Superior Complete Response Rate and Progression-Free Survival after Autologous Transplantation with up-Front Velcade-Thalidomide- Dexamethasone Compared with Thalidomide-Dexamethasone in Newly Diagnosed Multiple Myeloma

Blood ◽  
2008 ◽  
Vol 112 (11) ◽  
pp. 158-158 ◽  
Author(s):  
Michele Cavo ◽  
Paola Tacchetti ◽  
Francesca Patriarca ◽  
Maria Teresa Petrucci ◽  
Lucia Pantani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Induction Therapy ◽  
Progression Free Survival ◽  
Complete Response ◽  
Primary Study ◽  
Primary Therapy ◽  
Newly Diagnosed ◽  
Free Survival ◽  
End Point ◽  
Cd34 Cells

Abstract Over the last few years, Thalidomide-Dexamethsone (TD) has been one of the most commonly used induction regimens for the treatment of newly diagnosed multiple myeloma (MM). In a phase III study conducted by the Italian Myeloma Network GIMEMA, TD was compared with Velcade-Thalidomide-Dexamethasone (VTD) as induction therapy in preparation for, and as consolidation after, melphalan (200 mg/m2)-based double autologous stem-cell transplantation (ASCT) in pts aged ≤65 years with symptomatic MM. Up-front VTD comprised Velcade, 1.3 mg/m2 on d 1, 4, 8, and 11; Dexamethasone, 40 mg on each day of and after Velcade administration; Thalidomide, 200 mg/d through d 1 to 63. Pts randomized to TD received Thalidomide as in VTD and Dexamethasone, 40 mg/d on d 1–4 and 9–12 of every cycle. Primary study end point was the rate of complete response (CR)/near CR (nCR) following three 21-d cycles of induction therapy. The study was started in May 2006 and was closed to accrual in April 2008, after a total of 480 pts were enrolled. Of these, 399 pts (199 randomized to VTD and 200 to TD) could be evaluated for primary study end point and toxicity of induction regimens (secondary end point). All analyses were intent to treat. In comparison with TD, VTD effected significantly higher rates of response (≥partial response: 78.5% vs 92%, P<0.001), including CR (6% vs 21%, P<0.001), CR+nCR (12% vs 33%, P<0.001) and ≥very good partial response (VGPR) (30% vs 61%, P<0.001). Remarkably, no pt treated on VTD had disease progression, as compared to 4.5% of pts on TD (P=0.002). Serious adverse events were recorded in 13.5% of pts randomized to VTD vs 12.5% of those assigned to TD. Although grade ≥3 peripheral neuropathy (PN) and skin rash (SR) were more frequent with VTD than TD (PN: 9% vs 2.5% of pts, P=0.005) (SR: 7.5% vs 1% of pts, P=0.001), only 4 pts in the VTD arm (2 in each of the two toxicity sub-groups) necessitated early treatment discontinuation. Overall, discontinuation of primary therapy due to treatment-related adverse events was required in 4.5% of pts on VTD vs 5% of those on TD, including a single pt in VTD and 2 pts in TD who died early. Eight additional pts randomized to TD discontinued induction therapy and went off study due to disease progression. Peripheral blood stem-cell (PBSC) harvest and response to first ASCT (secondary study end points) could be assessed in 297 pts (145 randomized to VTD and 152 to TD) for whom data were available at the time of analysis. Pts who achieved the minimum threshold dose of CD34+ cells to safely perform double ASCT (≥4×106/kg) were 91% in the VTD arm vs 87% in TD; median yields were 9.3 and 10.6 (×106 CD34+ cells/Kg), respectively. Pts who actually received the first ASCT were 89% (129/145) in VTD and 80% (121/152) in TD. On an intention-to-treat basis, the rates of high-quality responses in the VTD arm were significantly higher than in TD, including CR (41% vs 20%, P<0.001), CR+nCR (54% vs 29%, P<0.001) and ≥VGPR (75% vs 53%, P<0.001). After a median follow-up of 15 months, progression-free survival (PFS) was significantly superior with VTD as compared to TD (20-month estimate: 93% vs 86%, P=0.04), while the 20-month overall survival rate was 93% for both treatment groups. We conclude that, in comparison with TD, three 21-d cycles of VTD as primary therapy for newly diagnosed MM significantly increased the CR+nCR rates, up to values previously seen with one or two autotransplants preceded by conventional chemotherapy. Importantly, response benefit with up-front VTD vs TD translated into significantly higher CR+nCR rates after ASCT and significantly improved PFS. Effective combinations of novel induction agents, such as VTD, can, thus, have a remarkable impact on both pre and post-ASCT clinical outcome. Updated results, including response to second ASCT and consolidation therapy, will be presented at the meeting.

