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Newly Diagnosed Myeloma
1. Best approach to newly
diagnosed multiple myeloma
Elisabet Manasanch M.D., M.H.Sc.
Assistant Professor, Department of Lymphoma/Myeloma
Division of Cancer Medicine
4. Overview
103,826 new cases
72,453 deaths
worldwide
Incidence rate
3-5/100,000
Kihyun Kim et al. Clinical profiles of multiple myeloma in Asia – An Asian Myeloma Network Study. 2014. AJH.
JH Lee et al. Multiple myeloma in Korea: past, present, and future perspectives. 2010. Int J Hematol.
Blacks
Age 70 years
Incidence rate
0.5-3/100,000
Age 62 years
5. Overview
Plasma cell malignancy – molecular heterogeneity
Natural history progression from MGUS/SMM
Evidence of end-organ damage
GROUPS Associated translocations
7 -> MF t(14;16) and t(14;20)
6 -> CD-2
CCND1/CCND3
t(11;14) and t(6;14) activating
Cyclin D 1 and Cyclin D3
5 -> CD-1
CCND1/CCND3
t(11;14) and t(6;14) activating
Cyclin D 1 and Cyclin D3
4 -> HY Hyperdiploidy
3 -> MS t(4;14), activation of FGFR3 and
MMSET
2 -> LB
Low Bone
Underexpression of DKK1
1 -> PR
PRoliferation
Increased proliferation index
Zhan et al. The molecular classification of multiple myeloma. Blood. 2006 / Lohr et al. Widespread genetic heterogeneity in multiple myeloma:
Implications for targeted therapy. Cancer Cell. 2014.
6. Treatment History
Dex VAD Thal+Dex CTD VD PAD Rd VTD RVD CRd
Melphalan/
prednisone
High-dose therapy with
autologous stem cell
HD dexamethasone
VAD
HD melphalan
Autologous BM
transplants
support
Lenalidomide
Thalidomide
Bortezomib
Carfilzomib
Pomalidomide
Elotuzumab
Daratumumab
100
80
60
40
20
0
Sarcolysine
1958 1962 1983-86 1996 1999 2003 2006 2012
Patients with ≥ VGPR (%)
S Kumar et al. Cancer Treatment Reviews 2010; Korde et al. ASH 2013.
7. Overview
DIAGNOSTIC APPROACH
Blood CBC with differential
Complete chemistries
LDH
Serum quantitative immunoglobulins
SPEP/IFE
Serum β2-M and albumin
Serum free light chain assay
Urine 24 hour UPEP/IFE
Pathology/Molecular Bone marrow biopsy (core and aspirate – unilateral)
Metaphase cytogenetics
FISH
BM aspirate flow cytometry
Gene expression profiling*
Imaging Skeletal survey
MRI/PETCT
RA Kyle and SV Rajkumar. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009. Manasanch
et al. Flow cytometric sensitivity and characteristics of plasma cells in patients with multiple myeloma or its precursor disease: influence of biopsy site
and anticoagulation method. Leukemia and Lymphoma. 2014. In press.
9. Fit patients
Absence of comorbidities, even if advanced age
IFM 2005/01 GIMEMA HOVON-GMMG PETHEMA/GEM
Harousseau
VD vs VAD
(n= 240 vs 242)
JCO 2010
Cavo
VTD vs TD
(n=241 vs 239)
Blood 2012
Sonneveld
PAD vs VAD
(n=417 vs 416)
JCO 2012
Rosinol
VTD vs VBCMP/VBAD+V
vs TD
(n=130 vs 129 vs 127)
Blood 2012
Results post-ASCT
CR
(nCR+sCR)
40% vs 18.4% 73.1% vs 60.9% 31% vs 15% 46% vs 38% vs 24%
PFS (months) 36 vs 29.7 (S) NR vs 32 35 vs 28 (S) 56.2 vs 35.5 vs 28.2 (S)
OS (months)
Not reached (32
months follow up)
90% vs 88% at 3
years
Not reached (66
months follow up)
74% vs 70% vs 65% (4
years) (NS)
Most patients are treated with ASCT
Phase III trials with bortezomib induction regimens
10. Combinations novel agents
Phase II studies with small numbers of patients
VRD
CyBorD
Richardson et al. Lenalidomide, bortezomib and dexamethasone combination therapy in patients with newly diagnosed mutiple
myeloma. Blood. 2010. / Reeder et al. Cyclophosphamide, bortezomib and dexamethasone induction for newly diagnosed
Multiple myeloma: high response rates in a phase II clinical trial. Leukemia. 2009.
