The 1st World Congress on Controversies in Hematology, Rome 3/9/2010 Should Therapy for Newly Diagnosed Multiple Myeloma Be Risk Adapted? Evangelos Terpos, MD University of Athens School of Medicine, Athens, Greece
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 + Melphalan + prednisolone (MP) dexamethasone (VAD) ‡ or Cyclophosphamide ± prednisolone* VAD-based regimen ( NOT ANYMORE ) Melphalan + prednisolone + thalidomide (MPT)* ‡ Thalidomide + dexamethasone,* ‡ T-VAD, ‡ other combinations Melphalan + prednisolone + bortezomib (MPV) ‡‡ Proteasome inhibitors (Bortezomib)- based regimens ‡ IMiDs (lenalidomide, pomalidomide) * 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 • β 2 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 1,376 patients 50 10-year relative survival (%) Survival of patients ≤70 years 45 Survival of patients >70 years <50 40 35 30 50–59 25 median OS: 33 months vs. 20 26 months; p=0.27 60–69 15 median OS: 74 months vs. 39 months; p<0.001 70–79 10 80+ 5 0 1984– 1987– 1990– 1993– 1996– 1999– 2002– 1986 1989 1992 1995 1998 2001 2004 Calendar period Brenner et al. Blood 2008;111:2521–26 Kastritis et al. Leukemia 2009;23:1152–7
Prognostic impact of t(4;14) / del(17p) with ISS Prognostic impact of t(4;14) / del(17p) with ISS - IMWG analysis - IMWG analysis 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 100% 80% 60% 40% 20% 0% 0 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) Avet-Loiseau et al . ASH 2009 (Abstract 749)
mSMART : Classification of Active MM mSMART : Classification of Active MM High-Risk (25%) Standard-Risk (75%) * FISH All others including: Del 17p t(4;14)* Hyperdiploid t(14;16) t(11;14) Cytogenetic Deletion 13 t(6;14) Cytogenetic hypodiploidy PCLI >3% *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 of high risk cytogenetic abnormalities of high risk cytogenetic abnormalities Regimen Results Reference (ASH 2009 abstract #) Zamagni 349 Thal/dex Thal/dex upfront does not overcome del13, t(4;14) or del17 CTD Morgan 352 Adverse FISH [t(4;14), t(14;16), t(14;20), 1p-, 1q+, 17p-] associated with reduced PFS and OS Thal maintenance In adverse FISH group, thal maintenance results in significantly reduced OS Survival from relapse impaired after thal maintenance, particularly in adverse FISH group
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 of 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 (IFM2005-01) IFM2005-01) Phase 3: VD vs. VAD ( Median follow-up 32.2 months Response data PFS VAD VD VAD VD P ≥ nCR PFS in all pts 30 months 36 months 0.057 Induction 7% 15% PFS in patients 23 months 33 months 0.006 ASCT 1 18% 35% with ISS 2 & 3 ASCT 2 32% 39% PFS in pts with 24 months 33 months 0.113 t(4;14) +/- del17 ≥ VGPR Induction 16% 39% ASCT 1 37% 54% ASCT 2 47% 68% Harousseau et al. ASH 2009 (abstract 353)
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 MM Stage II or III, Age 18–65 Randomization 3 x VAD 3 x PAD CAD + GCSF CAD + GCSF MEL 200 + PBSCT MEL 200 + PBSCT Depending on local Depending on local policy Allogeneic policy for patients ≥ PR for patients ≥ PR MEL Tx MEL 200 + PBSCT 200 + PBSCT Thalidomide Bortezomib 50 mg/day for 1.3 mg/m 2 / 2 weeks for 2 years maintenance 2 years maintenance Sonneveld et al. EHA 2009 Abstract 473
