Should Therapy for Newly Diagnosed Multiple Myeloma Be Risk - - PowerPoint PPT Presentation

Should Therapy for Newly Diagnosed Multiple Myeloma Be Risk Adapted?

Evangelos Terpos, MD University of Athens School of Medicine, Athens, Greece

The 1st World Congress on Controversies in Hematology, Rome 3/9/2010

Treatment of Newly-diagnosed Myeloma Treatment of Newly-diagnosed Myeloma

Choice depends on age, performance status, and whether high- dose chemotherapy (HDT) or stem cell rescue is planned HDT planned HDT not planned Vincristine + doxorubicin + dexamethasone (VAD)‡ or VAD-based regimen (NOT ANYMORE) Thalidomide + dexamethasone,* ‡

T-VAD,‡ other combinations

Proteasome inhibitors (Bortezomib)- based regimens‡ IMiDs (lenalidomide, pomalidomide) Melphalan + prednisolone (MP) Cyclophosphamide ± prednisolone* Melphalan + prednisolone + thalidomide (MPT)* ‡ Melphalan + prednisolone + bortezomib (MPV) ‡‡

* Oral therapies.

‡ Suitable for patients with renal failure.

Smith A, et al. Br J Haematol. 2005;132:410-51

What Are Factors That Confer A Poor Prognosis? What Are Factors That Confer A Poor Prognosis?

• Age
• β2 microglobulin, albumin - ISS
• Cytogenetic abnormalities
• Comorbidities, e.g. Renal impairment, extended

bone disease

Period estimates of 10-year survival of patients Period estimates of 10-year survival of patients with MM by major age groups in defined calendar with MM by major age groups in defined calendar periods from 1984–1986 to 2002–2004 periods from 1984–1986 to 2002–2004

Brenner et al. Blood 2008;111:2521–26

10-year relative survival (%) 1984– 1986 1987– 1989 1990– 1992 1993– 1995 1996– 1998 1999– 2001 2002– 2004 5 10 15 20 25 30 35 40 45 50 Calendar period <50 50–59 60–69 70–79 80+

median OS: 74 months vs. 39 months; p<0.001 Survival of patients ≤70 years Survival of patients >70 years median OS: 33 months vs. 26 months; p=0.27

1,376 patients

Kastritis et al. Leukemia 2009;23:1152–7

Overall survival by ISS and t(4;14) or del17 by FISH P-values: a v b<0.0001, a v c<0.0001, b v c<0.0001

0% 20% 40% 60% 80% 100% 5 10 15 Years from start of treatment

Estimate 4-year Deaths/N a ISS I or ISS II and Normal FISH 193/610 76% (72,79) b ISS I and Abnormal FISH/ISS III and Normal FISH 140/252 52% (45,58) c ISS II or ISS III and Abnormal FISH 146/196 32% (26,39)

Prognostic impact of t(4;14) / del(17p) with ISS Prognostic impact of t(4;14) / del(17p) with ISS

• IMWG analysis
• IMWG analysis

Avet-Loiseau et al. ASH 2009 (Abstract 749)

mSMART : Classification of Active MM mSMART : Classification of Active MM

• FISH
• Del 17p
• t(4;14)*
• t(14;16)
• Cytogenetic Deletion 13
• Cytogenetic

hypodiploidy

• PCLI >3%

All others including:

• Hyperdiploid
• t(11;14)
• t(6;14)

High-Risk (25%) Standard-Risk (75%) *

*Patients with t(4;14), b2M<4 mg/l and Hb≥10g/dl may have intermediate risk disease

Dispenzieri et al. Mayo Clin Proc 2007;82:323-341; v4 Revised and updated: June 2008

NO ANTIMYELOMA AGENT HAS BEEN APPROVED FOR USE IN HIGH-RISK PATIENTS ONLY

Thalidomide front-line studies in the presence Thalidomide front-line studies in the presence

• f high risk cytogenetic abnormalities
• f high risk cytogenetic abnormalities

Regimen Results Reference (ASH 2009 abstract #) Thal/dex Thal/dex upfront does not overcome del13, t(4;14) or del17

