MM: interpreting cytogenetic results for clinical practice · Clinical impact –IgH translocations...
Transcript of MM: interpreting cytogenetic results for clinical practice · Clinical impact –IgH translocations...
MM: interpreting cytogenetic results for clinical practice
Dr Sally MooreConsultant Haematologist
Royal United Hospital, BathChurchill Hospital, Oxford
This medical education meeting was organised and funded by Janssen-Cilag Ltd. EM-12168 | May 2019
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Advisory: Amgen, Celgene, Takeda
Educational activities: Amgen, Janssen, Roche
Disclosures – Dr Sally Moore
Learning objectives
• To understand what CAs are and how they may affect prognosis
• To explore treatment decisions regarding CAs through the use of patient case studies
• To explore factors that might affect future considerations regarding CAs in multiple myeloma
CA: cytogenetic abnormalities
Disease profiling
Landgren O, Morgan GJ. Clin Cancer Res. 2014; 20:804–13.FISH: fluorescence in situ hybridisation;
MGUS: monoclonal gammopathy of undetermined significance; miRNA: micro ribonucleic acid.
Frequency of CAs
Sonneveld P, et al. Blood. 2016; 127:2955–62.
Primary and secondary genetics events that can be identified by FISH
Ig: immunoglobulin; NA: not applicable.
Clinical impact – IgH translocations
• t(4;14) = ↓ PFS/OS1
Bortezomib improves survival vs vincristine2
↑ OS with HDT and tandem ASCT3
• t(14;16) and t(14;20) = predictors of poor outcome4
• t(11;14) associated with CD20 expression and LPL morphology. Reported as favourable in some studies, no impact in others5,6
• In general, t(6;14), t(11;14), gain(5q) and hyperdiploidy do not confer poor prognosis
1. Gertz MA, et al. Blood. 2005; 106:2837–40; 2. Sonneveld P, et al. J Clin Oncol. 2012; 30:2946–55; 3. Moreau P, et al. Leukemia. 2007; 21:2020–4; 4. Boyd KD, et al. Leukemia. 2012; 26:349–55; 5. Fonseca R, et al. Blood. 2002; 99:3735–41; 6. Avet-Loiseau H, et al. Blood. 2007; 109:3489–95.
ASCT: autologous stem cell transplantation;HDT: high-dose therapy; LPL: lymphoplasmacytic lymphoma;
OS: overall survival; PFS: progression-free survival.
Clinical impact – genomic imbalance
General• Due to selection of subclonal disease, the prognostic impact of CA may vary from diagnosis to refractory disease1
Diploidy• Hyperdiploidy (50% of NDMM) = ↑ PFS/OS2. Co-existing hyperdiploidy may not abrogate poor prognosis of adverse CA3
• Hypoploidy is regarded as a poor prognostic CA4
• t(4;14) PFS and OS can be negatively affected by hypodiploidy4
Deletions• Adverse impact of del(13q) is associated with del(17p) and t(4;14). Del(13q) alone does not confer poor survival1,5
• Del(17p) or del(17) has a negative impact on PFS/OS. DelTP53 induces clonal immortalisation and survival of tumour cells6
• What minimum % del(17p) cells = adverse prognosis? Minimums of 20% and 60% have been suggested4,5
• In solitary plasmacytoma or extramedullary disease, del(17p) may occur more frequently7
Gains• >3 copies of 1q = worse outcome (dosage effect)5
• Gain(1q) often associated with del(1p32), which confers poor prognosis8
NDMM: newly diagnosed multiple myeloma.
1. Walker BA, et al. J Clin Oncol. 2015; 33:3911–20; 2. Neben, et al. Haematologica. 2010; 95:1150–7; 3. Pawlyn C, et al. Blood. 2015; 125:831–40; 4. Hebraud, et al. Blood. 2015; 125:2095–100; 5. Boyd KD, et al. Leukemia. 2012; 26:349–55; 6. Teoh PJ, et al. Leukemia. 2014; 28:2066–74; 7. Billecke, et al. Br J Haematol. 2013; 161:87–94; 8. Hebraud B, et al. Leukemia. 2014; 28:675–9.