Consolidation and Maintenance in Newly Diagnosed Multiple Myeloma

2021 ◽  
pp. JCO.21.01045
Author(s):  
Pieter Sonneveld ◽  
Meletios A. Dimopoulos ◽  
Meral Beksac ◽  
Bronno van der Holt ◽  
Sara Aquino ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Minimal Residual Disease ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Primary Study ◽  
Controlled Clinical Trial ◽  
Newly Diagnosed ◽  
Consolidation Treatment ◽  
Minimal Residual

PURPOSE To address the role of consolidation treatment for newly diagnosed, transplant eligible patients with multiple myeloma in a controlled clinical trial. PATIENTS AND METHODS The EMN02/HOVON95 trial compared consolidation treatment with two cycles of bortezomib, lenalidomide, and dexamethasone (VRD) or no consolidation after induction and intensification therapy, followed by continuous lenalidomide maintenance. Primary study end point was progression-free survival (PFS). RESULTS Eight hundred seventy-eight eligible patients were randomly assigned to receive VRD consolidation (451 patients) or no consolidation (427 patients). At a median follow-up of 74.8 months, median PFS with adjustment for pretreatment was prolonged in patients randomly assigned to VRD consolidation (59.3 v 42.9 months, hazard ratio [HR] = 0.81; 95% CI, 0.68 to 0.96; P = .016). The PFS benefit was observed across most predefined subgroups, including revised International Staging System (ISS) stage, cytogenetics, and prior treatment. Revised ISS3 stage (HR, 2.00; 95% CI, 1.41 to 2.86) and ampl1q (HR, 1.67; 95% CI, 1.37 to 2.04) were significant adverse prognostic factors. The median duration of maintenance was 33 months (interquartile range 13-86 months). Response ≥ complete response (CR) after consolidation versus no consolidation before start of maintenance was 34% versus 18%, respectively ( P < .001). Response ≥ CR on protocol including maintenance was 59% with consolidation and 46% without ( P < .001). Minimal residual disease analysis by flow cytometry in a subgroup of 226 patients with CR or stringent complete response or very good partial response before start of maintenance demonstrated a 74% minimal residual disease–negativity rate in VRD-treated patients. Toxicity from VRD was acceptable and manageable. CONCLUSION Consolidation treatment with VRD followed by lenalidomide maintenance improves PFS and depth of response in newly diagnosed patients with multiple myeloma as compared to maintenance alone.

Targeting Complete Response with Upfront Bortezomib Followed By Autologous Transplantation and Consolidation Therapy for Untreated Multiple Myeloma (TUBA study)

Blood ◽  
2016 ◽  
Vol 128 (22) ◽  
pp. 3463-3463
Author(s):  
Hideki Nakasone ◽  
Kiriko Terasako-Saito ◽  
Teiichi Hirano ◽  
Atsushi Wake ◽  
Seiichi Shimizu ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Partial Response ◽  
Progression Free Survival ◽  
Complete Response ◽  
Induction Treatment ◽  
High Dose ◽  
Induction Phase ◽  
Consolidation Therapy ◽  
Newly Diagnosed ◽  
Free Survival