Zamagni 349

CTD Thal maintenance Adverse FISH [t(4;14), t(14;16), t(14;20), 1p-, 1q+, 17p-] associated with reduced PFS and OS In adverse FISH group, thal maintenance results in significantly reduced OS Survival from relapse impaired after thal maintenance, particularly in adverse FISH group

Morgan 352

Lenalidomide + dex in patients with Lenalidomide + dex in patients with cytogenetic abnormalities cytogenetic abnormalities

• Newly diagnosed MM (n=100)
• Significantly reduced PFS in

high-risk group defined by the presence of at least one

• f the following:

– hypodiploidy – monoallelic loss of chromosome 13 or its long arm by metaphase cytogenetics only – deletion of p53 (locus 17p13) – immunoglobulin heavy chain (IgH) translocations [t(4;14) or t(14;16)] by FISH or cytogenetics, – PCLI more than or equal to 3%

Kapoor et al. Blood 2009;114:518–521

Phase 3: VD vs. VAD ( Phase 3: VD vs. VAD (IFM2005-01) IFM2005-01)

VAD VD ≥ nCR Induction 7% 15% ASCT 1 18% 35% ASCT 2 32% 39% ≥ VGPR Induction 16% 39% ASCT 1 37% 54% ASCT 2 47% 68%

Harousseau et al. ASH 2009 (abstract 353)

VAD VD P PFS in all pts 30 months 36 months 0.057 PFS in patients with ISS 2 & 3 23 months 33 months 0.006 PFS in pts with t(4;14) +/- del17 24 months 33 months 0.113

Median follow-up 32.2 months PFS Response data

Randomization MM Stage II or III, Age 18–65 CAD + GCSF 3 x VAD CAD + GCSF 3 x PAD

MEL 200 + PBSCT

Depending on local policy for patients ≥PR

MEL 200 + PBSCT MEL 200 + PBSCT

Depending on local policy for patients ≥PR MEL

200 + PBSCT

Thalidomide 50 mg/day for 2 years maintenance

Allogeneic Tx

Bortezomib 1.3 mg/m2 / 2 weeks for 2 years maintenance

Phase III: PAD vs. VAD as induction treatment Phase III: PAD vs. VAD as induction treatment HOVON 65 MM / GMMG-HD4 study HOVON 65 MM / GMMG-HD4 study

Sonneveld et al. EHA 2009 Abstract 473

Interim analysis: n=300 PAD (n=150) VAD(n=150) P Response after induction (3 cycles) CR/nCR 7% 2% NS ≥VGPR 45% 17% <0.001 ≥PR 79% 57% <0.001 Responses after first ASCT CR/nCR 26% 14% 0.01 ≥VGPR 71% 44% 0.003 ≥PR 91% 79% 0.003 No significant impact of del(13) or t(4;14) on VGPR or CR/nCR rates

* Significant difference between arms

Phase III: PAD vs. VAD Phase III: PAD vs. VAD

Sonneveld et al. EHA 2009 Abstract 473

Novel agent combinations in elderly patients Novel agent combinations in elderly patients with MM: results from randomized trials with MM: results from randomized trials

Regimens approved in the non- transplant setting (EMEA)

• MPT:

– In 5 European studies, MPT In 5 European studies, MPT was superior to MP for PFS, was superior to MP for PFS, EFS and/or TTP EFS and/or TTP – In 2/5 studies (IFM), MPT was In 2/5 studies (IFM), MPT was superior to MP for OS superior to MP for OS

• VMP:

– Superior to MP for CR, ORR, Superior to MP for CR, ORR, TTP, OS TTP, OS

Regimens not approved in the non-transplant setting (EMEA)

• CTDa:

– Superior to MP for ORR, CR Superior to MP for ORR, CR and PFS (in pts with favorable and PFS (in pts with favorable cytogenetics) cytogenetics)

• RD vs Rd:

RD vs Rd: – Superior 1-year OS for Rd

• MPR+R maintenance:

– MPR+R maintenance superior to MP for CR, ORR, PFS – MPR not superior to MP for PFS

Phase III study of MPV versus MP in previously Phase III study of MPV versus MP in previously untreated multiple myeloma untreated multiple myeloma

