Front Line Therapy for Newly Diagnosed Multiple Myeloma

Front Line Therapy for Newly Diagnosed Multiple Myeloma
Vishal Kukreti, M.D., FRCPC Princess Margaret Hospital September 24, 2011

Objectives Overview of Myeloma Treatment options First Line Therapy
Transplant Eligible Non-Transplant Eligible

Multiple Myeloma Incurable cancer of plasma cells
Medullary and extra-medullary disease

Antibodies/Immunoglobulins
Plasma cells make antibodies (immunoglobulins, Igs) which consist of 2 heavy chains and 2 light chains One type of antibody is made to bind with one foreign substance (virus, bacteria, etc.)

Patterns of Antibody Production

Serum Protein Electropheresis
Normal SPEP Multiple Myeloma

Types of Multiple Myeloma

Diagnostic Criteria Diagnosis based on finding over 10% plasma cells (antibody forming cells) in bone marrow Symptomatic myeloma characterized by “CRAB” Anemia (<100 or 20g/L below normal) Bone lesions - lytic Kidney damage (Creatinine 176 umol/L) Elevated blood calcium (>2.8mmol/L)

Findings at diagnosis - MM
Anemia – 80% Renal dysfunction – 20% Hypercalcemia – 25% Bone destruction – 75% Hyperviscosity - <5% M-protein Identification Serum – 80% Urine – 20% Neither (non-secretory) – 1-2%

Age-specific incidence of MM
Transplant candidates Ineligible

Staging of Myeloma

International Staging System
Risk Category Characteristics 1  2 M  3.5 mg/L + albumin  35 g/L 2  2 M  3.5 mg/L+ albumin  35 g/L or  2 M  3.5 – 5.5 mg/L 3  2 M  5.5 mg/L

Survival and ISS score

FISH Cytogenetics in Myeloma
p53 deletion=10% (loss of tumor suppressor gene) t(4;14)=15% (dysregulation of FGFR3 and MMSET)

Combining Beta 2-Microglobulin and FISH Identifies 3 Prognostic Groups
No t(4;14), no del17p, b2m£4 mg/L, no del13 No t(4;14), no del17p, b2m£4 mg/L, del13 No t(4;14), no del17p, b2m>4 mg/L, no del13 No t(4;14), no del17p, b2m>4 mg/L, del13 t(4;14) or del17p, b2m£4 mg/L t(4;14) or del17p, b2m>4 mg/L 35% 50% FISH - a process which vividly paints chromosomes or portions of chromosomes with fluorescent molecules Identifies chromosomal abnormalities Used to identify the presence and location of a region of DNA or RNA within morphologically preserved chromosome preparations, fixed cells or tissue sections This means you can view a segment or entire chromosome with your own eyes p= 15% Avet-Loiseau H. Blood. 2007;109:

Treatment – Principles
Bisphosphonates Osteonecrosis of the jaw – 1.8 to 12.8% Duration of therapy Vertebroplasty/Kyphoplasty Infections Induction Therapy – Transplant Eligible vs Ineligible Autologous Stem Cell Transplant Maintenance therapy post-stem cell transplantation

Where We’ve Been with Initial Therapy
ASCT Melphalan + Prednisone Preceded by VAD, Dex alone or Thal/Dex x 4 cycles Melphalan 200 mg/m2 Overall response rate 80% CR/nCR rate 20% Median PFS mos Median OS mos Overall response rate 40-50% CR/nCR 5% Median PFS mos Median OS mos

Novel Agents in Multiple Myeloma
Thalidomide Bortezomib Lenalidomide

Agent Class Effects Toxicity Thalidomide (Thalomid®) IMiD Bortezomib
Immunomodulatory effects - inhibits TNFa, inhibits angiogenesis, stimulates T-cells (CD8), alters cytokine production, impedes binding to stromal cells Teratogenicity, PN, sedation, rash, constipation, DVT Bortezomib (VelcadeTM) Proteasome inhibitor Decreased adhesion, cytokine production, angiogenesis, NFkB, DNA repair Fatigue, PN, GI toxicity Decrease in neutrophils, platelets and lymphocytes Lenalidomide (CC-5013; Revlimid®) Stimulate T-cell proliferation, upregulate IL-2 and IFN-g, inhibit TNFa and IL-6Decreased adhesion, alter synthesis of cytokines, induce growth arrest and caspase dependent apoptosis NK cell cytotoxicity Myelosuppression, DVT