Abstract [Background] Multiple myeloma (MM) is generally considered incurable. Recently, novel drugs, including bortezomib, have demonstrated a survival benefit for newly diagnosed MM patients compared with classical treatments. Complete response (CR) after treatment is known to be associated with superior progression-free survival. Thus, we prospectively evaluated the efficacy and safety of boretezomib + dexamethasone (BD) for patients with newly diagnosed MM, followed by autologous hematopoietic stem cell transplantation (ASCT). We added BD consolidation therapy to aim CR if CR was not achieved after ASCT. [Patients and methods] This clinical study prospectively recruited newly diagnosed MM patients eligible for ASCT between 2010 and 2012. Due to health insurance issues in Japan, two courses of high-dose dexamethasone (HD-DX) had been administrated prior to BD induction treatment until Nov. 2011, while BD was administrated as an initial induction treatment since Dec. 2011. BD induction treatment included 1.3 mg/m2 of bortezomib on days 1, 4, 8, and 11 with 20mg of dexamethasone on days 1, 2, 4, 5, 8, 9, 11, and 12. This BD induction cycle was repeated every 3 weeks for 4 courses. Thereafter, filgrastim-based mobilization and ASCT following high-dose melphalan administration was performed. If patients did not achieve CR after ASCT, BD consolidation therapy (bortezomib: 1.3 mg/m2 on days 1, 8, and 15; dexamethasone 20 mg/day on days 1-2, 8-9, and 15-16) every 4 weeks was added to target CR (Figure 1) (UMIN-CTR: UMIN000002442). [Results] The median observational duration among survivors was 1536 days (range: 464-2023) at this analysis. Of the 47 enrolled MM patients, 46 (male 27; female 19) were eligible for BD induction treatment, while the remaining one achieved CR before BD induction. The median age of the patients was 59 (range: 35-67) years. Of the 44 patients whose karyotype analyses were available, normal karyotype was observed in 35. Abnormal karyotype included complex type in 4, diploid in 1, and other abnormalities in 4. FISH revealed deletion of p53 in 5 of 39 patients whose information was available; deletion of 13-chromosome in 16 of 42, IgH-MAF fusion in 1 of 40; IgH-FGFR3 fusion in 5 of 41; IgH-BCL1 fusion in 9 of 39. Of the 46 MM patients, 19 received HD-DX prior to BD induction, and 34 received ASCT after BD induction treatment (Figure 1). During the BD induction phase, 3 patients experienced disease progression, and BD treatment was discontinued in 9 patients because of their consent withdrawal (n=2) and adverse events (n=7) including interstitial pneumonia in 2, persistent neuropathy in 1, CMV enterocolitis in 1, heart failure in 1, diabetes mellitus in 1, and liver dysfunction in 1. After BD induction phase (n=46), their response was >= CR in 4 (8%), very good partial response (VGPR) in 10 (22%), partial response (PR) in 18 (39%), stable disease (SD) in 2 (4%), and progression or withdrawal in 12 (26%). After ASCT, their response was >=CR in 9 (20%), VGPR in 11 (24%), PR in 12 (26%), SD in 1 (2%), and additional progression or withdrawal in 1 (2%). Of the 24 patients who received ASCT and whose response was less than CR, 21 received BD consolidation therapy for a median of 4 courses (range: 1- 8). BD consolidation was discontinued in 4 patients due to persistent neuropathy or cytopenia. Finally, maximum response after ASCT with or without BD consolidation was >= CR in 19 (41%), VGPR in 7 (15%), PR in 6 (13%), < SD in 2 (2%, Figure 2). Through BD consolidation, CR was achieved in 8 of 11 patients with post-ASCT VGPR and 2 of 12 patients with post-ASCT PR. In total, 4-year progression-free survival (PFS) and overall survival (OS) was 43% (95%CI: 28-57%) and 80 % (95%CI: 64-90%), respectively. Focusing on CR patients after ASCT and those who actually received BD consolidation, PFS adjusted for karyotype and age were not different between CR patients after ASCT and after BD consolidation, while patients with VGPR or less after consolidation had significantly lower PFS (Figure 3). [Conclusion] BD induction and ASCT provided CR rate of 27% among ASCT patients, although BD induction may expectedly cause adverse events including persistent neuropathy and viral infections. Patients who achieved CR after ASCT showed good PFS, and targeting CR through BD consolidation might improve CR rate. It is worthwhile to prospectively compare the efficacy of BD consolidation only for patients who failed to achieve CR or universal consolidation strategy. Disclosures Kanda: Otsuka Pharmaceutical: Honoraria, Research Funding.

scholarly journals Case series: MRD negativity assessment using 11C-Acetate PET with 3-weekly daratumumab-based quadruplet induction in newly diagnosed multiple myeloma

2021 ◽  
Vol 12 ◽  
pp. 204062072110303
Author(s):  
Cheong Ngai ◽  
Shaji Kumar ◽  
Garrett Chi-lai Ho ◽  
Sirong Chen ◽  
Chor-sang Chim
Keyword(s):  
Multiple Myeloma ◽  
Residual Disease ◽  
Case Series ◽  
Progression Free Survival ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Positron Emission ◽  
Pet Ct ◽  
Subsequent Relapse