San Miguel et al. N Engl J Med. 2008;359:906-17

Phase III MMY-3002 VISTA study

MPV (N = 344) Bortezomib 1.3 mg/m2 on days: cycles 1–4: 1, 4, 8, 11, 22, 25, 29, and 32; cycles 5–9: 1, 8, 22, and 29 + melphalan 9 mg/m2 and prednisone 60 mg/m2 on days 1–4 MP (N = 338) Melphalan 9 mg/m2 and prednisone 60 mg/m2 on days 1–4 R A N D O M I Z A T I O N

682 untreated MM patients ineligible for HDT-SCT from 151 centres in 22 countries

• 9 × 6-week cycles
• 54 weeks treatment
• Stratification for

baseline β2-microglobulin and albumin levels and region

• Primary end-point TTP

CrCl <60 vs ≥60 mL/min2 Age ≥75 vs <75 years1 High-risk (t(4;14), t(14;16), del 17p vs standard-risk cytogenetics by FISH

TTP

Subjects without event (%) Time (months)

Age <75 years (N=237): 23.1 months (59 events) Age ≥75 years (N=107): not reached (24 events) HR=0.956 (95% CI: 0.579, 1.579), p=0.86 Age <75 years Age ≥75 years Standard risk (N=142): 23.1 months (34 events) High risk (N=26): 19.8 months (7 events) HR=1.297 (95% CI: 0.55, 3.06), p=0.55 Standard risk High risk

100 80 60 40 20 2 4 6 8 10 12 14 16 18 20 22 24 26

CrCI ³60 mL/min CrCI <60 mL/min

Subjects without event (%) Time (months) 100 80 60 40 20 2 4 6 8 10 12 14 16 18 20 22 24 26 Subjects without event (%) Time (months) 100 80 60 40 20 2 4 6 8 10 12 14 16 18 20 22 24 26

CrCI ≥60 mL/min (N=159): 21.7 months (43 events) CrCI <60 mL/min (N=185): median not reached (40 events) HR=0.666 (95% CI: 0.416, 1.066), p=0.09

OS

Age <75 years (N=237): median not reached (44 events) Age ≥75 years (N=107): median not reached (31 events) HR=1.572 (95% CI: 0.975, 2.535), p=0.0614 CrCI ≥60 mL/min (N=159): median not reached (31 events) CrCI <60 mL/min (N=185): median not reached (44 events) HR=1.205 (95% CI: 0.725, 2.005), p=0.4714 Standard risk (N=142):median not reached (29 events) High risk (N=26): median not reached (6 events) HR=1.104 (95% CI: 0.444, 2.743), p=0.8311

Survival distribution function Time (months)

Age <75 years Age ≥75 years Standard risk High risk

1.00 0.75 0.50 0.25 0.00

CrCI ³60 mL/min CrCI <60 mL/min

Survival distribution function Survival distribution function 1.00 0.75 0.50 0.25 0.00 1.00 0.75 0.50 0.25 0.00 4 8 12 16 20 24 28 32 36 Time (months) 4 8 12 16 20 24 28 32 36 Time (months) 4 8 12 16 20 24 28 32 36

San Miguel et al. Blood 2008; 112: Abstract 650

VMP (VISTA): subgroup analysis in patients VMP (VISTA): subgroup analysis in patients with poor prognostic characteristics with poor prognostic characteristics

Phase III: VMPT + VT vs. VMP in elderly patients with Phase III: VMPT + VT vs. VMP in elderly patients with newly diagnosed MM – GIMEMA study newly diagnosed MM – GIMEMA study

• Patients (n=511): >65 years old; median age 71 years
• Treatment

Palumbo et al. ASH 2009 (Abstract 128)

VMPT VMP

Maintenance (until relapse):

Bortezomib (1.3 mg/m2 days 1, 15) + Thalidomide (50 mg continuously)

9 x 5-week cycles:* Bortezomib Melphalan Prednisone No maintenance

*Protocol amended partway through study from twice-weekly bortezomib dosing (days 1,4,8,11,22,25,29,32) to once-weekly bortezomib dosing (days 1,8,15,22) 61 patients in VMP arm and 70 patients in VMPT arm received twice-weekly bortezomib dosing