Phase III: PAD vs. VAD Phase III: PAD vs. VAD 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 * Significant difference between arms No significant impact of del(13) or t(4;14) on VGPR or CR/nCR rates 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- Regimens not approved in the transplant setting (EMEA) non-transplant setting (EMEA) • MPT: • CTDa: – In 5 European studies, MPT – Superior to MP for ORR, CR In 5 European studies, MPT Superior to MP for ORR, CR was superior to MP for PFS, and PFS (in pts with favorable was superior to MP for PFS, and PFS (in pts with favorable EFS and/or TTP cytogenetics) EFS and/or TTP cytogenetics) – In 2/5 studies (IFM), MPT was In 2/5 studies (IFM), MPT was • RD vs Rd: superior to MP for OS RD vs Rd: superior to MP for OS – Superior 1-year OS for Rd • VMP: – Superior to MP for CR, ORR, • MPR+R maintenance: Superior to MP for CR, ORR, – MPR+R maintenance superior TTP, OS TTP, OS 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 Phase III MMY-3002 VISTA study R MPV (N = 344) A Bortezomib 1.3 mg/m 2 on • 9 × 6-week cycles N days: cycles 1–4: 1, 4, 8, 11, D 22, 25, 29, and 32; cycles 682 untreated • 54 weeks treatment O 5–9: 1, 8, 22, and 29 MM patients M + melphalan 9 mg/m 2 and • Stratification for ineligible for I prednisone 60 mg/m 2 on baseline HDT-SCT from Z days 1–4 β 2 -microglobulin and 151 centres in A albumin levels and T 22 countries region I MP (N = 338) O Melphalan 9 mg/m 2 and • Primary end-point TTP N prednisone 60 mg/m 2 on days 1–4 San Miguel et al. N Engl J Med. 2008;359:906-17
VMP (VISTA): subgroup analysis in patients VMP (VISTA): subgroup analysis in patients with poor prognostic characteristics with poor prognostic characteristics OS TTP 1.00 100 Survival distribution Subjects without 80 0.75 Age <75 years function event (%) Age <75 years 60 Age ≥ 75 years Age ≥ 75 years 0.50 Age ≥75 vs 40 Age <75 years (N=237): median not reached (44 events) <75 years 1 Age <75 years (N=237): 23.1 months (59 events) 0.25 Age ≥ 75 years (N=107): median not reached (31 events) 20 Age ≥ 75 years (N=107): not reached (24 events) HR=1.572 (95% CI: 0.975, 2.535), p=0.0614 HR=0.956 (95% CI: 0.579, 1.579), p=0.86 0.00 0 0 4 8 12 16 20 24 28 32 36 0 2 4 6 8 10 12 14 16 18 20 22 24 26 Time (months) Time (months) 1.00 Survival distribution 100 0.75 CrCI ³60 mL/min function Subjects without 80 CrCI <60 mL/min 0.50 CrCI ³60 mL/min event (%) 60 CrCI <60 mL/min CrCI ≥ 60 mL/min (N=159): median not reached (31 events) CrCl <60 vs 0.25 CrCI <60 mL/min (N=185): median not reached (44 events) 40 ≥60 mL/min 2 HR=1.205 (95% CI: 0.725, 2.005), p=0.4714 CrCI ≥ 60 mL/min (N=159): 21.7 months (43 events) 20 0.00 CrCI <60 mL/min (N=185): median not reached (40 events) 0 4 8 12 16 20 24 28 32 36 HR=0.666 (95% CI: 0.416, 1.066), p=0.09 0 Time (months) 0 2 4 6 8 10 12 14 16 18 20 22 24 26 1.00 Time (months) Survival distribution 0.75 Standard risk 100 function High risk 0.50 Subjects without 80 High-risk Standard risk Standard risk (N=142):median not reached (29 events) event (%) 60 0.25 High risk (N=26): median not reached (6 events) High risk (t(4;14), HR=1.104 (95% CI: 0.444, 2.743), p=0.8311 t(14;16), del 17p 40 0.00 vs standard-risk Standard risk (N=142): 23.1 months (34 events) 20 0 4 8 12 16 20 24 28 32 36 cytogenetics by High risk (N=26): 19.8 months (7 events) 0 Time (months) HR=1.297 (95% CI: 0.55, 3.06), p=0.55 FISH 0 2 4 6 8 10 12 14 16 18 20 22 24 26 San Miguel et al. Blood 2008; 112: Abstract 650 Time (months)
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