Clinical impact – multiple abnormalities
• Adverse IgH translocation: 62% have gain(1q) compared with 32.4% in controls1
• Del(17p) frequency is similar in patients without adverse IgH translocations1
• Triple combination of an adverse IgH translocation, gain(1q) and del(17p) had OS of 9.1 months, demonstrating impact of multiple adverse CAs on OS1
• In 110 patients with either t(4;14) or del(17p), 25 had both abnormalities2
• t(4;14): ↓ PFS seen in del(1p32), del(22q), and/or structural changes
↓ OS seen in del(13q14), del(1p32) and higher number of CAs2
• del(17p): ↓ PFS seen in del(6q)
↓ OS seen in del(1p32)2
1. Boyd KD, et al. Leukemia. 2012; 26:349–55; 2. Hebraud B, et al. Blood. 2015; 125:2095–100.
Clinical impact – good and adverse
• Hyperdiploidy: gain5(q31), trisomies 3 and 5 confer a favourable prognosis1,2
• In the Myeloma IX study, 58% had hyperdiploidy. Of these, 61% had ≥1 adverse lesion [t(4;14), t(14;16), t(14;20), gain1q or del(17p)]3
• PFS and OS were shorter in those with hyperdiploidy plus adverse lesion vshyperdiploidy alone (PFS: 23 vs 15.4 months; OS: 60.9 vs 35.7 months)3
• Alternatively, presence of hyperdiploidy did not change the outcome in patients with an adverse lesion3
• Trisomies in patients with t(4;14), t(14;16), t(14;20) or delTP53 reduced their adverse impact4
1. Hebraud B, et al. Blood. 2015; 125:2095–100; 2. Avet-Loiseau H, et al. J Clin Oncol. 2009; 27:4585–90;3. Morgan, et al. Blood. 2012; 119:7–15; 4. Kumar S, et al. Blood. 2012; 119:2100–5.
FISH – what is high risk?
• IMWG 2009 – at least one of: del(17p), t(4;14), t(14;16)1
• IMWG 20162 –
• Mayo Clinic – as above including hypodiploidy and t(14;20)3
• MRC IX – adverse lesions include t(4;14), t(14;16), gain(1q), del(13q) and del(17p)
• FR: absence of genetic lesion
• IR: one adverse CA
• HR: >1 adverse CA
• UHR: ≥3 adverse CAs4
1. Fonseca, et al. Leukemia. 2009; 23:2210–21; 2. Sonneveld P, et al. Blood. 2016; 127:2955–62;3. Stewart, et al. Leukemia. 2007; 21:529–34; 4. Boyd KD, et al. Leukemia. 2012; 26:349–55.
FR: favourable risk; GEP: gene expression profiling; HR: high-risk;IMWG: International Myeloma Working Group; IR: intermediate risk;
MRC: Medical Research Council; UHR: ultra high risk.
FISH cut-off
• IFM1
Percentage of plasma cells with adverse FISH correlates with outcome:
Del(13q) – cut-off 74% OS rate at 41 months 59% vs 80%
Del(17p) – cut-off 60% OS rate at 22.4 months 50% vs 75%
• IMWG R-ISS:2
FISH analyses were performed in a few European laboratories. Despite interlaboratory variability, the analyses of p53 deletion, t(4;14), and t(14;16) were commonly included in each multiple myeloma panel and tested using commercial probes. Of note, however, the cut-off levels were not identical, ranging from 8% to 20% for numerical aberrations and from 10% to 15% for immunoglobulin H translocations
Patients were considered positive for a given CA when it was present in a percentage higher than the cut-off threshold, defined by each local laboratory2
• Eurozone: Spanish 20%, French 60%, UK – number of abnormalities
1. Avet-Loiseau H, et al. Blood. 2007; 109:3489–95; 2. Palumbo A, et al. J Clin Oncol. 2015; 33:2863–9.IFM: Intergroupe Francophone du Myélome; R-ISS: Revised International Staging System.