Complete response (CR) is an important favorable factor for survival in multiple myeloma (MM). However, CR patients continue to relapse, especially in the presence of minimal residual disease (MRD). Bone marrow (BM) MRD is predictive of progression-free survival (PFS) in MM. However, myeloma outside the BM aspiration site may result in subsequent relapse despite MRD-negativity. Therefore, positron emission tomography-computed tomography (PET-CT) based on F-fluorodeoxyglucose (FDG) is a complementary tool to monitor residual disease in MM. However, FDG may miss myeloma lesions that are not FDG-avid. On the other hand, 11C-Acetate (ACT) has been found to be a more sensitive and specific tracer than FDG in MM. Recently, the addition of daratumumab to bortezomib, thalidomide, dexamethasone (VTd) or bortezomib, lenalidomide, dexamethasone (VRd) backbone has been proven to improve outcomes. Herein, we report three newly-diagnosed MM patients achieving deep responses with imaging CR using ACT PET in addition to conventional immunofixation CR and MRD-negative CR after a 3-weekly daratumumab-based quadruplet induction regimen.

Newly Diagnosed Multiple Myeloma Patients with 1q21 Amplification Treated by Autologous Stem Cell Transplantation Have Shorter Progression-Free Survival Interval.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 4758-4758
Author(s):  
Pavel Nemec ◽  
Henrieta Greslikova ◽  
Petr Kuglik ◽  
Hana Filkova ◽  
Romana Zaoralova ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Cell Transplantation ◽  
Autologous Stem Cell Transplantation ◽  
Progression Free Survival ◽  
Chromosome Band ◽  
Newly Diagnosed ◽  
Free Survival ◽  
End Point

Abstract Amplification of chromosome band 1q21 as well as increased expression of CKS1B gene in this area is a frequently mentioned prognostic factor for patients with multiple myeloma (MM). Total 39 newly diagnosed multiple myeloma patients (median age: 56 years) enrolled in Faculty Hospital Brno, Brno, Czech Republic, were examined for 1q21 amplification status. All patients received 4 cycles of vincristine, adriamycin and dexamethasone (VAD) as induction and one course melphalan 200mg/m2 followed by autologous stem cell transplantation (ASCT). The median follow-up from treatment start was 16.1 (range: 2.2–44.0) months. All the “end-point” intervals and treatment responses were assigned by IMWG criteria. Plasma cells were identified by cytoplasmic light-chain immunofluorescence followed by fluorescence in situ hybridisation (cIg-FISH). Amplification of 1q21 (Amp(1q21)) was assigned utilizing labelled BAC clone (RP11-205M9) DNA probe. Cut-off level for Amp(1q21) was established to 10% of total amount of cells with additional signals detected. Amp(1q21) was found in 41% (16/39) patients. Clinical parameters valid for patients with Amp(1q21) versus patients lacking Amp(1q21) were as follows: overall response rate (ORR) achieved 87.5% (14/16) vs. 91.3% (21/23) patients (p=0.404); overall survival (OS) median was 22.4 months vs. not yet reached (p=0.022); time to progression (TTP) median was 16.1 months vs. not yet reached (p=0.010); progression-free survival (PFS) median was 15.6 months vs. 25.2 months (p=0.023) and duration of response (DOR) median was 15.9 months vs. not yet reached (p=0.048). There were found statistical significant difference in all named “end-point” intervals (OS, TTP, PFS and DOR) between patients with/without Amp(1q21) but not in ORR. In conclusion, patients with Amp(1q21) treated by ASCT have significant shorter PFS median (15.6 months) when compared with patients lacking Amp(1q21) with PFS median 25.2 months (p=0.023). This findings is in accordance with previously published work (Chang et al., 2006).