11. Combinations novel agents
Randomized phase II study EVOLUTION (140 patients)
8 x 3 week cycles initial therapy followed by 6-week cycles of bortezomib maintenance
Small numbers of patients
PFS at one year: 86 vs 83 vs 93 vs 100 (%)
OS at one year: 94% vs 100% in all other arms
S Kumar et al. Randomized, multicenter, phase 2 study(EVOLUTION). Blood. 2012
12. CRd in newly diagnosed MM
Jakubowiak et al
(Phase I/II, n = 53)
Korde et al
(Phase II, n = 45)
Combination
therapy
CRd (Phase II Cfz 20/36 mg/m2)
8 cycles
CRd (Cfz 20/36 mg/m2)
8 cycles
Extended
dosing
CRd (Cfz every other week) 16 cycles, off-protocol
Ln at last tolerated dose d1-21
after 16 cycles
Ln 10 mg d1-21,
24 cycles
Transplant ≥PR stem cell collection, HDM optional Stem cell collection
Jakubowiak et al
(Phase I/II, n = 53)
Korde et al
(Phase II, n = 45)
ORR
62% nCR/CR, 81% VGPR, 98% PR after 12
cycles
51% CR/nCR, all MRD
negative (without ASCT)
PFS 92% (at 24 months) 97% (at 12 months)
A Jakubowiak et al. A phase ½ study of carfilzomib in combination with lenalidomide and low-dose dexamethasone
as a frontline treatment for multiple myeloma. Blood. 2012 / N Korde et al. Phase II Clinical and Correlative Study of
Carfilzomib, Lenalidomide, and Dexamethasone Followed by Lenalidomide Extended Dosing (CRD-R) Induces High Rates
of MRD Negativity in Newly Diagnosed Multiple Myeloma (MM) Patients. ASH abstract 538. 2013.
13. New agents in NDMM
RANDOMIZED PHASE 3 STUDIES
1.- IFM/DFCI: RVD with upfront or delayed autologous stem cell
transplant
2.- RVD vs CRd
EARLY PHASE TRIALS
1.- Carfilzomib, cyclophosphamide, dexamethasone
2.- Carfilzomib, bendamustine, dexamethasone
3.- Ixazomib, lenalidomide, dexamethasone
4.- Ixazomib, cyclophosphamide, dexamethasone
5.- RVD+ panabinostat
6.- Cyclophosphamide, lenalidomide, dexamethasone
15. Velcade as initial treatment in newly diagnosed
myeloma not eligible for transplant
Randomized, international, phase III trial of VMP vs MP in 682 previously untreated patients
with symptomatic MM who were not candidates for HDT-ASCT due to age (≥65 yrs) or
co-morbid conditions
VMP
Cycles 1–4
Bortezomib 1.3 mg/m2 IV: d 1,4,8,11,22,25,29,32
Melphalan 9 mg/m2 and prednisone 60 mg/m2:
d 1–4
Cycles 5–9
Bortezomib 1.3 mg/m2 IV: d 1,8,22,29
Melphalan 9 mg/m2 and prednisone 60 mg/m2:
d 1–4
MP
Cycles 1–9
Melphalan 9 mg/m2 and prednisone 60 mg/m2:
d 1–4
R
A
N
D
O
M
I
Z
E
9 x 6-week cycles (54 weeks) in both arms
• Primary end
point: TTP
• Secondary end
points: CR rate,
ORR, time to
response
J San Miguel et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. NEJM. 2008
16. VISTA trial
Time to progression Overall survival
VMP: 24.0 months
MP: 16.6 months
P < .000001
100
80
60
40
20
0
VMP
MP
Time (months)
Median follow-up: 25.9 months
3-year OS:
VMP: 72%
MP: 59%
P = .0032
VMP
MP
Time (months)
0 3 6 9 12 15 18 21 24 27
100
80
60
40
20
0
0 4 8 12 16 20 24 28 32 36 40
682 patients
RR: 71% VMP versus 35% MP
Rate of CR: 30% VMP versus 4% MP
J San Miguel et al. Bortezomib plus melphalan and prednisone for initial treatment of multiple myeloma. NEJM. 2008
17. HD vs LD lenalidomide. ECOG E4A03
Four 28-day cycles
1-yr OS 2-yr OS
HD/lenalidomide 87% 75%
LD/lenallidomide 96% 87%
Transplant-eligible
patients can
proceed to SCT
Continue therapy until
disease progression
Lenalidomide + High-Dose Dexamethasone (RD)a
Len: 25 mg/day, days 1-21
Dex: 40 mg/day, days 1-4, 9-12, 17-20
(n = 223)
Lenalidomide + Low-Dose Dexamethasone (Rd)
Len: 25 mg/day, days 1-21
Dex: 40 mg/day, days 1, 8, 15, 22
(n = 222)
Rajkumar et al. Lenalidomide plus high-dose dexamethasone versus lenalidomide plus low-dose dexamethasone as
initial therapy for newly diagnosed multiple myeloma: an open-label randomised controlled trial. Lancet Oncol. 2010.
