Treatment of Multiple Myeloma with Stem Cell ... lwm/ppt pdf/Akpek … · Treatment of Multiple...
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Treatment of Multiple Myeloma with Stem Cell Transplantation (SCT) Görgün Akpek, MD, MHS Director, SCT and Cellular Therapy Program Banner MD Anderson Cancer Center [email protected]
Transcript of Treatment of Multiple Myeloma with Stem Cell ... lwm/ppt pdf/Akpek … · Treatment of Multiple...
Treatment of Multiple Myeloma with Stem Cell Transplantation (SCT)
Görgün Akpek, MD, MHS Director, SCT and Cellular Therapy Program
Banner MD Anderson Cancer Center
MULTIPLE MYELOMA Plasma cell neoplasm
Malignant plasma cell proliferation in the BM Monoclonal Immunoglobulin (or light chain) in serum + urine
Multiple Myeloma Presenting Features
98% >40 years old 61% Males 79% Skeletal X-ray abnormalities 68% Bone pain 62% Anemia 55% Renal Insufficiency 30% Hypercalcemia 88% Proteinuria 49% Bence Jones Proteinuria 21% Hepatomegaly 5% Splenomegaly Kyle RA, Mayo Clin Proc 1975:50:29
Life expectancy is doubled in myeloma Now, average 7 years after diagnosis
Kumar S K et al. Blood 2008;111:2516-20
Longer survival is directly related to depth of response to therapy
• Complete response (CR): No detectable disease
• Partial response (PR): Still detectable disease
• No response: Poor outcome
Presenter
Presentation Notes
Overall survival from diagnosis of multiple myelomas. (A) The Kaplan-Meier curves for overall survival from diagnosis. The groups were divided based on the date of diagnosis: within last decade (after December 31, 1996) versus on or before December 31, 1996. (B) The Kaplan-Meier curves for overall survival from the time of diagnosis grouped into 6-year intervals based on the date of diagnosis.
Improvement in survival of patients with myeloma is multifactorial
• Initial (Induction) Therapy (2-4 months) • Stem Cell Transplantation (Highest CR rate) • Post-transplant Consolidation and Maintenance (Some
additional benefit) • Supportive Care (Critical) • Treatment of Relapsed Disease (Possible but expensive)
Stem Cell Donor Selection
• Autologous (from patients) • Matched Sibling/Related Donor (MRD) • Matched Unrelated Donor (MUD) • Cord Blood Unit (>4/6 match with adequate cell dose) • Mismatched Related/Unrelated (MMURD) • Haploidentical (parent or child) • Source of Stem Cells
– Peripheral Blood Stem cells • Shorter time to engraftment
– Bone Marrow Stem Cells • Less chronic GVH
How do we perform Stem Cell Transplantation?
Patients are initially treated to reduce myeloma cells in BM Stem cells are
mobilized from bone marrow into blood collected by apheresis processed & frozen in vaporized liquid nitrogen containers (-200 C)
Patients are treated with high dose Melphalan chemotherapy Stem cells are thawed at the bedside and infused to the
patients like a blood transfusion (Day 0) Stem cells grow in the empty but intact marrow and give rise
new blood cells within 2 weeks Patients are discharged home and followed in the clinic
Appelbaum F. N Engl J Med 2007;357:1472-1475
History of Hematopoietic Stem Cell Transplantation
Indications for Hematopoietic Stem Cell Transplants in the United States, 2009
Num
ber
of T
rans
plan
ts
0
500
1,000
1,500
2,000
2,500
3,000
3,500
4,000
4,500
5,000
5,500
Multiple Myeloma
NHL AML HD ALL MDS/MPD Aplastic Anemia
CML Other Leuk
Non- Malig
Disease
Other Cancer
Allogeneic (Total N=7,012) Autologous (Total N=9,778)
<65
Blood 2005 Stem cell transplant adds one more year to patient survival
Presenter
Presentation Notes
The IFM90 study randomized 200 patients to standard (conventional) chemotherapy or HDT with ASCT (Attal et al). EFS and OS were significantly longer in the HDT arm A prospective, randomized trial of autologous bone marrow transplantation and chemotherapy in multiple myeloma. Intergroupe Français du Myélome. Attal M, Harousseau JL, Stoppa AM, Sotto JJ, Fuzibet JG, Rossi JF, Casassus P, Maisonneuve H, Facon T, Ifrah N, Payen C, Bataille R. Department of Hematology, Hôpital Purpan, Toulouse, France. Comment in: Abstract BACKGROUND: The median survival of patients with myeloma after conventional chemotherapy is three years or less. Promising results have been reported with high-dose therapy supported by autologous bone marrow transplantation. We conducted a randomized study comparing conventional chemotherapy and high-dose therapy. METHODS: Two hundred previously untreated patients under the age of 65 years who had myeloma were randomly assigned at the time of diagnosis to receive either conventional chemotherapy or high-dose therapy (Mel 140 + TBI 800 cGy) and autologous bone marrow transplantation. RESULTS: The response rate among the patients who received high-dose therapy was 81 percent (including complete responses in 22 percent and very good partial responses in 16 percent), whereas it was 57 percent (complete responses in 5 percent and very good partial responses in 9 percent) in the group treated with conventional chemotherapy (P < 0.001). The probability of event-free survival for five years was 28 percent in the high-dose group and 10 percent in the conventional-dose group (P = 0.01); the overall estimated rate of survival for five years was 52 percent in the high-dose group and 12 percent in the conventional-dose group (P = 0.03). Treatment-related mortality was similar in the two groups. CONCLUSIONS: High-dose therapy combined with transplantation improves the response rate, event-free survival, and overall survival in patients with myeloma. J Clin Oncol. 