Double-hit myeloma
Walker BA, et al. Leukemia. 2019;33:159–70. ISS: International Staging System.
• N=1,273, whole genome and exome data
• HR = ISS III with either bi-allelic TP53 inactivation or ≥4 copies of 1q (6.1% of patients)
100
80
60
40
20
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0 12 24 36 48 60
OS
(%)
100
80
60
40
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0 12 24 36 48 60
Months
PFS
(%
)
Log-rank p-value <0.0001
MonthsDeaths / N 18-month estimate
IMWG: low/standard risk, RP-Risk: Low Risk 21 / 357 96% (94, 98)
IMWG: low/standard risk, RP-Risk: Intermediate Risk 59 / 296 85% (81, 90)
IMWG: low/standard risk, RP-Risk: Double Hit 10 / 24 73% (53, 93)
IMWG: high risk, RP-Risk: Low Risk 6 /30 88% (74, 100)
IMWG: high risk, RP-Risk: Intermediate Risk 6 / 53 94% (86, 100)
IMWG: high risk, RP-Risk: Double Hit 16 / 24 37% (16, 58)
Log-rank p-value <0.0001
Events / N 18-month estimate
IMWG: low/standard risk, RP-Risk: Low Risk 65 / 357 87% (84, 91)
IMWG: low/standard risk, RP-Risk: Intermediate Risk 126 / 296 67% (62, 73)
IMWG: low/standard risk, RP-Risk: Double Hit 15 / 24 44% (23, 65)
IMWG: high risk, RP-Risk: Low Risk 10 /30 69% (51, 88)
IMWG: high risk, RP-Risk: Intermediate Risk 21 / 53 74% (61, 87)
IMWG: high risk, RP-Risk: Double Hit 18 / 24 35% (15, 54)
IMWG Guidelines 2016• Consensus updates: abnormalities such as t(4;14), del(17/17p), t(14;16), t(14;20),
non-hyperdiploidy and gain(1q) confer poor prognosis. The prognosis of patients showing
these abnormalities may vary with the choice of therapy
• Treatment strategies have shown promise for HR cytogenetic diseases, such as PI +
lenalidomide combination, pomalidomide, double ASCT + PI, or IT with lenalidomide and
pomalidomide
• Bortezomib and carfilzomib appear to improve CR, PFS and OS for t(4;14) and del(17p)
• Lenalidomide may be associated with improved PFS in t(4;14) and del(17p)
• Patients with multiple adverse CAs do not benefit from these agents
• FISH data are implemented in the R-ISS for risk stratification
Sonneveld P, et al. Blood. 2016; 127:2955–62. CR: complete response; IT: immunotherapy; PI: proteasome inhibitor.
R-ISS 2005–2012
n=3,060 of 4,4451
HR: del(17p) and/or t(4;14)1
Data are generated from 3,060 patients from 11 international trials conducted from 2005 to 2012 that were pooled and analysed by the IMWG.1
1. Palumbo A, et al. J Clin Oncol. 2015; 33:2863–9; 2. Dispenzieri A. Hematology Am Soc Hematol Educ Program. 2016; 2016:485–94.
Figure adapted from Dispenzieri 2016.2
LDH: lactate dehydrogenase; Nml: normal; SR: standard risk.
R-ISS
Palumbo A, et al. J Clin Oncol. 2015; 33:2863–9. CI: confidence interval; F: female; HR: hazard ratio; M: male; NR: not reached.
• 69-year-old lady. PMH of well-controlled asthma; family history of breast cancer
• November 2016: numb lip – mandibular plasmacytoma
• PET-CT: extremely extensive disease. Cauda equina at L2–4
• IgG lambda paraprotein 33 g/l, Hb 76 g/l
• BMT November 2016: 100% plasma cells
• FISH: gain(1q), t(14;16)
• R-ISS III, ISS IIIBMT: bone marrow transplant; CT: computed tomography; Hb: haemoglobin;
PET: positron emission tomography; PMH: previous medical history.