Strategies to Improve ASCT Results
Improved induction therapy Risk Stratification – t(4;14) Improved dose intensive therapy Tandem ASCT New regimens (“Vel-Mel,” Bu-Mel, busulfex + bortezomib) Post-ASCT therapy Consolidation Maintenance

Induction Trials before ASCT
Many phase I-II trials of 3- and 4-drug regimens May allow option to continue regimen without ASCT Phase III trials that include ASCT 3 compare novel regimen with VAD 2 compare novel regimen with thalidomide + dex 1 compares novel regimen with bortezomib + dex

Novel Induction Regimens before ASCT
VAD or Dex BORTEZOMIB (VELCADE) Bortez+Dex* VTD* PAD* VCD Cybor-D RVDD THALIDOMIDE ThalDex* TAD* CTD* LENALIDOMIDE (REVLIMID) RD Rd RVD *Studied in phase III transplant trials Stem cell harvest High-dose melphalan + ASCT RD: Lenalidomide + high-dose dex Rd: Lenalidomide + low-dose dex

Study/Author N Induction regimen # ASCT Consolidation Maintenance
MAG/Macro 204 Thal + dex VAD 1 - HOVON-50/ Lokhorst 536 TAD Thal Interferon IFM / Harousseau 482 BD 1 or 2 +/- len HOVON 65/ GMMG-HD4/ Sonneveld 613 PAD Thal 50 mg/d B 1.3 mg/m (q 2 weeks) GIMEMA MMY-3006/ Cavo 447 VTD 2 Dex PETHEMA/ GEM05MEN0S65/Rosinol 306 VBMCP/VBAD/ Vel IFM /Moreau 199 Vel/dex vTD

Study/Author Induction regimen # ASCT + Post-Rx Post-ASCT Response (%) VGPRc(CR+nCR) Median PFS (mos) Median Overall Survival MAG/Macro TD 1 44 - HOVON-50/ Lokhorst TAD 1+Thal 66 (31) 34 73 IFM / Harousseau BD 1 or 2 +/- Len 54 (35) 36 81% (3 yrs) HOVON 65/GMMG-HD4/ Sonneveld PAD 1 or 2 + bortez 75 (50) 42% 78% GIMEMA MMY-3006/Cavo VTD 2 + VTD + Dex 87 (55*) 85% (2 yrs) 96% PETHEMA/ Rosinol (46*) NYR 76% (4 yrs) IFM /Moreau Vel/dex vTD 73 (61)

“CYBOR-D”: Phase II Trial Newly Diagnosed Myeloma
28 day cycle Schedule Bortezomib Cyclophosphamide Dex Dose (mg/m2) Day Days (300 mg/m2) Days (40 mg) Biweekly 1.3 1,4,8,11 1,8,15,22 1-4, 9-12, 17-20 Weekly 1.5 Same x 2 cycles, then decreased to 1,8,15,22 Rapid onset Responses after 4 cycles of weekly dosing: ORR 98% ≥VGPR 68% CR/nCR 43% No issues with SC collection 33 pts in first cohort receiving biweekly, 30 in second cohort receiving weekly Vel. Reeder C, et al. Leukemia 2009; 23: ; Reeder CB, et al. Blood 2010; 115:

Induction Therapy before ASCT - Summary
Advantages of bortezomib-containing induction Rapid induction of remission Effective in renal failure Effective in high-risk cytogenetic subgroups Some evidence that 3- and 4-drug regimens produce higher remissions, and convey better PFS Combinations of bortezomib and IMiDs very costly Weekly bortezomib carries much lower risk of PN PMH approach is to use CYBOR-D x 4 cycles