2005 Dec 20;23(36):9227-33. Epub 2005 Nov 7. High-dose therapy and autologous blood stem-cell transplantation compared with conventional treatment in myeloma patients aged 55 to 65 years: long-term results of a randomized control trial from the Group Myelome-Autogreffe. Fermand JP, Katsahian S, Divine M, Leblond V, Dreyfus F, Macro M, Arnulf B, Royer B, Mariette X, Pertuiset E, Belanger C, Janvier M, Chevret S, Brouet JC, Ravaud P; Group Myelome-Autogreffe. Immuno-Hematology Unit and Department of Biostatistics, Hôpital Saint Louis, Paris, France. [email protected] Abstract PURPOSE: To study the impact of high-dose therapy (HDT) with autologous stem-cell support in patients with symptomatic multiple myeloma (MM) between the ages of 55 and 65 years. PATIENTS AND METHODS: One hundred ninety patients between 55 and 65 years old who had newly diagnosed stage II or III MM were randomly assigned to receive either conventional chemotherapy (CCT; ie, monthly courses of a regimen of vincristine, melphalan, cyclophosphamide, and prednisone) or HDT and autologous blood stem-cell transplantation (using either melphalan alone 200 mg/m(2) intravenous [IV] or melphalan 140 mg/m(2) IV plus busulfan 16 mg/kg orally as pretransplantation cytoreduction). RESULTS: Within a median follow-up of 120 months, median event-free survival (EFS) times were 25 and 19 months in the HDT and CCT groups, respectively. Median overall survival (OS) time was 47.8 months in the HDT group compared with 47.6 months in the CCT group. A trend to better EFS (P = .07) was observed in favor of HDT, whereas OS curves were not statistically different (P = .91). The period of time without symptoms, treatment, and treatment toxicity (TwiSTT) was significantly longer for the HDT patients than for the CCT patients (P = .03). CONCLUSION: With a median follow-up time of approximately 10 years, this randomized trial confirmed a benefit of HDT in terms of EFS and TwiSTT but did not provide evidence for superiority of HDT over CCT in OS of patients aged 55 to 65 years with symptomatic newly diagnosed MM. PMID: 16275936 [PubMed - indexed for MEDLINE] High-dose therapy intensification compared with continued standard chemotherapy in multiple myeloma patients responding to the initial chemotherapy: long-term results from a prospective randomized trial from the Spanish cooperative group PETHEMA. Bladé J, Rosiñol L, Sureda A, Ribera JM, Díaz-Mediavilla J, García-Laraña J, Mateos MV, Palomera L, Fernández-Calvo J, Martí JM, Giraldo P, Carbonell F, Callís M, Trujillo J, Gardella S, Moro MJ, Barez A, Soler A, Font L, Fontanillas M, San Miguel J; Programa para el Estudio de la Terapéutica en Hemopatía Maligna (PETHEMA). Hematology Department, Hospital Clínic, IDIBAPS, Villarroel 170, 08036 Barcelona, Spain. [email protected] Abstract The aim of the present randomized trial was to compare high-dose therapy (HDT) with continued conventional chemotherapy in patients with multiple myeloma (MM) who responded to the initial treatment. From May 1994 to October 1999, 216 patients (122 men/94 women; stage II or III; Eastern Cooperative Oncology Group [ECOG] score less than 3) entered the study. Initial chemotherapy consisted of 4 cycles of alternating vincristine, BCNU, melphalan, cyclophosphamide, prednisone/vincristine, BCNU, Adriamycin, dexamethasone (VBMCP/VBAD). Responding patients were randomly assigned to receive 8 additional cycles of VBMCP/VBAD, intensification with melphalan 200 mg/m2, or melphalan 140 mg/m2 plus 12 Gy fractionated total body irradiation (TBI). One-hundred sixty-four patients were randomly assigned, 83 to continued chemotherapy and 81 to HDT. The complete remission (CR) rate was significantly higher with HDT (30% vs 11%; P = .002). However, progression-free survival (PFS) was not significantly different between HDT and conventional therapy (median, 42 vs 33 months; P = not significant [NS]), and overall survival (OS) was similar in both groups (median, 61 vs 66 months). Finally, survival after relapse was identical in the 2 arms (15.9 vs 16.4 months). In conclusion, these results show that HDT intensification, when given to myeloma patients who have responded to the initial chemotherapy, significantly increases the CR rate but has no significant impact on PFS or OS. The MRC7 trial (Child et al) comparing ABCM with C-VAMP followed by HDT also showed significantly longer EFS and OS in the HDT arm. High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma. Child JA, Morgan GJ, Davies FE, Owen RG, Bell SE, Hawkins K, Brown J, Drayson MT, Selby PJ; Medical Research Council Adult Leukaemia Working Party. Academic Unit of Haematology and Oncology, Cancer Research United Kingdom Clinical Centre, University of Leeds, Leeds, United Kingdom. [email protected] Comment in: Abstract BACKGROUND: High-dose therapy with supporting autologous stem-cell transplantation remains a controversial treatment for cancer. In multiple myeloma, first-line regimens incorporating high-dose therapy yield higher remission rates than do conventional-dose treatments, but evidence that this translates into improved survival is limited. METHODS: In this multicenter study, the Medical Research Council Myeloma VII Trial, we randomly assigned 407 patients with previously untreated multiple myeloma who were younger than 65 years of age to receive either standard conventional-dose combination chemotherapy or high-dose therapy (Mel 200) and an autologous stem-cell transplant. RESULTS: Among the 401 patients who could be evaluated, the rates of complete response were higher in the intensive-therapy group than in the standard-therapy group (44 percent vs. 8 percent, P<0.001). The rates of partial response were similar (42 percent and 40 percent, respectively; P=0.72), and the rates of minimal response were lower in the intensive-therapy group than in the standard-therapy group (3 percent vs. 18 percent, P<0.001). Intention-to-treat analysis showed a higher rate of overall survival (P=0.04 by the log-rank test) and progression-free survival (P<0.001) in the intensive-therapy group than in the standard-therapy group. As compared with standard therapy, intensive treatment increased median survival by almost 1 year (54.1 months [95 percent confidence interval, 44.9 to 65.2] vs. 42.3 months [95 percent confidence interval, 33.1 to 51.6]). There was a trend toward a greater survival benefit in the group of patients with a poor prognosis, as defined by a high beta2-microglobulin level (more than 8 mg per liter). CONCLUSIONS: High-dose therapy with autologous stem-cell rescue is an effective first-line treatment for patients with multiple myeloma who are younger than 65 years of age. These results are consistent with those of a population-based historical case control study from the Nordic Myeloma Study Groups, which included 70% of all patients in the relevant age range (Lenhoff et al) Attal M et al. N Engl J Med. 1996;335:91 Fermand J et al. Blood. 1998;92:3131 Bladé J et al. Blood. 2005; Child JA et al. N Engl J Med. 2003;348:1875
Why Stem Cell Transplant in the Era of Novel Therapy?