Case study 1
1. CTD
2. Bortezomib-based regimen
3. Myeloma XI
4. CARDAMON trial (KCD)
5. Other
CTD: cyclophosphamide, thalidomide, dexamethasone; KCD: carfilzomib, cyclophosphamide, dexamethasone; Tx: treatment.
Which initial induction Tx?
• CTD vs CVAD (up to six cycles) and ASCT
• FISH – 50%
• n=293 adverse CA [t(4;14), t(14;16), t(14;20) gain(1q), del(1p32) del(17p)], n=333 favourable
Morgan GJ, et al. Haematologica. 2012;97:442–50.
PFS = 20 months with adverse interphase FISH vs 34 months with favourable interphase FISH
Transplant-eligible – CTD Myeloma IX
CVAD: cyclophosphamide, vincristine, doxorubicin, dexamethasone.
Transplant-eligible – bortezomib induction
Meta-analysis: n=1,572; four studies
All-comer CR rates 33–55% for bortezomib-based induction vs 20–35% for non-bortezomib-based induction
Sonneveld P, et al. J Clin Oncol. 2013; 31:3279–87.
PFS (intent-to-treat)
Time (years)
PFS OS (%)
All t(4;14) del(17p) All t(4;14) del(17p)
VD1,2
3/4 36/12 28/12 14/12* 81 63 49
VAD1,2 30/12 16/12 NR 77 32 50
VTD3
368% 31% NR 86 NR NR
TD3 56% 63% NR 84 NR NR
*Event-free survival.1. Harousseau JL, et al. J Clin Oncol. 2010; 28:4621–9; 2. Avet-Loiseau H, et al. J Clin Oncol. 2010; 28:4630–4;3. Cavo M, et al. Lancet. 2010; 376:2075–85.
Transplant-eligible – bortezomib induction
NR: not reported; TD: thalidomide, dexamethasone; VAD: vincristine, doxorubicin, dexamethasone;
VD: bortezomib, dexamethasone; VTD: bortezomib, thalidomide, dexamethasone.
Jackson G, et al. Presentation at ASH 2018. Abstract 302 and oral presentation.
Myeloma XI
Bortezomib-based
regimen
No bortezomib-
based regimen
Maximum response
PDSD
MRPR
CRVGPR
R 1:1
R 1:1
R 1:1
• Primary endpoints: PFS and OS for each randomisation
• Median follow-up of 34.5 monthsCRD: cyclophosphamide, lenalidomide, dexamethasone; K: carfilzomib;
MR: minimal response; PD: progressive disease; PR: partial response; R: randomised; SD: stable disease; TE: transplant-eligible; VGPR: very good partial response.
Myeloma XI
Jackson G, et al. Presentation at ASH 2018. Abstract 302 and oral presentation. BM: bone marrow.
Myeloma XI
Jackson G, et al. Presentation at ASH 2018. Abstract 302 and oral presentation.
• SR: absence of any high-risk lesions
• HR: presence of any one of t(4;14), t(14;16), t(14;20), del(17p) or gain(1q)
• UHR: presence of more than one lesion
HR: hazard ratio.
CARDAMON trial• CARDAMON: KCD-ASCT-Kd vs KCD-Kd
• FORTE: n=474
Gay F, et al. Presentation at ASH 2018. Abstract 121 and oral presentation;ClinicalTrials.gov. NCT02315716. Available at: https://clinicaltrials.gov/ct2/show/NCT02315716 [accessed January 2019].
KRd: carfilzomib, lenalidomide, dexamethasone; MRD: minimal residual disease; neg: negative;
sCR: stringent complete response.
Transplant-eligible – ASCT
• RV-MM-EMN-441 (n=127)
• Rd induction – RCD vs ASCT (some tandem) – lenalidomide vs lenalidomide/prednisone
• HR FISH: three-year PFS 43% (ASCT) vs 17% (RCD); three-year OS 78% vs 67%
Dispenzieri A. Hematol Am Soc Hematol Educ Program. 2016; 2016:485–94; Greipp PR, et al. J Clin Oncol. 2005; 23:3412–21; Avet-Loiseau H, et al. Leukemia. 2013; 27:711–7; Palumbo A, et al. J Clin Oncol. 2015; 33:2863–9; Gay F, et al. Lancet Oncol. 2015; 16:1617–29.