Role Of Double Stem Cell Transplantation For Newly Diagnosed Multiple Myeloma In The Era Of Novel Agents

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 2171-2171
Author(s):  
Shotaro Hagiwara ◽  
Risen Hirai ◽  
Miki Nakamura ◽  
Akira Tanimura ◽  
Masataka Takeshita ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Stem Cell Transplantation ◽  
Induction Therapy ◽  
Partial Remission ◽  
Progression Free Survival ◽  
Novel Agents ◽  
Newly Diagnosed ◽  
Free Survival

Abstract Background Autologous stem cell transplantation (ASCT) has been a part of the standard therapy for newly diagnosed multiple myeloma and several studies showed double ASCT improved the outcome in comparison with single ASCT, especially the patients who failed to achieve very good partial remission (VGPR). Recently, the introduction of novel agents significantly improved the response rate of the treatment for the multiple myeloma. Although ASCT is still crucial for newly diagnosed myeloma patients, the role of the double ASCT is unclear in the era of novel agents. We performed a single institution-based retrospective study. Methods We reviewed the medical records of patients who treated with ASCT for multiple myeloma between January 2001 and April 2013 in National Center for Global Health and Medicine, Tokyo, Japan. The regimen of the remission induction therapy, number of stem cell transplantations, survival after the first ASCT, progression free survival, the response after the induction therapy and the first ASCT were analyzed. Results Since 2001, we performed ASCT for 167 patients. Ninety-three patients were treated with double ASCT, and 2 patients were treated with tandem ASCT–allogeneic SCT. In 127 patients were treated with vincristine, adriamycin, and dexamethasone (VAD) as an induction therapy, and 40 patients were treated with bortezomib and dexamethasone (BD). Very-good-partial-remission (VGPR) or complete remission (CR) was obtained in 25.2%, 34.6% of the patients treated with VAD, and in 45.7%, 54.3% with BD regimen before and after the transplantation respectively. Overall survival (OS) and progression free survival (PFS) did not differ significantly between VAD and BD induction, the estimated 2 year-OS was 89.8% vs. 79.5%, and the 2 year-PFS was 43.2% vs. 63.5% respectively. Double transplantation improved PFS and OS in VAD induction than single transplantation (p=0.000, p=0.002). In BD induction, patients who failed to achieve VGPR or better after the first ASCT, double transplantation improved OS (p=0.010) but not PFS. In both VAD induction and BD, there was no significant survival benefit in double transplantation in patients who achieved VGPR or better. Conclusion The achievement of VGPR or better after the ASCT resulted in significantly better PFS. The role of double transplantation is still crucial for patients with inadequate response after the first ASCT even in the era of novel agents. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Carfilzomib or bortezomib with melphalan-prednisone for transplant-ineligible patients with newly diagnosed multiple myeloma

Blood ◽  
2019 ◽  
Vol 133 (18) ◽  
pp. 1953-1963 ◽  
Author(s):  
Thierry Facon ◽  
Jae Hoon Lee ◽  
Philippe Moreau ◽  
Ruben Niesvizky ◽  
Meletios Dimopoulos ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Response Rate ◽  
Residual Disease ◽  
Progression Free Survival ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Intention To Treat ◽  
Significant Difference ◽  
Grade 3

Abstract The phase 3 CLARION study compared carfilzomib-melphalan-prednisone (KMP) with bortezomib-melphalan-prednisone (VMP) in transplant-ineligible newly diagnosed multiple myeloma (NDMM) patients. Patients were randomized 1:1 to KMP or VMP for nine 42-day cycles (C). Patients received carfilzomib on days (D) 1, 2, 8, 9, 22, 23, 29, 30 (20 mg/m2: C1D1, C1D2; 36 mg/m2 thereafter) or bortezomib on D1, 4, 8, 11, 22, 25, 29, 32 (1.3 mg/m2; D4, 11, 25, 32 omitted for C5-9). Melphalan (9 mg/m2) and prednisone (60 mg/m2) were administered on D1-4. The primary endpoint was progression-free survival (PFS). Nine hundred fifty-five patients were randomized (intention-to-treat population: KMP, n = 478; VMP, n = 477). Median PFS was 22.3 months with KMP vs 22.1 months with VMP (hazard ratio [HR], 0.906; 95% confidence interval [CI], 0.746-1.101; P = .159). Median overall survival was similar and not reached in either group (HR, 1.08; 95% CI, 0.82-1.43). Overall response rate was 84.3% for KMP and 78.8% for VMP. Complete response rate was 25.9% for KMP and 23.1% for VMP. Minimal residual disease–negative rates were 15.7% (KMP) and 15.5% (VMP). Adverse events (AEs) of interest (any grade) occurring with a ≥5% higher patient incidence in the KMP arm were acute renal failure (13.9% [KMP] vs 6.2% [VMP]) and cardiac failure (10.8% vs 4.3%). Grade ≥3 AE rates were 74.7% (KMP) and 76.2% (VMP). Grade ≥2 peripheral neuropathy was lower for KMP vs VMP (2.5% vs 35.1%). Treatment with KMP in CLARION did not yield a statistically significant difference in PFS vs VMP. This trial was registered at www.clinicaltrials.gov as #NCT01818752.