• Safer than before – Deaths due to transplant 1-2% (was 3-5%)
• Improves outcome when combined with newer agents – Doubles CR rate 30-35% (Harousseau J, JCO 2010, Cavo M,
Lancet 2010) – More durable responses (remission of disease)
– Probably still longer overall survival with SCT
• Longer duration of remission and better Quality of Life with upfront (early) Stem Cell Transplant
• Cumulative cost of SCT is similar to novel agents x 6 mos
Presenter
Presentation Notes
*<1% at MDACC median F/U of 12 years in TT1 (Zangari et al. BJH 2008) After initial 4-6 weeks, not meds or prophylactic anticoag; neuropathy improves
Why early SCT is recommended?
Chemotherapy or Novel agent therapy alone (No transplant)
Early transplant R R R R
R R R R
R = Recurrence of Myeloma
65%
35%
R R
How can we further improve transplant outcomes?
• Planned Tandem (double) transplants – Select cases
• Consolidation therapy after initial transplant – Some centers
• Maintenance therapy – Cost/benefit ratio is high
• Reduced intensity allogeneic transplantation – Benefit in select cases
• New Preparative Regimens – Needed
4643
Somewhat higher CR rate and questionable survival benefit with double SCT
Presenter
Presentation Notes
Single vs Double ASCT for Newly Diagnosed MM Single vs double autotransplantation in newly diagnosed MM patients was compared OS advantage for double transplantation was only seen in the IFM94 trial Differences among the studies are likely due to differences in study design, enrollment criteria, baseline patient characteristics, HDT administered prior to ASCT, and response criteria Attal M et al. N Engl J Med. 2003;349:2495 (Mel 140/TBI vs. Mel 140 (TP1) and Mel140/TBI (TP2)) Single versus double autologous stem-cell transplantation for multiple myeloma. Attal M, Harousseau JL, Facon T, Guilhot F, Doyen C, Fuzibet JG, Monconduit M, Hulin C, Caillot D, Bouabdallah R, Voillat L, Sotto JJ, Grosbois B, Bataille R; InterGroupe Francophone du Myélome. Department of Hematology and Biostatistics, Hôpital Purpan, Toulouse, France. [email protected] Erratum in: Comment in: Abstract BACKGROUND: We conducted a randomized trial of the treatment of multiple myeloma with high-dose chemotherapy followed by either one or two successive autologous stem-cell transplantations. METHODS: At the time of diagnosis, 399 previously untreated patients under the age of 60 years were randomly assigned to receive a single or double transplant. RESULTS: A complete or a very good partial response was achieved by 42 percent of patients in the single-transplant group and 50 percent of patients in the double-transplant group (P=0.10). The probability of surviving event-free for seven years after the diagnosis was 10 percent in the single-transplant group and 20 percent in the double-transplant group (P=0.03). The estimated overall seven-year survival rate was 21 percent in the single-transplant group and 42 percent in the double-transplant group (P=0.01). Among patients who did not have a very good partial response within three months after one transplantation, the probability of surviving seven years was 11 percent in the single-transplant group and 43 percent in the double-transplant group (P<0.001). Four factors were significantly related to survival: base-line serum levels of beta2-microglobulin (P<0.01) and lactate dehydrogenase (P<0.01), age (P<0.05), and treatment group (P<0.01). CONCLUSIONS: As compared with a single autologous stem-cell transplantation after high-dose chemotherapy, double transplantation improves overall survival among patients with myeloma, especially those who do not have a very good partial response after undergoing one transplantation. Fermand JP et al. Hematol J. 2003;4(suppl 1):S59 ** Abstract only Sonneveld P et al. Haematologica. 2007;92:928 Intermediate-dose melphalan compared with myeloablative treatment in multiple myeloma: long-term follow-up of the Dutch Cooperative Group HOVON 24 trial. Sonneveld P, van der Holt B, Segeren CM, Vellenga E, Croockewit AJ, Verhoe GE, Cornelissen JJ, Schaafsma MR, van Oers MH, Wijermans PW, Westveer PH, Lokhorst HM; Dutch-Belgian Hemato-Oncology Cooperative Group (HOVON). Erasmus Medical Center Rotterdam, The Netherlands. [email protected] Abstract BACKGROUND AND OBJECTIVES: The Dutch-Belgian HOVON group performed a randomized phase 3 trial to compare single non-myeloablative intensive treatment with double, intensive treatment in previously untreated patients with multiple myeloma (MM). DESIGN AND METHODS: Three hundred and three patients with stage II/III MM were randomized after VAD induction chemotherapy to receive two cycles of non-myeloablative intermediate-dose melphalan (70 mg/m2) (single treatment) or the same regimen followed by