RCD: lenalidomide, cyclophosphamide, dexamethasone; Rd: lenalidomide, dexamethasone; R/P: lenalidomide/prednisone.
Tandem ASCT• Pooled analysis of four trials, n=606, 23% of patients with t(4;14)/del(17p)1
• All received bortezomib induction. Single ASCT n=254, tandem=3521
• <CR post-bortezomib induction resulted in longer PFS and higher OS rate with tandem ASCT vs single ASCT1
• PFS: 42 months vs 21 months; OS: 67 months vs 31.5 months1
1. Cavo M, et al. Blood. 2013; 122: Abstract 767; 2. Cavo M, et al. Blood. 2012; 120:9–19.
• GIMEMA MM-BO20052
• VTD or TD induction, tandem ASCT, consolidation. Patients with t(4;14) on bortezomib-based induction had almost identical PFS as SR patients
PFS for patients with HR cytogenetics and who failed CR after bortezomib-based induction regimens
0.75
0.50
0.25
0.00
Months240 12 36 48
HR=0.41, p=0.006
Single ASCT
Double ASCT
1.00
HR=0.41, p=0.006
Single ASCT
Double ASCT
Months240 12 36 48
0.75
0.50
0.25
0.00
OS for patients with HR cytogenetics and who failed CR after bortezomib-based induction regimens1.00
EMN02/HO95
• Three-year PFS:
• Single ASCT 64%, double ASCT 73%; HR 0.7; p=0.04
• ↑ PFS with double ASCT in all groups including:
• High-risk cytogenetic profile [cyto-3; t(4;14), t(14;16), or del(17p)]:
Hazard ratio 0.42 (95% CI 0.21–0.84; p=0.014)
• Highest-risk cytogenetic profile [(cyto-5; amp(1q), del(1p) and t(4;14),
t(14;16) or del(17p)]:
Hazard ratio 0.65 (95% CI 0.42–1.01; p=0.059)
Cavo M, et al. Presentation at ASH 2017. Abstract 401.
What would you do?
Treatment
DXT: radiotherapy; VTD: bortezomib, thalidomide, dexamethasone.
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IMWG recommendations 2016
• Thalidomide does not abrogate the effect of t(4;14), t(14;16), t(14;20), del(17), del(17p) and gain(1q) in transplant-eligible patients
• Bortezomib partly overcomes the effect of t(4;14) and possibly del(17p) on CR, PFS and OS. There is no effect in t(4;14) and del(17p) in transplant-eligible patients
• Lenalidomide partly improves the adverse effect of t(4;14) and del(17p) on PFS, but not OS, in transplant-eligible patients
• Combining a PI with lenalidomide/dexamethasone greatly reduces the adverse effect of t(4;14) and del(17p) on PFS in NDMM. Carfilzomib/lenalidomide seems effective in patients with HR cytogenetics
• ASCT is standard therapy for transplant-eligible patients with NDMM. It contributes to improved outcomes across prognostic groups
• Double HDT/ASCT combined with a PI may improve PFS in t(4;14) or del(17p), or both. HDT plus double ASCT is recommended for patients with HR cytogenetics
• Allogeneic SCT or tandem auto-allo-SCT may improve PFS in t(4;14) or del(17p)
Sonneveld P, et al. Blood. 2016; 127:2955–62.
Maintenance?
1. None
2. Thalidomide
3. Lenalidomide
4. Carfilzomib
5. Ixazomib
6. Other
Maintenance post-ASCT – thalidomide
MRC-IX
Morgan, et al. Blood. 2012; 119:7–15.
Pat
ien
ts (
%)
Pat
ien
ts (
%)
PFS (months) OS (months)
CTDa: cyclophosphamide, thalidomide, dexamethasone attenuated; ITT: intent-to-treat; MP: melphalan, prednisone.