scholarly journals Short-course lenalidomide plus low-dose dexamethasone in the treatment of newly diagnosed multiple myeloma— a single-centre pragmatic study

2017 ◽  
Vol 24 (5) ◽  
pp. 361 ◽  
Author(s):  
W.M. Jose ◽  
K. Pavithran ◽  
T.S. Ganesan
Keyword(s):  
Multiple Myeloma ◽  
Overall Survival ◽  
Deep Vein Thrombosis ◽  
Low Dose ◽  
Progression Free Survival ◽  
Complete Response ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Vein Thrombosis ◽  
Deep Vein

Purpose We assessed response to treatment, toxicity, time to progression, progression-free survival, and overall survival in patients newly diagnosed with multiple myeloma who were ineligible for or unwilling to undergo transplantation and who were treated with a combination of lenalidomide and low-dose dexamethasone for a fixed 6 cycles in a resource-constrained environment.Methods This pragmatic study, conducted in a single tertiary cancer centre in South India, enrolled patients from May 2009 till April 2011. Treatment included lenalidomide 25 mg daily for 21 days, with dexamethasone 40 mg on days 1, 8, 15, and 22 of a 28-day cycle, for 6 cycles. Response was evaluated after the 3rd and 6th cycles of treatment. All patients were followed for 5 years.Results The study enrolled 51 patients. Median age in the group was 61 years (range: 38–76 years). Immunoglobulin G or A myeloma constituted 70.6% of the diagnoses, and light-chain myeloma constituted 29.4%. Stages i, ii, and iii (International Staging System) disease constituted 21.4%, 28.6%, and 50% of the diagnoses respectively. All patients were transplantation-eligible, but 34 (66.7%) refused for economic reasons. After treatment, 19.6% of the patients achieved a stringent complete response; 35.3%, a complete response; 5.9%, a very good partial response; and 29.4%, a partial response, for an overall response rate of 90.2%. Stable disease was seen in 3.9% of patients, and progressive disease, in 5.9%. Grade 3 or greater nonhematologic and hematologic toxicity occurred in 35.2% and 11.7% of patients respectively. Pulmonary embolism occurred in 1 patient. No patient experienced deep-vein thrombosis or peripheral neuropathy. The median follow-up duration was 66 months. All patients experienced disease progression. Median progression-free survival was 16 months. In 10 patients, re-challenge with lenalidomide and dexamethasone achieved a second complete response. At the time of writing, 19 patients had died. The overall survival rate at 5 years was 62.74%. Median overall survival is not yet reached.Conclusions In a resource-constrained setting, lenalidomide with low-dose dexamethasone is an effective treatment with acceptable toxicity in patients newly diagnosed with multiple myeloma and not planned for transplantation. Complete responses were significantly more frequent than reported in the Western literature. Occurrence of clinical deep-vein thrombosis was rare, but hyperglycemia was common. An abbreviated course of treatment is suboptimal in multiple myeloma. Maintenance regimens should be advocated.

Superiority of Double over Single Autologous Stem-Cell Transplantation for Newly Diagnosed Multiple Myeloma and Prognostic Impact of Complete Response: Final Analysis of “Bologna 96” Study.