cyclophosphamide 120 mg/kg iv plus total body irradiation (TBI) 9 Gy and autologous stem cell transplantation (double, intensive treatment). In both treatment arms interferon .IIa was given as maintenance until relapse/progression. RESULTS: A significantly higher proportion of patients achieved a complete remission (CR) on protocol treatment with double, intensive therapy (32 % vs 13 %, p<0.001). Double treatment produced better outcome in terms of event-free survival (median 22 vs 21 months, 28% vs 14% at 4 years and 15% vs 7% at 6 years after randomization; logrank p=0.013; univariate HR 0.74, 95% CI, 0.58-0.94), progression-free survival (median 27 vs 24 months, 33% vs 16% at 4 years, and 17% vs 9% at 6 years after randomization; logrank p=0.006; HR=0.71, 95% CI 0.56-0.91), but not overall survival (median 50 vs 55 months, 52% vs 56% at 4 years and 39% vs 36% at 6 years after randomization; logrank p=0.51; HR=1.10, 95% CI 0.83-1.46). The achievement of a CR had a favorable prognostic impact on event-free survival (HR=0.60 , 95% CI=0.44 -0.82 , p=0.001) and progression-free survival (HR=0.62 , 95% CI=0.45 -0.84, p=0.002). INTERPRETATION AND CONCLUSIONS: Double, intensive treatment resulted in a better CR rate, event-free survival and progression-free survival but not overall survival compared to single non-myeloablative treatment in previously untreated patients with multiple myeloma. Cavo M et al. J Clin Oncol. 2007;25:2434 (Mel 200 vs. Mel 200 and Mel 120/Bu 12mg/kg) Prospective, randomized study of single compared with double autologous stem-cell transplantation for multiple myeloma: Bologna 96 clinical study. Cavo M, Tosi P, Zamagni E, Cellini C, Tacchetti P, Patriarca F, Di Raimondo F, Volpe E, Ronconi S, Cangini D, Narni F, Carubelli A, Masini L, Catalano L, Fiacchini M, de Vivo A, Gozzetti A, Lazzaro A, Tura S, Baccarani M. Istituto di Ematologia ed Oncologia Medica [Seràgnoli], Università di Bologna, Bologn, Italy. [email protected] Abstract PURPOSE: We performed a prospective, randomized study of single (arm A) versus double (arm B) autologous stem-cell transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma (MM). PATIENTS AND METHODS: A total of 321 patients were enrolled onto the study and were randomly assigned to receive either a single course of high-dose melphalan at 200 mg/m2 (arm A) or melphalan at 200 mg/m2 followed, after 3 to 6 months, by melphalan at 120 mg/m2 and busulfan at 12 mg/kilogram (arm B). RESULTS: As compared with assignment to the single-transplantation group (n = 163 patients), random assignment to receive double ASCT (n = 158 patients) significantly increased the probability to attain at least a near complete response (nCR; 33% v 47%, respectively; P = .008), prolonged relapse-free survival (RFS) duration of 18 months (median, 24 v 42 months, respectively; P < .001), and significantly extended event-free survival (EFS; median, 23 v 35 months, respectively; P = .001). Administration of a second transplantation and of novel agents for treating sequential relapses in up to 50% of patients randomly assigned to receive a single ASCT likely contributed to prolong the survival duration of the whole group, whose 7-year rate (46%) was similar to that of the double-transplantation group (43%; P = .90). Transplantation-related mortality was 3% in arm A and 4% in arm B (P = .70). CONCLUSION: In comparison with a single ASCT as up-front therapy for newly diagnosed MM, double ASCT effected superior CR or nCR rate, RFS, and EFS, but failed to significantly prolong overall survival. Benefits offered by double ASCT were particularly evident among patients who failed at least nCR after one autotransplantation.
The study was not statistically powered to evaluate this difference
We probably don’t need to do second transplant in all patients
Presenter
Presentation Notes
OS According to Presence/Absence of VGPR at First ASCT Attal et al determined that the effect of a single or a double ASCT on OS differed according to the response achieved 3 months after the first ASCT Only patients who did not have at least a VGPR after the first ASCT had a significant benefit from the second ASCT. The rates of survival at 7 years were 11% in the single-ASCT group vs 43% in the double-ASCT group (P<.001). Patients who had ≥VGPR did not benefit significantly from the second ASCT (P=.70) Attal M et al. N Engl J Med. 2003;349:2495
Post-transplant Consolidation Therapy
• Short-term multiagent treatment after auto-HCT to improve the depth of response
• It is associated with – Improvement in CR – Improvement in PFS
• Cavo M et al. Blood 2012
• Consider in select high risk cases who have less than CR after auto-SCT and not eligible to undergo tandem SCT (Medicare patients).