21. High risk MM
Genomic abnormalities
FISH
- del 17p
- t(14:16)
- t(14:20)
GEP
- High risk signature
Laboratory abnormalities
Renal failure
Circulating plasma cells
Increased LDH or B2M
Moreau et al. Combination of International Scoring System 3, High Lactate Dehydrogenase, and t(4;14)
and/or del(17p) Identifies Patients With Multiple Myeloma (MM) Treated With Front-Line Autologous
Stem-Cell Transplantation at High Risk of Early MM Progression–Related Death. JCO. 2014
22. High risk MM
* Bortezomib containing regimens as initial treatment
* Use of bortezomib consolidation/maintenance
* Use of ASCT as consolidation
* Explore tandem ASCT
* Enroll in clinical trials if this is a possibility
AK Nooka et al. Consolidation and maintenance therapy with lenalidomide,
bortezomib and dexamethasone (RVD) in high-risk myeloma patients. Leukemia. 2014.
23. Conclusions
* Fit patients:
*3 drug combination as initial therapy.
*Stem cell collection and evaluation for ASCT.
* Unfit patients:
*VMP (other MPR, MPT)
*Rd continuous treatment
* High risk patients:
*Refer for clinical trials
*Use bortezomib (proteasome inhibitors) in
consolidation/maintenance
*Evaluate for ASCT/tandem ASCT
24. MDACC Myeloma Center
Dr. Robert Orlowski
Dr. Jatin Shah
Dr. Donna Weber
Dr. Sheeba Thomas
Dr. Michael Wang
Dr. Parmar
Dr. Qazilbash
Dr. Shah
Dr. Bashir
Stem Cell Transplant Department
Support staff, nurses, coordinators
Patients
Hinweis der Redaktion
Reeder: Thirty-three newly diagnosed, symptomatic patients with MM
received bortezomib 1.3 mg/m2 intravenously on days 1, 4, 8
and 11, cyclophosphamide 300 mg/m2 orally on days 1, 8, 15
and 22 and dexamethasone 40 mg orally on days 1–4, 9–12 and
17–20 on a 28-day cycle for four cycles.
All patients undergoing stem cell harvest
Richardson:
Abstract
This phase 1/2 study is the first prospective evaluation of lenalidomide-bortezomib-dexamethasone in front-line myeloma. Patients (N = 66) received 3-week cycles (n = 8) of bortezomib 1.0 or 1.3 mg/m2 (days 1, 4, 8, 11), lenalidomide 15 to 25 mg (days 1-14), and dexamethasone 40 or 20 mg (days 1, 2, 4, 5, 8, 9, 11, 12). Responding patients proceeded to maintenance or transplantation. Phase 2 dosing was determined to be bortezomib 1.3 mg/m2, lenalidomide 25 mg, and dexamethasone 20 mg. Most common toxicities included sensory neuropathy (80%) and fatigue (64%), with only 27%/2% and 32%/3% grade 2/3, respectively. In addition, 32% reported neuropathic pain (11%/3%, grade 2/3). Grade 3/4 hematologic toxicities included lymphopenia (14%), neutropenia (9%), and thrombocytopenia (6%). Thrombosis was rare (6% overall), and no treatment-related mortality was observed. Rate of partial response was 100% in both the phase 2 population and overall, with 74% and 67% each achieving very good partial response or better. Twenty-eight patients (42%) proceeded to undergo transplantation. With median follow-up of 21 months, estimated 18-month progression-free and overall survival for the combination treatment with/without transplantation were 75% and 97%, respectively. Lenalidomide-bortezomib-dexamethasone demonstrates favorable tolerability and is highly effective in the treatment of newly diagnosed myeloma. This study is registered at http://clinicaltrials.gov as NCT00378105.
had a successful collection. Twenty-three patients underwent
stem cell transplantation (SCT) and are evaluable through day
100 with CR/nCR documented in 70% and XVGPR in 74%.
VRD:
Bz 1.3 1,4,8,11
Dex 40 mg weekly
Cyclophosphamide 500 mg/m2 days 1 and 8 and 15 in vdc-mod
Vdcr len 15 mg 1-14
Vdr len 25 mg 1-14
VMP
Cycles 1–4
Bortezomib 1.3 mg/m2 IV: d 1,4,8,11,22,25,29,32
Melphalan 9 mg/m2 and prednisone 60 mg/m2:
d 1–4
Cycles 5–9
Bortezomib 1.3 mg/m2 IV: d 1,8,22,29
Melphalan 9 mg/m2 and prednisone 60 mg/m2:
d 1–4
MP
Cycles 1–9
Melphalan 9 mg/m2 and prednisone 60 mg/m2:
d 1–4
This ECOG trial is well recognized for determining that dexamethasone dosing of 40 mg/day on a 4-days-on, 4-days-off schedule is too high. This randomized trial of lenalidomide and dexamethasone compared the then-standard dosing of dexamethasone to a once-weekly dosage of 40 mg and found that survival was significantly improved in the low-dose dexamethasone arm -- 1-year OS was 87% with len/high-dose dex vs 96% with len/low-dose dex.
Objective: to assess if a reduced dose of dex decreases toxicity while maintaining efficacy
Primary endpoint: ORR after first 4 cycles
aBased on the superiority of the Rd regimen, the study was stopped at a median follow-up of 12.5 months and patients in the RD arm crossed over to Rd therapy.
* Half of the patients start with VMP and half with Rd.
Treatment duration: 74 weeks