Maintenance post-ASCT – lenalidomide
• Meta-analysis, lenalidomide maintenance vs placebo/observation post-ASCT, n=1,2081
• Improved PFS if HR for lenalidomide maintenance vs observation, but no improvement in OS (most patients did not have FISH data)
• Myeloma XI2
• FISH data available: 22.8% lenalidomide maintenance arm, 30.1% observation arm
1. McCarthy PL, et al. J Clin Oncol. 2017; 35:3279–89; 2. Jackson G, et al. Blood. 2016; 128: Abstract 1143.
Maintenance post-ASCT – ixazomib
• TOURMALINE MM3
• Ixazomib maintenance for 26 cycles vs placebo
• Discontinuation rates similar in both arms
• PFS 26.5 months for ixazomib vs 21.3 months for placebo;benefit seen in HR patients and those ISS III
• Maintenance in patients not eligible for transplant pending
Dimopoulos MA, et al. Presentation at ASH 2018. Abstract 301.
Continuous Tx post-ASCT (+/- consolidation) KRD
• KRD x 4 – ASCT – KRD x 4 – KRD reduced dose to C18
• sCR: 20% post-ASCT, 69% post-4 x consolidation, 82% post-KRD maintenance
• MRD-negative: 66% at C8, 71% C18
• Two-year PFS: 97%
• Two-year OS: 99%
• No difference in outcomes with HR and SR
Zimmerman T, et al. Blood. 2016; 128:675. C: cycle.
Allogeneic SCT
• Limited data
• n=73, auto-allo tandem SCT1
• 21.9% had t(4;14)/del(17p); five-year PFS 29% equivalent to non-HR group
• n=143 (1999–2008) retrospective, multicentre analysis2
• HR vs normal: three-year OS 45% (HR) vs 39% (normal)
1. Kröger N, et al. Biol Blood Marrow Transplant. 2013; 19:398–404; 2. Roos-Weil D, et al. Haematologica. 2011; 96:1504–11.
VTD and DXT
HarvestASCT
CD
IRd
Daratumumab
PCd
CD: cyclophosphamide, dexamethasone;IRd: ixazomib, lenalidomide, dexamethasone;
PCd: pomalidomide, cyclophosphamide, dexamethasone.
Progress update
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Case study 2
• 70-year-old lady. PMH breast cancer (lumpectomy, DTX, tamoxifen), complex nerve pain, BCC nose and arm, recurrent UTIs
• March 2014: incidental finding, IgG kappa 14 g/l
• SS: NAD, MRI spine: degenerative changes only
• Hb 120, normal U&Es
• ISS I
• BM: 17% plasma cells on aspirate
• FISH: gain(1q), gain(4p) and gain(11q)
BCC: basal cell carcinoma; MRI: magnetic resonance imaging; NAD: no abnormality detected; SS: skeletal survey;
U&E: urea and electrolytes; UTI: urinary tract infection.
Which initial induction Tx?
1. CTD
2. Bortezomib-based regimen
3. Myeloma XI
4. Other
Transplant-ineligible – bortezomib
VISTA1
• VMP vs MP – normalised outcomes with HR
1. Mateos MV, et al. J Clin Oncol. 2010; 28:2259–66. MP: melphalan, prednisone; VTP: bortezomib, thalidomide, prednisone.
Figure adapted from Mateos, et al. 20101
OS in patients treated with VMP
Transplant-ineligible – bortezomib
n=902, HR as per IMWG (27% HR)
VMP plus maintenance vs VMP (GIMEMA-MM-03-05) and MPR vs CPR (EMN01)
Larocca A, et al. Blood. 2017; 130:744.BORT: bortezomib; CPR: cyclophosphamide, prednisone, lenalidomide; HiR: high-risk;
LEN: lenalidomide; MPR: melphalan, prednisone, lenalidomide; PS: performance status; StR: standard-risk.