Blood ◽  
2007 ◽  
Vol 110 (11) ◽  
pp. 730-730
Author(s):  
Michele Cavo ◽  
Giulia Perrone ◽  
Michela Ceccolini ◽  
Vito Michele Lauta ◽  
Massimo Offidani ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Stem Cell ◽  
Induction Therapy ◽  
Complete Response ◽  
Survival Duration ◽  
Prognostic Impact ◽  
Newly Diagnosed ◽  
Free Survival ◽  
Younger Patients ◽  
To Receive

Abstract We performed a prospective, randomized study of single (arm A) versus double (arm B) autologous stem-cell (SC) transplantation (ASCT) for younger patients with newly diagnosed multiple myeloma. A total of 321 patients were enrolled in the study and were randomly assigned to receive either a single course of SC-supported melphalan, 200 mg/m2 (MEL-200) (n=163 patients) or MEL-200 followed, 3 to 6 months apart, by melphalan, 120 mg/m2, and busulfan, 12 mg/kg (n=158 patients). As compared with arm A, randomization to receive double ASCT significantly increased the probability to attain at least a near (n) complete response (CR) (33% vs 47%, respectively; P=0.008). Patients who responded to induction therapy had a CR or nCR rate following either single or double ASCT of 73% and 52%, respectively (P=0.010). Both these values were much higher than those observed among patients who failed to respond to induction therapy, whose posttransplantation ≥ nCR rate was 11% in arm A and 12% in arm B (P=0.20). On multivariate analysis, randomization to double ASCT (P<0.001) and partial response to induction therapy (P<0.001) were independent significant predictors of posttransplantation attainment of CR or nCR. In comparison with a single autotransplantation, double ASCT resulted in a significant prolongation of both relapse-free survival (RFS) (median: 42 vs 23 months, respectively; P<0.001) and event-free survival (EFS) (median: 35 vs 23 months, respectively; P=0.001). The most important and independent variable favorably influencing RFS and EFS in a multivariate model was ≥nCR (P<0.001 for both RFS and EFS). Additional prognostic factors for extended EFS included baseline platelet count greater than 150.000/μL (P=0.004), randomization to double ASCT (P=0.005), hemoglobin level greater than 10 g/dL at diagnosis (P=0.01) and less than 55 years of age (P=0.04). Administration of a second transplantation and of novel agents, including thalidomide or bortezomib, for the treatment of sequential relapses in up to 50% of patients who were randomized to single transplantation likely contributed to prolong the survival duration of the whole group, whose 7-year rate (46%) was similar to that of the double-transplant group (43%) (P=0.9). Prolonged OS was significantly related to baseline hemoglobin concentration greater than 10 g/dL (P<0.001), serum creatinine level less than 177 μmol/L at diagnosis (P=0.001) and ≥ nCR (P=0.001). Benefits offered by double ASCT in terms of extended RFS and EFS were particularly evident among patients who failed at least nCR after the first autologous transplantation (P<0.001 for both RFS and EFS). At the opposite, among patients achieving CR or nCR following one transplantation, final outcomes of ASCT(s) were not significantly influenced by study randomization. Because of its potential of inducing long-term EFS and OS in the 30% to 50% range, double ASCT still remains the standard of care for younger patients with newly diagnosed MM. Attainment of CR is a surrogate marker of extended RFS, EFS and OS, and represents an important objective of novel treatment strategies combining high-dose chemotherapy with agents targeting the bone marrow microenvironment.

Phase I/Ib Trial of the Efficacy and Safety of Combination Therapy with Lenalidomide/Bortezomib/Dexamethasone (RVD) and Panobinostat in Transplant-Eligible Patients with Newly Diagnosed Multiple Myeloma

Blood ◽  
2014 ◽  
Vol 124 (21) ◽  
pp. 33-33 ◽  
Author(s):  
Jatin J. Shah ◽  
Lei Feng ◽  
Elisabet E. Manasanch ◽  
Donna M. Weber ◽  
Sheeba K. Thomas ◽  
...  
Keyword(s):  
Multiple Myeloma ◽  
Adverse Events ◽  
Board Of Directors ◽  
Induction Therapy ◽  
Research Funding ◽  
Progression Free Survival ◽  
Newly Diagnosed ◽  
Advisory Committees ◽  
Free Survival ◽  
Depth Of Response