Presenter
Presentation Notes
Blood. 2012 Jul 5;120(1):9-19. doi: 10.1182/blood-2012-02-408898. Epub 2012 Apr 12. Bortezomib-thalidomide-dexamethasone is superior to thalidomide-dexamethasone as consolidation therapy after autologous hematopoietic stem cell transplantation in patients with newly diagnosed multiple myeloma. Cavo M, Pantani L, Petrucci MT, Patriarca F, Zamagni E, Donnarumma D, Crippa C, Boccadoro M, Perrone G, Falcone A, Nozzoli C, Zambello R, Masini L,Furlan A, Brioli A, Derudas D, Ballanti S, Dessanti ML, De Stefano V, Carella AM, Marcatti M, Nozza A, Ferrara F, Callea V, Califano C, Pezzi A, Baraldi A, Grasso M, Musto P, Palumbo A; GIMEMA (Gruppo Italiano Malattie Ematologiche dell'Adulto) Italian Myeloma Network. Collaborators (142) Source Istituto di Ematologia Seràgnoli, Università degli Studi di Bologna, Policlinico S. Orsola-Malpighi, Bologna, Italy. [email protected] Abstract In a randomized, phase 3 study, superior complete/near-complete response (CR/nCR) rates and extended progression-free survival were demonstrated with bortezomib-thalidomide-dexamethasone (VTD) versus thalidomide-dexamethasone (TD) as induction therapy before, andconsolidation after, double autologous stem cell transplantation for newly diagnosed myeloma patients (intention-to-treat analysis; VTD, n = 236; TD, n = 238). This per-protocol analysis (VTD, n = 160; TD, n = 161) specifically assessed the efficacy and safety of consolidation with VTD or TD. Before starting consolidation, CR/nCR rates were not significantly different in the VTD (63.1%) and TD arms (54.7%). After consolidation, CR (60.6% vs 46.6%) and CR/nCR (73.1% vs 60.9%) rates were significantly higher for VTD-treated versus TD-treated patients. VTD consolidation significantly increased CR and CR/nCR rates, but TD did not (McNemar test). With a median follow-up of 30.4 months from start of consolidation, 3-year progression-free survival was significantly longer for the VTD group (60% vs 48% for TD). Grade 2 or 3 peripheral neuropathy (8.1% vs 2.4%) was more frequent with VTD (grade 3, 0.6%) versus TD consolidation. The superior efficacy of VTD versus TD as induction was retained despite readministration as consolidation therapy after double autologous transplantation. VTD consolidation therapy significantly contributed to improved clinical outcomes observed for patients randomly assigned to the VTD arm of the study. The study is registered at www.clinicaltrials.gov as #NCT01134484.
Maintenance Therapy after Transplant
• Thalidomide – Attal et al. Blood 2006 (597 patients)
• Observation vs. Pamidronate vs. Thalidomide • 3-year EFS: 38, 39 and 51% • 4-year OS: 77, 74 and 87%
– Spencer et al. JCO 2009 (269 patients) • Prednisolone vs. Thalidomide + Prednisolone • 3-year PFS: 23 vs. 42% • 3-year OS: 75 vs. 86%
– 1 trial (MRC IX) showed improvement in PFS but not OS • Morgan GI et al. Blood 2012
Presenter
Presentation Notes
IFN-a. Cunningham D et al; Br J Haematol 1998 Jul;102(2):495-502. High-dose chemotherapy (melphalan) with autologous marrow stem cell support (AMSCS) results in high response rates in multiple myeloma (MM), with up to 50% of patients achieving complete remission. However, these remissions are generally not durable. As the cytokine interferon alpha has been shown to prolong partial response following conventional chemotherapy, this trial was conducted to evaluate its role following high-dose chemotherapy. 85 patients were randomly assigned to maintenance treatment with interferon alpha, 3 x 10(6) units/m2 subcutaneously three times weekly until relapse or no further treatment following recovery from high-dose chemotherapy (melphalan 140-200 mg/m2 or busulphan 16 mg/kg) combined with AMSCS. At 5.8 years following the accrual of the last patient in this trial, 38 patients had died, 17 in the interferon arm and 21 in the control arm. The median progression-free survival (PFS) in the 42 patients randomized to interferon alpha was 46 months versus 27 months in the controls. Both overall survival and PFS, which were highly significant at median follow-up of 52 months, have now ceased to be significant, because most patients have ultimately succumbed to their disease. Interferon was tolerated by the majority of patients with very good compliance. Toxicity consisted mainly of flu-like symptoms and malaise which were usually self-limiting. The results of such a pilot study should be carefully interpreted and the benefits of interferon should be confirmed in larger multicentre studies in the setting of minimal residual disease following autologous transplantation. Barlogie B et al; J Clin Oncol. 2006 Feb 20;24(6):929-36. Epub 2006 Jan 23. PURPOSE: Results of a prospective randomized trial conducted by the Intergroupe Francais du Myelome (IFM 90) indicated that autologous hematopoietic cell-supported high-dose therapy (HDT) effected higher complete response rates and extended progression-free survial (PFS) and overall survival (OS) compared with standard-dose therapies (SDT) for patients with multiple myeloma (MM). PATIENTS AND METHODS: In 1993, three North American cooperative groups launched a prospective randomized trial (S9321) comparing HDT (melphalan [MEL] 140 mg/m2 plus total-body irradiation 12 Gy) with SDT using the vincristine, carmustine, MEL, cyclophosphamide, and prednisone regimen. Responders on both arms (> or = 75%) were randomly assigned to interferon (IFN) or no maintenance treatment. RESULTS: With a median follow-up time of 76 months, no differences were observed in response rates between the two study arms (HDT, n = 261 patients; SDT, n = 255 patients). Similarly, PFS