PFS
Months Months
OS
OverallSex
FemaleMale
Age≤75 years>75 years
FISHStRHiRMissing
ISSIIIIII
Karnofsky PS90–10070–8950–69
LDH≤450>450Missing
Hazard ratio (95% CI) Interaction-p
0.76 (0.66–0.88)
0.78 (0.64–0.95)0.74 (0.61–0.90)
0.74 (0.63–0.88)0.81 (0.62–1.06)
0.87 (0.72–1.05)0.54 (0.41–0.72)0.78 (0.59–1.04)
0.85 (0.65–1.12)0.74 (0.60–0.91)0.71 (0.54–0.94)
0.69 (0.56–0.84)0.83 (0.67–1.02)0.87 (0.56–1.34)
0.78 (0.67–0.92)0.68 (0.44–1.05)0.69 (0.48–0.98)
0.66
0.55
0.01
0.62
0.34
0.71
0.41 1 1.34
Transplant-ineligible – lenalidomide
• Lenalidomide/dexamethasone – does not normalise HR FISH1,2
• FIRST3
• MPT vs lenalidomide/dexamethasone
• Lenalidomide/dexamethasone confers no advantage with HR FISH
• Myeloma XI4
1. Kapoor, et al. Blood. 2009; 114:518–21; 2. Jacobus, et al. Br J Haematol. 2011; 153:340–8; 3. Avet-Loiseau. Blood. 2015; 126: Abstract 730; 4. Jackson G, et al. Blood. 2018; 128: Abstract 1143. MPT: melphalan, prednisone, thalidomide.
Progress update
Complicated by pseudo-obstruction, urosepsis, D and V, AKI
Hb 78, WCC 6.1, neuts 4.3, plts 243BM 30% plasma cells
What would you do?
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01/06/2015 30/11/2015 01/06/2016
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Cyclophosphamide omitted for last two cycles Vomiting, pneumococcal sepsis
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01/06/2015 30/11/2015 01/06/20160
30/11/2016 02/06/2017 01/12/2017
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PAS: patient access scheme.
Progress update
Case study 3
• 58-year-old nurse consultant. PMH Addison’s disease, idiopathic urticaria, lichen sclerosis, osteopenia
• June 2015: lytic lesion R femoral diaphysis ‘thigh pain’
• SS:
• Hb 126, Cr 103, Ca 2.54
• Paraprotein IgA lambda 19 g/l
• ISS I
• BM 60% plasma cells
• FISH t(4;14), gain(1q)
CA: calcium; Cr: creatinine.
Initial treatment
IgA levels
What would you do?
25
20
15
10
5
0
01/06/2015 30/11/2015
Which re-induction Tx?
1. Induction with CTD and second ASCT
2. ACCORD trial with plan for second ASCT
3. PI-based regimen
4. Other
Myeloma X
Cook G, et al. Lancet Oncol. 2014; 15:874–85.
Myeloma X
Included: • Progression ≥12/12
Exclusion criteria:• Tx for relapsed disease
• ECOG PS 3–4
• Grade 2 peripheral neuropathy
• Comorbidity precluding ASCT
1. Cook G, et al. Lancet Oncol. 2014; 15:874–85. ECOG: Eastern Cooperative Oncology Group; TTP: time to progression.
Table adapted from Cook, et al. 20141
Myeloma X
Patients missing from the table received no treatment; *Includes both sCR and CR.†Early death after induction was defined as death between registration and up to and including 21 days after the final cycle commenced; early death after randomised treated was defined as death between randomisation and up to and including 100 days after randomisation.Cook G, et al. Lancet Oncol. 2014; 15:874–85.
Best response in all registered patients after induction and in all randomly assigned patients after randomised treatment
Response after induction (n=297)
Myeloma X
OS 67 vs 52/12
Cook G, et al. Lancet Oncol. 2014; 15:874–85.
Subgroup analysis of TTPOS in the intent-to-treat population
Myeloma XII – ACCoRd
• RRMM post-ASCT relapse: • ITD-ASCT vs ITD-ASCT(augmented)
• Ixazomib vs observation post-ASCT maintenance
• 68.2% SR, 24.2% HR, 6.1% UHR at relapse
• ORR did not differ by genetic risk (SR/HR: ORR 57.8% vs 50.0%, p=0.55)
• Previous PI exposure important (exposed vs naïve: ORR 57.8% vs 75.9%, p=0.03)
• PD more commonly seen in PI-exposed (18.6%) and HR (18.8%) vs overall population (11.9%)
Cook G, et al. Presentation at ASH 2018. Abstract 255.ITD: ixazomib, thalidomide, dexamethasone;
ORR: overall response rate; RRMM: relapsed/refractory multiple myeloma.