Phase III: VMPT + VT vs. VMP Phase III: VMPT + VT vs. VMP

VMPT + VT (n=250) VMP (n=253) P CR 38% 24% 0.0008 ≥VGPR 59% 50% 0.03 ≥PR 89% 81% 0.01 3-year PFS 60% 42% <0.007 3-year TTNT 75% 60% 0.0029 3-year OS 88.8% 89.2% 0.96

Median follow-up: 21.6 months

Palumbo et al. ASH 2009 (Abstract 128)

VMPT + VT maintenance improves response rates and PFS VMPT + VT maintenance improves response rates and PFS

Comparable PFS in patients with and without t(4;14) or t(14;16)

• r del17

Phase III: VMP vs. VTP in newly diagnosed elderly Phase III: VMP vs. VTP in newly diagnosed elderly patients with MM - (PETHEMA/GEM study) patients with MM - (PETHEMA/GEM study)

• Patients (n=260), >65 years old (median age 73 years)
• Multicenter, two-stage randomized trial

Mateos et al. ASH 2009 (Abstract 3)

VMP VTP vs VT VP VT VP

Randomization step 1 Randomization step 2

vs vs

Induction (max. 6 cycles)

–One 6-week cycle, bortezomib

2x weekly

–Five 5-week cycles,

bortezomib 1x weekly

Maintenance (up to 3 years)

Bortezomib: 1.3 mg/m2 (days 1, 4, 8, 11), every 3 months + thal: 50 mg daily or pred: 50 mg every 48 hours

Phase III: VMP vs. VTP in elderly patients Phase III: VMP vs. VTP in elderly patients

VMP (n=130) VTP (n=130) ORR 80% 81% CR IF- 20% 27% CR IF+ 12% 10% PR 48% 46% Median time to first response 1.6 months1.6 months Median time to CR 4.4 months4.9 months

Response to induction

Mateos et al. ASH 2009 (Abstract 3)

VT (n=91) VP (n=87) ORR 98% 99% CR IF- 44% 39% CR IF+ 15% 16% PR 39% 44%

Response to maintenance therapy Similar efficacy with VMP and VTP Both maintenance regimens increased CR rate

VTP-VP* VTP-VT VMP-VP VMP-VT

45 40 35 30 25 20 15 10 5 1.0 0.8 0.6 0.4 0.2 0.0

PFS

VTP+VP vs VMP+VT HR 1.6, P=0.008

OS

45 40 35 30 25 20 15 10 5 1.0 0.8 0.6 0.4 0.2 0.0

VMP+VT: NR VMP+VP: 32 m VTP+VT : NR VTP+VP: :26.5 m VMP+VT: 88% at 2 y VMP+VP: 88% at 2 y VTP+VT : 84% at 2 y VTP+VP : 81% at 2 y

Cox regression analysis of PFS and OS with inverse probability weghting (P=0.8 for the interaction term)

Outcome of different cohorts (n=178) Outcome of different cohorts (n=178)

Mateos et al. ASH 2009 (Abstract 3)

VMP vs. VTP: Efficacy in high-risk cytogenetic VMP vs. VTP: Efficacy in high-risk cytogenetic abnormalities abnormalities

OS

50 45 40 35 30 25 20 15 10 5 1,0 0,8 0,6 0, 4 0,2 0,0

From 1st randomization

50 45 40 35 30 25 20 15 10 5 1,0 0,8 0,6 0,4 0,2 0,0

PFS

Standard risk: 55% at 2 y High-risk: 58% at 2 y Standard risk: 77% at 2 y High-risk: 74% at 2 y

From 2nd randomization

40 35 30 25 20 15 10 5 1,0 0,8 0,6 0,4 0,2 0,0 40 35 30 25 20 15 10 5 1,0 0,8 0,6 0,4 0,2 0,0

PFS OS

Standard risk: 61% at 2 y High-risk: 58% at 2 y Standard risk: 84% at 2 y High-risk: 82% at 2 y

Mateos et al. ASH 2009 (abstract No 3)

RVD (Lenalidomide + Bortezomib + Dexamethasone) Phase I/II Trial in Newly Diagnosed Multiple Myeloma (MM) Patients

Best Responses (%) to RVD Response Phase I (n=66) Phase II (n=35) CR/nCR 39 57 ≥ VGPR 67 74 ≥ PR 100 100

CR, complete response; nCR, near complete response; PR, partial response; VGPR, very good partial response.