and OS durations did not differ between the HDT and SDT arms, with 7-year estimates of PFS of 17% and 16%, respectively, and OS of 37% and 42%, respectively. Of 242 patients achieving at least 75% tumor reduction, no difference was observed in PFS or OS among the 121 patients randomly assigned to IFN and the 121 patients randomly assigned to no maintenance therapy. Among 157 patients relapsing on SDT, 87 received a salvage autotransplantation; their median survival time of 30 months was only slightly better than the survival time of the remaining patients who were managed with further SDT (23 months; P = .13). CONCLUSION: The HDT and SDT regimens used in S9321 yielded comparable response rates and PFS and OS durations. IFN maintenance therapy did not benefit patients who achieved > or = 75% tumor reduction on either arm. Thalidomide Intergroupe Francophone du Myelome (IFM) trial — A prospective randomized trial of 597 myeloma patients younger than 65 years who had undergone tandem autologous HCT for standard risk myeloma randomly assigned treatment with no maintenance (arm A), pamidronate (90 mg IV every 4 weeks, arm B), or pamidronate plus thalidomide (mean dose 200 mg/day PO, arm C) two months after completing the second transplant [Attal et al. Blood 2006]. Results included: - A complete or very good partial response was achieved in 55, 57, and 67 percent of patients in arms A, B, and C, respectively. - The 3-year rates of relapse-free survival for these three arms were 38, 39, and 51 percent, respectively - Estimated 4-year overall survival rates were 77, 74, and 87 percent, respectively. - The proportion of patients who had a skeletal event did not differ among treatment arms (24, 21, and 18 percent, respectively). Drug related adverse events results in thalidomide discontinuation in approximately 30 percent of patients. While thalidomide significantly improved event-free, relapse-free, and overall survival rates, on subgroup analysis it was without benefit in patients who had a deletion of chromosome 13 as well as in those who had at least a very good partial remission following HCT. It is also not clear whether most patients in Arms A and B had access to thalidomide at the time of relapse, given the drug's restricted availability and cost. Spencer et al. JCO 2009 Australian study — A prospective trial of 269 patients with newly diagnosed MM who had received up to 12 months of induction therapy followed by a single autologous HCT were randomly assigned maintenance therapy with either prednisolone alone or prednisolone plus thalidomide for 12 months [45]. Patients assigned to maintenance with prednisolone plus thalidomide demonstrated significantly higher rates of progression-free survival (42 versus 23 percent) and overall survival (86 versus 75 percent) at three years when compared to patients assigned to prednisolone therapy alone. A significant number of patients assigned to the thalidomide-containing arm were able to convert a partial response to a very good partial response or a complete response after 8 to 12 months. The treatment in this trial is considered consolidation rather than maintenance, since the thalidomide was given for a fixed duration. DC vaccine Yi Q; Br J Haematol 2002 May;117(2):297-305. Vaccination with idiotype protein-pulsed dendritic cells (DCs) has been explored in multiple myeloma and the results have been disappointing. These studies used immature DCs, which are less potent at activating T cells and could differentiate to macrophages once the cytokines were withdrawn. After intravenous administration, DCs accumulate in the lungs and liver for up to 48 h, thus reducing their potential to migrate to lymphoid organs and interact with T cells. To improve the efficacy of DC vaccination in myeloma, we investigated the use of idiotype-pulsed mature DCs administered subcutaneously. Five patients (three IgG and two IgA myeloma) with stable partial remission following high-dose chemotherapy were enrolled. DC vaccines were administered three times at 2-week intervals at least 4 months post transplantation. Idiotype-specific T-cell responses, detected using enzyme-linked immunospot (ELISPOT) (four patients) and proliferation (two patients) assays, were elicited in four and anti-idiotypic B-cell responses in all five patients. The cytokine-secretion profile of activated T cells demonstrated a type-1 response. A 50% reduction in serum M-component was observed in one immunologically responding patient that persisted for 6 months and stable disease (for 6 months) resulted in the other three patients. The remaining patient without an immune response to the vaccination relapsed. No major side-effects were noted. Thus, subcutaneous administration of idiotype-pulsed mature DCs induced idiotype-specific T- and B-cell responses. Current efforts are geared towards optimizing the conditions of DC generation and administration, and the development of in vitro assays to monitor the cytotoxicity of the T cells. **A significant proportion of patients now receive thalidomide or lenalidomide as initial therapy, and most studies discussed below did not use these drugs as initial therapy making it harder to generalize their findings. Further, in most studies, a survival benefit is only seen in a subset of patients, such as those who fail to achieve a very good partial response with transplant or those with cytogenetic abnormalities. Therefore, until results of additional randomized trials are available, we reserve post-transplant thalidomide maintenance primarily for patients on clinical trials or those with high-risk disease.