ReLApsE – ASH 2018• n=282
• Arm A: Rd continuous, Arm B: Rd x3 – ASCT #2 – R maintenance
• Arm B: 29.5% did not receive planned ASCT
• HR FISH: A: 31.6%; B: 42.9%
• ORR at LM analysis (post C5): A: 69.6%; B: 82.3%
• Multivariate LM analysis: superior PFS (hazard ratio 0.6, p=0.01) and OS (hazard ratio 0.39, p=0.006)
• LR FISH and R-ISS I demonstrated superior OS with B over A. Benefit not seen with HR FISH or R-ISS II/III
Arm A Arm B
ORR 74.6% 77.9%
≥VGPR 47.1% 49.3%
PFS 18.8 months 20.7 months
OS NR 62.7 months
LM analysis Arm A Arm B p-value
PFS 20.1 months 23.3 months 0.09
OS NR 57 months 0.046
Goldschmidt H, et al. Presentation at ASH 2018. Abstract 253 and 254. LM: landmark; LR: low risk; R: lenalidomide.
Progress update
VTD
ASCT
ITD (Myeloma XII) DT-PACE
Rd
40
30
20
10
001/06/2015 30/11/2015 01/06/2016 30/11/2016 02/06/2017 01/12/2017 03/06/2018 02/12/2018 04/06/2019
25
20
10
001/06/2015 30/11/2015 01/06/2016 30/11/2016 02/06/2017 01/12/2017 03/06/2018 02/12/2018 04/06/2019
15
5
What would you do?
Progress update
VTD
ASCT
ITD (Myeloma XII) DT-PACE
RD
40
30
20
10
001/06/2015 30/11/2015 01/06/2016 30/11/2016 02/06/2017 01/12/2017 03/06/2018 02/12/2018 04/06/2019
25
20
10
001/06/2015 30/11/2015 01/06/2016 30/11/2016 02/06/2017 01/12/2017 03/06/2018 02/12/2018 04/06/2019
15
5
DT-PACE: dexamethasone, thalidomide, cisplatin, doxorubicin, cyclophosphamide, etoposide.
Which subsequent Tx?
1. RD
2. IRD
3. Daratumumab
4. Pomalidomide-based triplet
5. Pomalidomide (+/- clarithromycin)
6. Pomalidomide (+/- cyclophosphamide)
7. Bortezomib-based regimen
Principles of treating HR disease
• Accurately identifying patients
• Rapid disease control
• Scheduling
• Tailoring treatment to disease biology
• Avoid alkylating agents
• Aim to achieve outcomes similar or ‘less than expected’ difference to SR disease
Dr Sally Moore, personal communication.
CA considerations
• Most labs only test FISH according to R-ISS
• Sample quality is essential
• Much unknown re. confounding factors
• Role of repeat FISH at relapse – clonal evolution
• Limited by Tx algorithm/NICE appraisals
• Role of clinical trials
• Balance of toxicity with response
• Elderly add in third drug to doublet if issues with tolerability?
Dr Sally Moore, personal communication.
2018 updated guidelines on diagnosis, risk stratification and management
Rajkumar SV, et al. Am J Hematol. 2018; 93:1091–110.
Non-transplant-eligible
mSMART risk stratification
Bortezomib-based regimen
Bortezomib-based regimen x 3–4 cycles
PI-based maintenance
Bortezomib-based regimen
Risk groupPercentage of newly diagnosed patients with the abnormality
SR 75%
Trisomies
t(11;14)
t(6;14)
IR 10%
t(4;14)
Gain(1q)
HR 15%
t(14:16)
t(14;20)
del(17p)
Transplant-eligible
PI-based maintenance
PI-based maintenance
Thank [email protected]