Randomized Tandem ASCT Trials
Post-ASCT Rx CR/VGPR rate (%) Single Tandem Median PFS (months) Single Tandem Median OS Attal, 2003 399 α IFN 42 50 25 30* 48 58* Fermand, 277 None 39 37 31 33 49 73 Goldschmidt, 2005 268 -- 22 NYR* 23 NYR Sonneveld, 2004 303 13 28 20 22* 55 Cavo, 2007 321 38 35* 65 71 * p< 0.05

Newer Post-ASCT Strategies
Consolidation VTD (GIMEMA trial) Lenalidomide + dexamethasone (IFM ) Bortezomib (Nordic Myeloma Study Group trial) RVD (CTN trial) Maintenance Lenalidomide (CALGB trial, IFM )

HDM + ASCT recommended at relapse
IFM/Dana Farber 2009 Trial VRD x 3 SC collection CY + G-CSF VRD x 5 Melphalan 200 mg/m2 + ASCT VRD x 2 Rev maintenance x 1 yr Rev maintenance x 1 yr HDM + ASCT recommended at relapse ASCT will be considered pertinent if EFS is prolonged by ≥ 9 months

ASCT in Myeloma Summary and Conclusions
Several approaches integrating novel agents with ASCT improve outcome Difficult to dissect contribution of induction, consolidation, maintenance Improved response rates with newer strategies ≥ VGPR rates 60-75%; CR/nCR rates % Median PFS has improved from 2 to 3 years 3 ½ years with lenalidomide maintenance Overall survival results are improved in some studies

Where We Are Now ASCT MPT or MPV or Lenalidomide + Dex
Preceded by novel induction regimens Melphalan 200 mg/m2 +/- second ASCT +/-thalidomide maintenance Overall response rate 80-90% CR/nCR rate 35-50% Median PFS 36 mos 2 year OS 90-93% Overall response rate 65-75% CR/nCR 20-25% Median PFS mos Median OS mos 2 year OS 70-93%

Transplant-Ineligible Patients – Balancing the Toxicities and Efficacy of Novel Agents

How do we choose initial therapy in non-transplant patients?
Drug availability Practical considerations Patient-related features Co-morbidities (diabetes, peripheral neuropathy) Marrow reserve Renal function Disease-related features Aggressive biology, such as t(4;14) Light chain nephropathy Treatment related features Rapidity of response Toxicity profile (VTE, peripheral neuropathy)

New Treatment Options for Newly Diagnosed Myeloma Patients Non-transplant Candidates
Add novel agent to melphalan + prednisone Continuous suppressive therapy with IMiD + dexamethasone (lenalidomide + weekly dex) Combination therapy with 3-4 drug regimens +/- maintenance CTD • VDC • VMPT6 RVD • VDCR4 CyborD • Thal + dex + PLD5 1Morgan G, et al. Blood 2007;110: abstract Richardson PG, et al. Blood 2008;112: abstract 92; 3Reeder CB, et al. Leukemia 2009;23: ; Kumar S et al. Blood 2009; 114: abstract 127; 5Offandini M, et al. Br J Haematol 2009;144: ; 6Palumbo A, et al. Blood 2009; 114: abstract 128.

Duration of therapy (wks) Overall response rate (CR+nCR) (%)
Best Reported Outcomes with Newer Non-ASCT Regimens in Phase III Trials Author Rx Duration of therapy (wks) Overall response rate (CR+nCR) (%) Median PFS (mos) Median OS 2 year OS (%) Facon1 MPT 72 76 (18) 27.5* 51.6* 78 Palumbo2 MPT+ T 24+ 76 (28) 21.8* 45 82 Hulin3 61 (7) 24* 45* 70 San Miguel4 VMP 54 71 (35) NYR* 83 Palumbo5 MPR+ R 40+ 77 (18) NYR ~70 Rajkumar6 Len+dex Until prog 70 (14 CR) 25.3 87 *Significant benefit over MP alone 1Facon T, et al. Lancet 2007:370; ; 2Palumbo A , et al. Blood 2008;112: ; 3 Hulin C, et al. Blood 2007; 110: abstract 75;4San Miguel JF, et al. N Engl J Med 2008; 359: ; 5 Palumbo A, et al. Blood 2009; 114: abstract 613; 6Rajkumar SV, et al. Lancet Oncol 2010; 11:

IFM 99/06: MPT vs MP vs Mel100 65-75yo
PFS OS MPT MPT MP MP MP (melphalan, 4 mg/m2, days 1-7; and prednisone, 40mg/m2, days 1-7) or MP plus thal (MPT), 100 mg/d for 6 cycles.120 Patients in the MPT arm continued taking maintenance thal after the 6 cycles until relapse. Six months after initiation of therapy, 76% of patients in the MPT arm had a response (CR or PR) compared with 47.6% in the MP arm, which translated to a doubling of EFS at 2 years (54% vs 27%). However, grade 3 and 4 adverse events nearly doubled with the addition of thal (48% for MPT vs 25% for MP), and 11 patients in the MPT group died of toxicityrelated events compared with 6 patients in the MP group. Deep venous thrombosis was the most common grade 3 or 4 adverse event in the MPT group; it developed in 13 of the 9rst 65 patients. After introduction of enoxaparin prophylaxis, thrombosis developed in only 2 of the remaining 64 patients, and that occurred after interruption of enoxaparin. The incidence of early deaths might be reduced in patients younger than 80 years with normal cardiac and pulmonary functions, and with better management of side-effects with antibiotic and anticoagulant prophylaxis. MP Melphalan 0.25mg/kg and Prednisone 2mg/kg, days 1-4, for 12 cycles, q 6 weeks MPT MP plus thal mg/d (with no maintenance thalidomide phase) MEL100 VADx2 + MEL100x2 + ASCTx2 Facon et al, IFM 99/06, Lancet 2007

MPT vs MP studies Study ORR (%) CR PFS Median (mos) OS Median (mos) OS
p-value IFM 99/06 Facon1 76 v 35 13 v 2 28 v 18 52 v 33 0.0006 IFM 01/01 Hulin3 61 v 31 7 v 1 24 v 19 44 v 29 0.03 HOVON Wijermans5 62 v 47 2 v 2 15 v 11 40 v 31 0.05 GIMEMA Palumbo2 76 v 48 16 v 4 22 v 15 45 v 48 NS Nordic Waage 4 57 v 38 13 v 4 15 v 14 29 v 33 Palumbo’s MP arm did much better than average – using less Melphalan (4mg/kg vs 12mg/kg in IFM arms ?less is more) – but therefore failed to demonstrate a survival advantage. Also used inadequate VTE prophylaxis for the 1st half of the trial. Enoxaparin 40mg SQ daily prophylaxis added part way thru the study, reducing the VTE rate from 20% to 3% Waage: Certain aspects that may have significance for the differences between the studies are discussed here. There were differences in inclusion criteria between the studies, which was reflected in particular by the fact that 30% of the patients in our study had WHO performance status 3 or 4 compared with 6% to 8% and 6% in the Italian3 and French5,6 studies. The proportion of patients with WHO performance status more than 3 in our study is similar to our earlier population-based, unselected, and nearly complete registra- tion studies.10In addition, the scheduled dose of melphalan and thalidomide varied considerably between the studies. However, none of the studies was designed for evaluating optimal dose of thalidomide, and it is difficult to draw detailed conclusions about dose or duration of treatment and effect across the studies. We notice that beneficial effect has been observed at a dose of 100 mg daily, indicating that a dose in the lower range is sufficientThe median age in all studies was quite similar, ranging from 70 to 74 years in 4 of the studies.3,5,7 Age alone is therefore probably not of major importance. This is further underlined by the French study on patients older than 75 years, which demonstrates a survival benefit of thalidomide.6In conclusion, patient selection and, in particular, differences in proportion of WHO performance status more than 3, differences in dose and schedule of thalidomide and melphalan may have impact on the result. 1Facon T, et al. Lancet 2007;370: ; 2Palumbo A, et al. 2008; 112: ; 3Hulin C, et al. J Clin Oncol 2009 May 18 [Epub¸ahead of print]; 4Waage A, et al. Blood 2007;110:abstract # 76; 5Wijermans P, et al. Blood 2008; 112: abstract #649; 6San Miguel J, et al. 2008; New Engl J Med 2008; 359:

Select toxicities: MPT vs MP (Grade3-4) Facon et al
Select toxicities: MPT vs MP (Grade3-4) Facon et al., IFM 99–06: yo MP (N=193) MPT (N=124) P-value Neutropenia 26% 48% <0.0001 Thrombosis/embolism 4% 12% 0.0008 Peripheral neuropathy 6% 0.001 Solmolence/fatigue/dizziness 8% Cardiac (arthymia, CHF) 0.5% 2% Rate too low constipation 10% MP (melphalan, 4 mg/m2, days 1-7; and prednisone, 40mg/m2, days 1-7) or MP plus thal (MPT), 100 mg/d for 6 cycles.120 Patients in the MPT arm continued taking maintenance thal after the 6 cycles until relapse. Six months after initiation of therapy, 76% of patients in the MPT arm had a response (CR or PR) compared with 47.6% in the MP arm, which translated to a doubling of EFS at 2 years (54% vs 27%). However, grade 3 and 4 adverse events nearly doubled with the addition of thal (48% for MPT vs 25% for MP), and 11 patients in the MPT group died of toxicityrelated events compared with 6 patients in the MP group. Deep venous thrombosis was the most common grade 3 or 4 adverse event in the MPT group; it developed in 13 of the 9rst 65 patients. After introduction of enoxaparin prophylaxis, thrombosis developed in only 2 of the remaining 64 patients, and that occurred after interruption of enoxaparin. The incidence of early deaths might be reduced in patients younger than 80 years with normal cardiac and pulmonary functions, and with better management of side-effects with antibiotic and anticoagulant prophylaxis.

40 VISTA: VELCADE as Initial Standard Therapy in multiple myeloma:
Assessment with melphalan and prednisone VMP Cycles 1-4 Bortezomib 1.3 mg/m2 IV: days 1,4,8,11,22,25,29,32 Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4 Cycles 5-9 Bortezomib 1.3 mg/m2 IV: days 1,8,22,29 R A N D O M I S E Primary Endpoint: TTP Secondary Endpoints: CR rate ORR TTR DOR PFS TNT OS QoL Patients with newly diagnosed MM not transplant eligible due to age (≥65 years) or coexisting conditions 9 x 6-week cycles (54 weeks) in both arms Conducted at 151 centres in 22 countries in Europe, North and South America, and Asia. MP Cycles 1-9 Melphalan 9 mg/m2 and prednisone 60 mg/m2 days 1-4 Conducted at 151 centres in 22 countries in Europe, North and South America, and Asia. San Miguel et al. N Engl J Med 2008; 359: 40

VISTA: Select patient demographics and disease characteristics
VMP MP Median age 71 ≥75yo 31 30 KPS ≤70%, (~ECOG 2+) % 35 33 ISS Stage I / II / III, % 19 / 47 / 35 19 / 47 / 34 Lytic bone lesions, % 65 66 Serum creatinine, median (mg/dL) 1.1 CrCl ≤30 / >30-60 / >60 ml/min, % 6 / 48 / 46 5 / 50 / 46 History of neurological conditions, % 18 20 History of cardiac conditions, % San Miguel et al. N Engl J Med 2008; 359:

VISTA: VMP vs MP (9 cycles)
TTP OS Of 121 patients in the control group who received subsequent therapy, only 45% received therapy that included bortezomib. San Miguel et al. (VISTA). N Engl J Med 2008;359:

High-risk vs. standard-risk cytogenetics
VMP: Consistent efficacy in patients with poor prognostic characteristics High-risk vs. standard-risk cytogenetics TTP 1 OS 2 high standard standard high Time (months) Time (months) Median follow up: 25.9 months Median follow up: 36.7 months 1. San Miguel et al. N Engl J Med 2008; 359: (Suppl) 2. Mateos et al. J Clin Oncol 2010; 28:

Select Grade 3-4 Adverse events: VISTA Updated data
VMP (N=340) MP (N=337) Neutropenia 40 38 Thrombocytopenia 31 Anemia 19 28 Leukopenia 24 20 Lymphopenia 11 Pneumonia 7 5 Peripheral sensory neuropathy 14 Fatigue 8 2 Diarrhoea 1

Once weekly bortezomib is new standard schedule!
Minimizing Neuropathy: once- vs. twice-weekly bortezomib – GIMEMA study VMP (Twice weekly) (Once weekly) CR 27% 23% 3years 32% 35% 3 years 86% 85% Sensory peripheral neuropathy Any grade 43% 21% Grade 3-4 14% 2% PN discontinuation 16% 4% Total planned dose 67.6 mg/m2 46.8 mg/m2 Total delivered dose 41 mg/m2 40 mg/m2 Once weekly bortezomib is new standard schedule! Palumbo et al; ASH 2010, Abstract #620

E4A03: Phase III trial of LD vs Ld in newly diagnosed MM
If PD within 4 mo Lenalidomide + High- Dose Dexamethasone (LD) [40 mg, d 1-4, 9-12, 17-20] Salvage therapy Thalidomide 200 mg/d po, days 1-28 High-dose (Arm III) vs Low- dose (Arm IV) Newly Diagnosed Myeloma N = 445 DSMB mandated crossover to Low-dose dex (Ld) March 27, 2007 N = 79 patients on study at time of crossover Lenalidomide + Low- Dose Dexamethasone (Ld) [40 mg, d 1, 8, 15, 22] Lenalidomide: 25 mg daily, days 1-21 of 28-day cycle; D: High-dose Dex: total 480 mg/28-day cycle; d: Low-dose Dex: total 160 mg/28-day cycle Vesole DH et al. ASH 2010; Abstract 308.

LD vs Ld: Overall Survival by age
Len plus low-dose dex is safe and effective for both older and younger patients Vesole et al; ASH 2010, Abstract 308

LD versus Ld: Toxicities
n=223 Ld n=220 P-value Response at 4 cycles 79% 68% 0.008  VGPR 42% 24% <0.008 Blood clots 26% 12% <0.001 Infection 16% 9% 0.043 Severe toxicity 53% 31% <.001 Early deaths 5% 0.5% 0.003 Severe toxicity = grade 3-4 RD in comparison to Rd is slightly more effective but significantly more toxic. Once weekly DEX is now widely used and is generalized to the relapsed setting and to use with other novel agents Rajkumar et al Lancet Oncol 2010;11:29-37

Conclusions Not all elderly are the same. Not all myeloma is the same
Bortezomib-based induction (e.g. VMP) is reasonably well tolerated and associated with enhanced OS in most patients >65yo and >75yo (and is funded in Ontario) Oral induction regimens (e.g. MPT, MP or len/dex) may be appropriate in some non high-risk patients In patients with renal impairment or t(4;14), -17p a velcade-based induction regimen is preferred (e.g. VMP) Higher intensity regimens less beneficial and may be adverse in frail patients Weekly bortezomib is a new standard of administration Low dose dex is the standard of care in lenalidomide Niesvizky et al. Haematologica 2011; 96 (s1): S98 (Abstract P-228); poster presentation at IMW 2011

PMH Approach to Front Line Therapy
Transplant Eligible (<65) Non-Transplant Eligible (>70) Ages 65-70 Cybor D Induction (clinical trials) VMP MPT MP (Clinical trials) ASCT (Tandem if high risk) Maintenance Lenalidomide

Front Line Therapy for Newly Diagnosed Multiple Myeloma

Similar presentations

Presentation on theme: "Front Line Therapy for Newly Diagnosed Multiple Myeloma"— Presentation transcript:

Similar presentations

About project

Feedback

Log in

Auth with social network:

Front Line Therapy for Newly Diagnosed Multiple Myeloma

Similar presentations

Presentation on theme: "Front Line Therapy for Newly Diagnosed Multiple Myeloma"— Presentation transcript:

Similar presentations

About project

Feedback