Maintenance Therapy after Transplant
• Lenalidomide vs. Placebo – Attal et al. IFM Trial. NEJM 2012
• 614 patients • Median EFS: 40 vs. 23 months
– McCarthy et al. CALGB trial. NEJM 2012 • 568 patients • Median TTP: 46 vs. 27 months • OS: p=0.03
– Lenalidomide was associated with: • Neutropenia • Immunosuppression • Blood clots • Increased second cancers
Presenter
Presentation Notes
Attal et al. ASCO 2010 Background: High-dose therapy with autologous stem cell transplantation (ASCT) is a standard treatment for myeloma patients. However, a residual disease (RD) responsible for relapse is always present. Effective maintenance treatment would be required. However, such treatment is still to be defined. We previously reported that thalidomide reduced RD. However, neuropathy was a major limiting factor. Lenalidomide, a thalidomide analog devoid of neurological toxicity, was thus attractive to investigate. Methods: Patients, under 65 years of age, with non-progressive disease after a first line ASCT (performed within the last 6 months) were randomized to receive a consolidation with lenalidomide (25 mg/d, 21 days/month, for 2 months) followed by a maintenance with either lenalidomide (10 to 15 mg/d) until relapse (Arm A) or placebo (Arm B). From July 2006 to August 2008, 614 patients were randomized. Patient's characteristics of each group were similar and no significant differences were found with regard to age (57 years), ISS stage, FISH analysis, induction regimen (VAD/bortezomib-dex/thalidomide-dex/others=49%/44%/3%/2%), diagnosis-randomization interval (10 months), and response at time of randomization. Results: In December 2009, with a median follow up of 24 months from randomization, the first pre-planned interim analysis was performed. The independent data and safety monitoring committee recommended to unblind the trial due to the PFS superiority of arm B (primary end point). Consolidation improved the response in 20% of patients. Maintenance with LEN improved the 3-year PFS from randomization: 35% in arm A versus 68% in arm B (HR=0.46, p<10-6). This benefit was observed both among patients achieving or not a complete response after ASCT. In multivariate analysis, PFS was related to response after consolidation, beta-2 microglobulin at diagnosis, and treatment arm. A strong interaction (p<0.04) was found between the efficacy of arm B and beta 2-microglobulin (HR=0.3, p <10-4 for beta-2 m <=3 mg/l; HR=0.58, p<0.003 for beta-2 m > 3 mg/l). The 2-year survival was similar in both treatment arms (95%) Conclusions: Lenalidomide is an effective maintenance treatment which prolongs PFS after ASCT. Mccarthy et al ASCO 2010 Background: Disease relapse/progression is the primary cause of treatment failure after ASCT for MM. Methods: The primary objective of CALGB 100104 was to investigate if maintenance lenalidomide would prolong time to progression (TTP) following single ASCT. Eligibility included: Stage I-III disease, ≤ 1 year from diagnosis, ≥ 2 months of induction with Stable Disease or better (≥ SD) and age < 70 years. ASCT regimen was melphalan 200 mg/m2. Patients (pts) with ≥ SD were randomized double-blind at day 100-110 post-ASCT to lenalidomide or placebo until disease progression, after stratification by diagnostic β-2 microglobulin (β-2M) level and prior thalidomide or lenalidomide therapy. Starting dose was 10 mg/day, escalated to 15 mg/day after 3 months. Drug was held for ≥ Gr 3 toxicity, restarted at resolution to ≤ Gr 2 and was de- escalated by 5 mg or maintained at 5, 10 or 15 mg/day as tolerated. Results: 568 pts were enrolled (04/15/05 - 07/03/09). The second interim analysis, based on 418 randomized pts occurred on 09/09 after 28% of the required number of events (progression or death before progression) had been observed. The median follow-up was 12 months. The number of events among 210 pts randomized to lenalidomide was 29 compared to 58 among 208 pts randomized to placebo. The one-sided unadjusted P-value was < 0.0001. The estimated hazard ratio was 0.42 (95% CI=0.27,0.67) corresponding to a 58% reduction in event risk in the lenalidomide arm. The estimated median TTP was 25.5 months for the placebo arm. The median TTP has not been reached for the study arm. Deaths in the study and placebo arms were 11 and 17 respectively (P=0.2). Significant delay in TTP in the lenalidomide arm was observed regardless of β-2M level or prior thalidomide or lenalidomide therapy. For 285 reported pts, the post-randomization, highest grade, overall AEs were Gr 3 (n=19), Gr 4 (n=111) and Gr 5 (n=1) for the lenalidomide arm and Gr 3 (n=4) Gr 4 (n=115) and Gr 5 (n=1) for placebo. The majority of AEs were hematologic in both arms. Conclusions: Lenalidomide initiated at day 100-110 post-ASCT in MM patients significantly delays TTP and has a similar AE profile when compared to placebo. �
The Improved Outcome in Myeloma is Not Seen in High-Risk Patients
Life expectancy: – Standard Risk Disease : 8-9 years – High Risk Disease: 2-3 years
Investigations for Risk Stratification
• Conventional studies – Conventional Karyotyping (Cytogenetics) – Fluorescent in-situ hybridization (FISH)
• Newer Studies – Comparative Genomic Hybridization (CGH) Array – Single Nucleotide Polymorphism (SNP) array – Gene expression profiling (GEP) – Positron Emission Tomography (PET)
• >3 FDG-avid lesions Poor – Magnetic Resonance Imaging (MRI)
• CR on MRI correlates with superior outcome
Risk Stratification of Myeloma (IMWG)
• High-Risk – By conventional karyotyping
• del 13 or 13q • t(4;14) • del 17p
– By FISH • t(4;14) • t(14;16) • Del 17p
• Standard-Risk – All others
Standard-risk (70%) • Hyperdiploidy • t (11;14) • t (6;14)
Intermediate-risk (10-15%) • t (4;14) • Deletion 13 or hypodiploidy by conventional
karyotyping High-risk (15% of all cases)
• 17p deletion • t (14;16) • t (14;20) • High-risk gene expression profiling signature • Plasma cell leukemia • Multiple extramedullary plasmacytomas
Risk Stratification of Myeloma (Mayo Clinic)
Treatment Goal in High-Risk MM
• Achievement and maintenance of CR with more intense treatment strategies – Rajkumar SV AJH 2012; Haessler J, Clin Cancer Res 2007
• Bortezomib should be part of treatment in all phases in
patients with t(4;14)
• Thalidomide or Lenalidomide do not improve outcome in t (4;14) or del 17p
Multiple myeloma: Update on diagnosis, risk‐stratification, and management
Blood 2011; 87: 78-88
Presenter
Presentation Notes
Approach to the treatment of newly diagnosed myeloma in patients eligible for transplantation (A) and not eligible for transplantation (B). Abbreviations: ASCT, autologous stem‐cell transplantation; CR, complete response; Dex, dexamethasone; Rd, lenalidomide plus low‐dose dexamethasone; VCD, bortezomib, cyclophosphamide, dexamethasone; VGPR, very good partial response; VRD, bortezomib, lenalidomide, dexamethasone. Modified from: Rajkumar SV. Treatment of Multiple Myeloma. Nat Rev Clin Oncol 2011;8:479–491. © This slide is made available for non-commercial use only. Please note that permission may be required for re-use of images in which the copyright is owned by a third party.