• 57% CR/nCR and 74% VGPR in phase II is very encouraging
• Induction regimen that may allow autologous stem cell transplant (ASCT)

to be kept in reserve

• Favorable tolerability profile (50% Grade 1, 20% Grade 2 neuropathy)

Anderson KC et al. 2010 ASCO. Abstract 8016.

RVD for Newly Diagnosed MM RVD for Newly Diagnosed MM

Poor Cytogenetics* Predict for Inferior PFS in the Poor Cytogenetics* Predict for Inferior PFS in the relapsed/refractory setting relapsed/refractory setting

RD VRD

Dimopoulos et al. Leukemia 2010; in press

*Non-hyperdiploid karyotype or del13q by

metaphase karyotype or del17p or add 1q21 or t(4;14) or t(14;16)

del17 and PFS del17 and PFS

RD VRD

no del17 (n=43) – median PFS 9 months del17 (n=3) – median PFS 2 months no del17 (n=37) – median PFS 9 months del17 (n=7) – median PFS 3 months

Dimopoulos et al. Leukemia 2010; in press

Cytogenetics and Novel Agents: Summary Cytogenetics and Novel Agents: Summary

• Limitations of these studies:

– usually post-hoc subgroup analyses of phase III studies or expanded access programs (no validation in prospective trials) – limited numbers of patients – evaluation of response, but no reporting of TTP, PFS, and OS

• Studies suggest that novel agents may have an effect on high-

risk features: – bortezomib may be able to overcome negative prognosis

• f t(4;14)

– IMiDs clinical data on cytogenetic subgroups controversial – No agent suitable to override del 17p

MYELOMA PATIENTS WITH RENAL IMPAIRMENT

Criteria for the Definition of Renal Response Criteria for the Definition of Renal Response to anti-Myeloma Therapy to anti-Myeloma Therapy

*eGFR based on MDRD equation IMWG guidelines, Dimopoulos et al, J Clin Oncol 2010; in

press

Response BASELINE eGFR* (ml/min/1.73 m2) Best CrCl RESPONE CRrenal <50 ml/min ≥60 ml/min PRrenal <15 ml/min 30-59 ml/min MRrenal <15 ml/min 15-29 ml/min 15-29 ml/min 30-59 ml/min

Phase II prospective study: Phase II prospective study: bortezomib- bortezomib- doxorubicin-dex in renal failure (1) doxorubicin-dex in renal failure (1)

• Patients (n=71) previously treated and untreated
• Treatment

– Bortezomib + doxorubicin + dex

• Results

Ludwig et al. ASH 2009 (Abstract 3862)

CRrenal: GFR ≥60 ml/min, PRrenal: GFR from <15 mL/min at baseline to 30–<60 ml/min during treatment

– Tumor response: ≥VGPR 62%, ORR 84% – Renal response: CRrenal 36%, ORRrenal 72%

• Time to first renal response: 38 days
• Median time to CRrenal: 111 days

– Well tolerated

Phase II prospective study: Phase II prospective study: bortezomib- bortezomib- doxorubicin-dex in renal failure (2) doxorubicin-dex in renal failure (2)

Ludwig et al. ASH 2009 (Abstract 3862)

• Median GFR increased from

20 mL/min to 48.8 mL/min

• Renal response correlated with

tumor response Conclusion

• Improvement of renal function more often seen in patients with significant tumor

response

• CRrenal more likely in patients with less severe renal impairment

140 120 100 80 60 40 20 CR–VGPR (n=36) PR–VMR (n=13) SD–PD (n=9) GFR (mL/min)

Baseline 20 Baseline 24.5 Baseline 11.8 Best GFR 16.8 6.6–57.9 mL/min Best GFR 59.6 14.7–131.3 mL/min Best GFR 38.9 14.7–135.5 mL/min

Median range

Retrospective study: reversibility of renal Retrospective study: reversibility of renal failure and the role of failure and the role of novel agents novel agents

