Line Treatment Of Multiple Myeloma Research Articles

The Impact of Allogeneic Stem Cell Transplantation As Part of First Line Treatment on Outcome of Patients with Multiple Myeloma Depends on the Method of Analysis

The value of allogeneic hematopoietic stem cell transplantation (alloHSCT) in the treatment of multiple myeloma (MM) patients continues to be debated. Previously, we reported a donor versus no donor (DvND) analysis of MM patients, who were enrolled in the prospective upfront HOVON50 trial (Lokhorst, Blood 2012). By intention to treat, donor availability did not appear to be associated with better outcome. However, as a considerable number of MM patients with a matched related donor (MRD) were not transplanted, a DvND analysis may underestimate the effect of alloHSCT. Therefore, we performed a re-analysis using alloHSCT as a time dependent variable; this method has recently gained more attention since it may more closely evaluate the real impact of alloHSCT. In addition, a landmark (LM) analysis was performed and subsequently the 3 methods were compared.Briefly, the HOVON50 study included adult patients up to the age of 65 years with newly diagnosed Salmon and Durie stage II or III MM, who were randomized to receive induction therapy with vincristine, adriamycine, dexamethasone or thalidomide, adriamycine, dexamethasone. Subsequently, patients received high dose melphalan (HDM) and autoHSCT followed by maintenance therapy. Patients with a MRD were intended to receive alloHSCT following reduced intensity conditioning (RIC). 260 MM patients underwent HDM in the HOVON50 trial, including 122 patients with a MRD of whom 99 patients actually proceeded to alloHSCT. Methods of analysis were compared with respect to overall survival (OS), progression free survival (PFS), non-relapse mortality (NRM), and the cumulative incidence of progression (CIP). To evaluate the impact of alloHSCT (or donor, for the DvND method) the hazard ratio (HR) and 95% confidence interval (95%CI) using a multivariate Cox model with adjustment for age, sex, disease status at the time of HDM, Salmon and Durie classification, LDH, adverse cytogenetics and treatment arm were assessed. The maintenance group constituted the reference group, while the no-donor group constituted the reference in the DvND comparison.The DvND comparison did not show differences between patients with (n=122) or without (n=138) a MRD as from the time of HDM; median follow-up was 93 months. By time dependent analysis, all patients started in the control “maintenance” group and only those patients, who were actually transplanted, switched to the alloHSCT-group at the exact date of transplantation. For a LM analysis, all patients, who were alive and disease-free at 6 months after HDM (n = 239) were included and outcome was evaluated, according to whether they received (n = 91) or did not receive (n = 148) an alloHSCT. By time dependent analysis, it appeared that alloHSCT significantly improved PFS, while the DvND did not reveal a PFS benefit (Table). The 6-months LM analysis also revealed an advantage in PFS for patients who underwent alloHSCT. None of the 3 methods revealed an advantage in OS, although HR’s following LM analysis and the time dependent analysis were < 1.0 (respectively 0.82 and 0.89, not significant (ns)), while the DvND analysis yielded a HR of 1.22 (ns). Moreover, the graft versus myeloma (GvM) effect in terms of reducing the CIP appeared stronger after LM and time dependent analysis as compared to the DvND analysis (respectively 0.46 (p=0.001) vs 0.49 (p<0.001) vs 0.60 (p=0.008).Collectively, our results show that the efficacy of alloHSCT is underestimated by a DvND analysis, while both the time dependent analysis and a landmark analysis may more reliably and quantitatively reflect the allogeneic GvM effect of RIC alloHSCT as part of first line treatment in MM. Exclusion of the bias of the guarantee-time and the inclusion of all patients with either a MRD or MUD, actually being transplanted further constitute advantages of the time dependent approach as compared to a LM analysis. We conclude that the value of alloHSCT in MM should be reassessed using a time dependent analysis as preferred method in future studies.Abstract 1209. TableDonor vs No donorTime dependentLandmarkHR95%CIpHR95%CIpHR95%CIpOS1.22[0.81-1.86]0.3450.89[0.57-1.39]0.6010.82[0.51-1.33]0.422PFS0.80[0.56-1.13]0.2010.69[0.47-0.99]0.0470.63[0.43-0.93]0.019CIP0.60[0.41-0.88]0.0080.49[0.33-0.75]0.0010.46[0.30-0.71]< 0.001NRM6.15[2.09-18.08]0.0016.79[2.27-20.27]0.0013.91[1.50-10.21]0.005 DisclosuresNo relevant conflicts of interest to declare.

Neurotoxicity induced by antineoplastic proteasome inhibitors

In the last ten years, the proteasome has become one of the most attractive targets for the treatment of several cancer malignancies. Like other types of antineoplastic agents, proteasome inhibitors cause toxic peripheral neuropathy, which indeed is one of the limiting side effects of these treatments, and which thus curtails its potential effectiveness. Bortezomib was the first proteasome inhibitor approved for clinical use and is currently the first line treatment for multiple myeloma. The incidence of neuropathy induced by bortezomib is around 30–60%. Although the neurotoxic mechanisms are not completely understood, experimental studies suggest that aggresome formation, endoplasmic reticulum stress, mitotoxicity, inflammatory response, and DNA damage could contribute to this neurotoxicity. Additionally, the second generation of proteasome inhibitors, headed by carfilzomib, is currently being developed in order to reduce the toxic profile, with promising results. However, more extensive clinical experience and further experimental research are needed in order to determine the potential benefits of the second generation over bortezomib. The present review summarizes the main clinical features and mechanistic events related to the neuropathy induced by proteasome-inhibitors.

