Macleod Ahmed Kurdi Yujia Shi Oksana Zavidij Amir Yosef Ken Anderson, Rob Soiffer, Nikhil Munshi, Paul Richardson, Ben Ebert Other collaborators: David Scadden, Ola Landgren, Shaji Kumar, Antonio Palumbo, Herve Ave L oiseau, Xavier Leleu, Bob Orlowski, Leif Bergsagel, Marta hesi, Bruno Paiva, Jesus San Miguel, Richard Hynes, George Daley, Franziska Michor, Jon Licht, Gad Getz, David Root. Support: R01A133799, RO1A133799, R01A125690, R01A154648, Leukemia and Lymphoma Society (LLS) SOR, TRP, NIA, MMRF, DOD, Pharmaceutical collaborators and our patients Our patients and their support

40 QUESTIONS?