Randomized Phase II Trial Of CD3/CD28 Activated Id-KLH Primed Autologous Lymphocytes In Patients With Myeloma Undergoing Autologous Transplant Phase II Study of the combination of MLN 9708 with Lenalidomide as Maintenance Therapy post Autologous Stem Cell Transplant in Patients with Multiple Myeloma Allogeneic Hematopoietic Stem Cell Transplantation for High-Risk Myeloma
Advances in Cellular Therapy in Myeloma University of Texas
MD Anderson Cancer Center
Idiotype Vaccine Preparation
Activated T Cell Production Ex Vivo
1. Leukapheresis, enrich, deplete, or isolate cells of interest
3. Large scale cell expansion
Reinfuse cells
4. Remove beads, wash and concentrate cells
2. Stimulate cells with aAPC
5. Quality Control
J Immunol 1997; 159: 5921 Science 1997; 276: 273 Immunol. Rev. 1997; 160: 43 Mol. Ther. 2004; 9; 902 Exp. Opin. Biol. Ther. 2008; 8: 475
Anti-CD3 Anti-CD28
Artificial APC: Bead
Signal 1
CD28 CTLA4 TcR/CD4
Signal 2
Activated T Cell Production with Artificial APCs Cellular and Vaccine Production Facility CVPF
MLN9708 (Ixazomib)
• Second generation small molecule proteasome inhibitor.
• Orally bioavailable.
• Longer survival time in mice vs. bortezomib.
• Less risk of neuropathy.
• Several trials have demonstrated efficacy in relapsed/refractory myeloma.
Chauhan et al. CCR 2011
Allogeneic SCT for Multiple Myeloma
• Only therapy with a potential to cure the disease
• Graft-versus-myeloma effect – Usually associated with GVHD – Not effective in extramedullary myeloma
• Treatment-related mortality remains a major obstacle
– GVHD, regimen related toxicity, and infection.
Allogeneic SCT is potentially curative in myeloma
Barlogie et al. JCO 2006
Presenter
Presentation Notes
(A) Progression-free survival (PFS) and (B) overall survival (OS) from first random assignment. There was a trend for improved PFS on the high-dose therapy arm versus the standard-dose therapy arm (P[r] = .16), whereas OS was identical. (C) After allotransplantation, more than 50% of patients died within 3 months, mainly as a result of treatment-related complications. At 7 years, 22% of patients remain progression free, and 39% remain alive. HDCTX, high-dose cyclophosphamide; PBSC, peripheral-blood stem cell; Autol BMT, autologous bone marrow transplantation; chemo, chemotherapy.
TRM has decreased with RIC regimens
Crawley et al. Blood 2007
FM100 vs. FM140 (Protocol # ID01-518)
41 vs. 24% @ 2-yr P=0.12
63 vs. 45% @ 2-yr P=0.38
Bashir et al MDACC. Submitted 2013
Bortezomib With Tacrolimus And Methotrexate Reduces The Risk Of GVHD In Mismatched Transplantation
Koreth et al. JCO 2012
Conclusions
• Patients with standard-risk myeloma benefit from advances in stem cell transplantation and incorporation of novel agents in treatment plans
• High-risk myeloma has significantly worse outcome even in the era of novel agents and tandem transplants
• New anti-myeloma agents and novel cellular therapies targeting common myeloma antigens are likely to change the poor prognosis in high-risk myeloma.
Stem Cell Transplantation Program Jan 14, 2014 (First year)
Additional Slides
Adoptive T Cell Therapy • Adoptive transfer comprises of the infusion of immunocompetent
cells for the treatment of cancer or infectious disease • Adoptively transferred T cells can persist for at least a decade in
humans • T cells produce effector and central memory subsets that have
extensive replicative capacity and stem cell like qualities • Dr. June’s laboratory has developed a novel “prime-and-boost”
strategy by collecting T lymphocytes from patients that have been vaccine-primed in vivo
• These cells are activated and expanded ex vivo with anti-CD3/CD28 coated magnetic beads (artificial antigen -presenting cells), and reinfused after lymphocytotoxic chemotherapy
• Adoptive T-cell transfer can facilitate both humoral and cellular immune responses to vaccination despite cytotoxic therapy
100
10
1
0.1
0.01
T cell expansion
ex vivo
Cancer Vaccine
“Threshold for cure” % Tumor
specific T cells in
vivo
Hypothesis
Combining Active and Passive Immunotherapy