• Overall, 3/9 patients became dialysis-independent; 2/4 in bortezomib arm

Multivariate analysis: bortezomib-based regimens significantly associated with higher renal response rate (p=0.024; HR: 7.0, 95%CI 1.5-25)

• CrCl <30 mL/min associated with significantly lower probability of renal

response in groups A and B (P<0.01), but not in group C (P=0.529)

Roussou et al. Leuk Res 2010;34:1395-7

Median time to renal PR Renal CR + PR Renal CR Group A (conventional chemo + dex- based) (n=32) 1.8 months 47% 41% Group B (IMiD-based) (n=47) 1.6 months 51% 45% Group C (bortezomib-based) (n=17) 0.7 months 82% 71%

• Consecutive patients (n=96) with newly diagnosed MM and RI (CrCI <50 mL/min)

IMiDs in renal impairment/failure IMiDs in renal impairment/failure

Thalidomide

• <1% cleared by kidneys1
• Pharmacokinetics similar in patients

with and without renal failure2

• Use feasible in renal failure

– Efficacy and tolerability similar to patients with normal renal function3,4 – Recovery of renal function in most responsive patients – Case reports of hyperkalemia

1Izzedine et al. Nephrol Dial Transplant 2005;20:2011–2012 2Eriksson et al. J Pharm Pharmacol 2003;55:1701–1706 3Tosi et al. Eur J Haematol 2004;73:98–103 4Tosi et al. IMW 2009: Abstract 174

Lenalidomide

• Primarily excreted by kidneys
• Subanalysis of Phase III len/dex trials5

– Patients with moderate or severe renal impairment respond equally well

• Improvement in renal function seen in

some patients with Len/dex combination6,7

• Increased myelosuppression in patients

with high creatinine levels5,8

• Dose reduction mandatory6-10
• 5. Weber et al. ASCO 2008: Abstract 8542
• 6. Roig et al. ASH 2009 (abstract 1886)
• 7. Dimopoulos et al. ASH 2009 (abstract 3871)
• 8. Reece et al. Blood 2006;108: Abstract 3548
• 9. Revlimid SmPC January 2009
• 10. Chen et al. J Clin Pharmacol 2007;47:1466–1475

Len + Dex is effective in patients with mild to moderate renal insufficiency

MM-009 and MM-010: prospective subgroup analysis

• f MM patients with renal insufficiency

Dimopoulos et al, Cancer 2010;116:3807-14

CR VGPR PR ORR 10 20 30 40 50 60

Patients (%) None Mild Moderate Severe

70 17 13 21 6 14 22 12 31 33 27 26 12 64 64 62 50

Renal function impairment

Renal impairment summary / IMWG guidelines Renal impairment summary / IMWG guidelines

In patients with renal impairment

• Available data support the safety and efficacy of bortezomib-

based therapies in this setting and thus bortezomib plus dexamethasone is the recommended treatment for myeloma patients with renal impairment of any grade.

• Thalidomide is also an option for patients with severe renal

impairment, although data are less extensive. A triple combination of bortezomib, thalidomide and dexamethasone maybe also considered.

• Lenalidomide is a feasible and effective treatment option for

patients with mild-to-moderate renal impairment, if it is used at the recommended reduced dose based on renal function.

Dimopoulos et al. J Clin Oncol 2010; in press.

MYELOMA PATIENTS WITH BONE DISEASE

Baseline NTX is an Independent Prognostic Baseline NTX is an Independent Prognostic Indicator of Death Indicator of Death

Reduced Multivariate 1 2 3 4 5 6 Univariate Univariate Reduced Multivariate .0057 .0120 P value .0033 .0103 NTX ≥ 50 NTX (per 100-unit increment) Relative risk of death 1.79 2.59 2.41 1.93

Terpos et al. Leukemia

Bortezomib Affects Markers of Bone Bortezomib Affects Markers of Bone Resorption and Osteoclast Stimulators Resorption and Osteoclast Stimulators

C= Control; PT = Prior treatment; *After cycle number. P <.001 P =.01 P <.001

sRANKL (pmol/L)