Abstract Background: Induction therapy prior to consolidation with autologous stem cell transplantation (ASCT) continues to improve with the use of proteasome inhibitors and imids and combination regimens such as RVD. Bortezomib-based induction therapy has improved overall response rates (ORR) prior to transplant, which has translated to improvements in ORR and progression free survival post ASCT. However, complete remission (CR) rates with RVD remain low (10-15%) after 4 cycles of induction therapy. Panobinostat, a histone deacetylase inhibitor, in combination with bortezomib/dexamethasone, has demonstrated a significant improvement in depth of response and progression free survival in patients (pts) with relapsed myeloma as seen in PANORMA I. Preclinical data demonstrate synergy between the combination of bortezomib and panobinostat. We undertook a phase I/Ib trial in pts with newly diagnosed myeloma (NDMM) of RVD + Panobinostat to establish the safety of the combination and goal of improving the depth of response with induction therapy prior to ASCT. Methods: The primary objective was to determine the maximum tolerated dose (MTD) and safety/tolerability of RVD + panobinostat in NDMM. Secondary objectives were to determine efficacy as measured by the CR/nCR rate after 4 cycles, ORR, tolerability/toxicity, and progression free survival. Pts had to have NDMM with indication for therapy, candidates for ASCT with and had adequate organ function. Panobinostat was administered on days 1, 3, 5, 8, 10, 12; bortezomib 1.3 mg/m2 was administered subcutaneously on days 1, 4, 8, 11; lenalidomide 25 mg on days 1-14; dexamethasone 20 mg on days 1, 2, 4, 5, 8, 9, 11, and 12 on a 21 day cycle. Dose-escalation of panobinostat used a standard 3+3 schema with dose-limiting toxicities (DLTs) assessed during cycle 1. Three dose levels were studied with Panobinostat escalated from 10 to 20 mg. Adverse events (AEs) were graded by NCI-CTCAE v4, while responses were assessed by the modified International Uniform Response Criteria. Results: 22 pts were enrolled; 12 pts in the completed phase 1 dose escalation portion of the study and 10/20 in the ongoing dose expansion. The median age was 61 (range 53-79); ISS stage I 12; stage II 7/20; stage III in 3/20 pts. No DLTs were observed in 3 pts dosed in cohort 1, with Panobinostat at 10 mg. In cohort 2, panobinostat was dosed at 15 mg, 2/6 pts encountered a DLT. One patient experienced Grade 4 (G4) thrombocytopenia, and the second patient had G3 diarrhea without supportive measures, for <12 hours and resolved with supportive measures. In cohort 1, 3 additional patients were enrolled and no DLTs were encountered in the remaining 3 pts. The final recommended dose was Panobinostat 10 mg in combination with RVD in NDMM. Treatment emergent SAEs related to therapy observed in 5 pts with 2 incidences of G3 diarrhea; 2 pts with atrial fibrillation; and other events included G4 thrombocytopenia; G3 bacteremia, G3 cellulitis, G3 myocardial infarction (MI), G3 pulmonary emboli; G3 pneumonia. Hematologic adverse events G3/4 included anemia 3/22; neutropenia 4/22; thrombocytopenia 7/22. G3/4 nonhematologic toxicities included ALT elevation (n=2); AST elevation (n=1); constipation (n=2); diarrhea (n=2); fatigue/muscle weakness (n=2); MI (n=1); pneumonia (n=3). Among 18/22 pts who have completed 4 cycles of therapy and are evaluable for efficacy, the ORR (≥PR) was 100%: including nCR/CR in 5/18 (28%), VGPR in 5/18 (28%), PR in 8/18 (44%). Conclusions: MTD has been established at level 1, with panobinostat 10 mg and full dose RVD in NDMM. The DLTs were diarrhea (irrespective of supportive care) and thrombocytopenia. This is the first experience with panobinostat and subcutaneous bortezomib and first experience in combination with RVD. The combination is well tolerated with limited toxicity and side effects can be managed with supportive care. The preliminary activity after 4 cycles of therapy demonstrated a high ORR of 100% and a promising depth of response with a nCR/CR of 27%. Enrollment in a dose expansion cohort is near completion and full data will be presented at ASH. Disclosures Shah: Onyx Pharmaceuticals: Consultancy, Research Funding; Celgene: Consultancy, Research Funding; Millennium Pharmaceuticals: Consultancy, Research Funding; Novartis: Consultancy, Research Funding; Array: Consultancy, Research Funding. Off Label Use: Carfilzomib for use in front-line tx of multiple myeloma . Weber:OncPep: Research Funding. Thomas:Novartis, Celgene, Millenium, Idera Pharmaceuticals: Consultancy, Research Funding. Orlowski:Onyx Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Pharmaceuticals: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding.

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