1.4 1.2 1.0 0.8 0.6 0.4 0.2

• 0.2

5 4 3 2 1

• 1

RANKL/OPG ratio

P <.0001 P =.01 P =.01 2.0 1.5 1.0 0.5

• 0.5

5 5 4 4 3 3 2 2 1 1

CTX (ng/mL)

P <.0001 P <.001 P =.001 N = 33 34 32 19 C PT 4* 8*

TRACP-5b (U/L)

N = 33 34 32 19 C PT 4* 8* P <.0001 P <.001 P <.01

Terpos et al. Br J Haematol 2006;135:688-692

Bortezomib Affects Markers of Bone Formation Bortezomib Affects Markers of Bone Formation and Osteoblast Stimulators and Osteoblast Stimulators

C= Control; PT = Prior treatment; *After cycle number.

DKK-1 (ng/mL)

P =.007 P =.035 P =.001

200 150 100 50 bALP (U/L) 200 150 100 50

P <.0001 P <.001 P <.01 N = 33 34 32 19 C PT 4* 8*

OC (ng/mL)

70 60 50 40 30 20 10

• 10

P <.001 P <.01 P <.01 N = 33 34 32 19 C PT 4* 8*

OPG (pmol/L)

11 10 9 8 7 6 5 4 3 2 1 P =.23 P =.24 P =.15

Terpos et al. Br J Haematol 2006;135:688-692

Effect of RD and VRD on Bone Formation Effect of RD and VRD on Bone Formation

after 6 cycles of therapy after 6 cycles of therapy Terpos et al. ASH 2009

BMD: Pre- and Post-bortezomib BMD: Pre- and Post-bortezomib

4/27 patients (14%) showed at least 10% of increase in L1-L4 BMD; all these patients had osteoporosis according to DXA, had responded to VD therapy (3 PR and one CR), and had received VD as second line treatment

Terpos et al. Ann Oncol 2010;21:1561-2

Pre-Bor Post-Bor

BV/TV = 12.85% Tb.Th = 0.1 Tb.Sp. = 0.7 Tb.N. = 1.5 BV/TV = 90% Tb.Th = 0.7 Tb.Sp. = 0.2 Tb.N. = 2.8

Zangari et a EHA 2007 (abstract 69

Patient who received MPV (from VISTA subanalysis Patient who received MPV (from VISTA subanalysis by Delforge et al) by Delforge et al)

A C B D

Summary for the Effect of Bortezomib on Summary for the Effect of Bortezomib on Myeloma Bone Disease Myeloma Bone Disease

• Preclinical and clinical data indicate that bortezomib

reduces bone resorption

• Bortezomib increases also bone formation and BMD in

a subset of myeloma patients. The anabolic bone effect of bortezomib has not been reported with any

• ther anti-myeloma agent.
• Healing of lytic lesion on MRIs has been observed in

patients treated with bortezomib.

• VERY LIMITED DATA IN THE UPFRONT SETTING
• Long-term bortezomib studies with clinical endpoints

(SRE and BMD) are needed

Conclusions Conclusions

• There is no strong prospective data

There is no strong prospective data suggesting the suggesting the risk-adapted therapy in newly diagnosed MM patients. risk-adapted therapy in newly diagnosed MM patients.

• HDM plus ASCT after induction with bortezomib- or

HDM plus ASCT after induction with bortezomib- or IMiD-based regimen is the standard of care for IMiD-based regimen is the standard of care for younger patients (<65 years) while MPT or MPV are the younger patients (<65 years) while MPT or MPV are the preferred treatment options for patients who are not preferred treatment options for patients who are not eligible for ASCT. eligible for ASCT.

• These treatment options are irrespective of the

These treatment options are irrespective of the presence of high-risk myeloma features presence of high-risk myeloma features. .

• We need more data for newly-diagnosed patients with

We need more data for newly-diagnosed patients with renal impairment and with extended bone disease – renal impairment and with extended bone disease – bortezomib-based therapies? bortezomib-based therapies?

• In the future, I wish we will be able to have risk-

In the future, I wish we will be able to have risk- adapted therapy for MM in our effort to better manage adapted therapy for MM in our effort to better manage

• ur patients.
• ur patients.