Improved response with post‐ASCT consolidation by low dose thalidomide, cyclophosphamide and dexamethasone as first line treatment for multiple myeloma

The use of consolidation or maintenance to improve disease response, and hence clinical outcome, following autologous stem cell transplantation (ASCT) remains the subject of intense clinical research. We carried out a single-arm study to assess the toxicity and efficacy of a short block of consolidation therapy with cyclophosphamide, low dose thalidomide and dexamethasone (CTD) in patients within 6 months following ASCT, as part of frontline therapy for symptomatic multiple myeloma. Forty-five patients who had not progressed were enrolled on the study, and 43 completed treatment on protocol. This regimen was well tolerated soon after ASCT, with only grade 1/2 toxicity apart from neutropenia, and no long-term sequelae. Importantly, CTD consolidation improved the depth of response in treated patients, increasing the complete/very good partial response rate from 44% at 3 months, to 72% at 12 months, which was significantly higher compared with a historical group of control patients (P = 0·002). There was a trend to longer progression-free survival that favoured the study group. Consolidation therapy did not adversely affect subsequent disease response to salvage therapies at relapse. We conclude that CTD consolidation may be a useful, non-toxic and cost-effective strategy to deepen disease response following ASCT, and deserves further study in a randomized trial.

RAD (Lenalidomide, Adriamycin and Dexamethasone) Is a Novel and Very Effective Induction Regimen in Newly Diagnosed Multiple Myeloma Preceding a Risk-Adjusted Transplant Strategy,

Abstract 3967 BackgroundTriple combinations utilizing dexamethasone, at least one of the “novel drugs” and either an alkylating agent or an anthracycline are currently considered standard induction regimens in newly diagnosed multiple myeloma (MM). In patients (pts) deemed medically fit, subsequent autologous (auto) stem cell transplantation (SCT) yet is a mainstay of care. Whether allogeneic (allo) SCT in first line treatment of MM further improves prognosis remains, however, a matter of debate. We have shown the RAD regimen to be highly effective and well tolerated in relapsed and refractory MM. Therefore, we decided to integrate this combination as a means of induction into the up-front management. Patients and methods The current phase-II trial (DSMM XII) was designed to include pts up to the age of 65 years with newly diagnosed, symptomatic MM. We chose four cycles of RAD induction (lenalidomide 25 mg/day d 1–21; infusional adriamycin 9 mg/m2 and day d1-4; dex 40 mg d1-4 and 17–20; pegfilgrastim 6 mg d 6) every 4 weeks followed by chemomobilization (cyclophosphamide, etoposide) of peripheral blood stem cells. Thromboprophylaxis by low molecular weight heparin is mandatory. All pts are scheduled to receive two transplants, the first of which being an auto SCT following standard high-dose melphalan (200 mg/m2). A subsequent allo SCT after preparation with treosulfan/fludarabin is scheduled for pts featuring at least one cytogenetic or serologic risk factor (RF). Those without any RF (“very favourable risk”) are to proceed to a second auto SCT. All patients will receive 12 months of lenalidomide maintenance. The primary end point of this trial is response to risk-adapted transplant as assessed after second SCT. This is the first planned efficacy interim analysis after 50 pts having terminated induction treatment. Results 148 pts with a median age of 55.5 (range, 30–66) years have been enrolled by 16 German centers between 9/2009 and 7/2011. In addition to the intended sample size, 2 pts had progressive disease for a total of 52 pts being evaluable for post-induction response according to the IMWG criteria. 32 pts (62%) had ISS stage II and III disease and all except three were evaluable for cytogenetic analysis based on fluorescence in situ hybridization (FISH). Incidences of chromosomal abnormalities were as follows: deletion of 13q, 31%; translocation (4;14), 15%; and deletion of 17p, 12%. Overall response rate was 79% including a 52% rate of at least very good partial response (VGPR). Seven pts (13%) achieved confirmed complete response (CR) and stringent CR. 18/52 pts (35%) experienced severe treatment-emergent adverse events (t-SAEs) with an incidence of hematologic events of 4%. Incidences of infections and venous thromboembolism were 8% and 6%, respectively. Conclusions Results from this interim analysis indicate RAD to be a very effective and well tolerated induction protocol in newly diagnosed MM. High-quality response (VGPR or better) to induction is known to be a major prognosticator for long-term prognosis in a given patient. Thus, combination of RAD with risk-adjusted SCT may contribute to enhanced disease control in a substantial proportion of pts. Disclosures:Knop:Celgene Germany GmbH: Consultancy. Off Label Use: Lenalidomide in combination with dexamethasone and adriamycine in first line treatment of multiple myeloma. Langer:Celgene Germany GmbH: Consultancy. Gramatzki:Novartis, Celgene: Consultancy, Research Funding. Einsele:Celgene Germany GmbH: Consultancy, Honoraria. Bargou:Celgene Germany GmbH: Consultancy, Honoraria, Research Funding.

Lenalidomide plus low-dose dexamethasone compared with thalidomide plus low-dose dexamethasone in the treatment of newly diagnosed multiple myeloma: Results of an ongoing prospective randomized phase III trial.

e18572 Background: Both Thalidomide and Lenalidomide are approved for first line treatment of multiple myeloma (MM). We compared the efficacy and safety and assessed quality of life (QOL) of the two agents in combination with dexamethasone. Methods: Between March 2009 and December 2010, 39 newly diagnosed MM patients (median age 52 years, range, 20 to 70 years, M: F=16:7. ISS stage: I-14, II-14, III-11. Durie-Salmon stage: IIA-2, IIIA-30 and IIIB-7. Patients received Lenalidomide, 25 mg/d, d 1-21 every 28 d or Thalidomide 100-200 mg/d along with dexamethasone (dex) 20 mg PO d 1-4 and d 9-12 every 28 d in both arms. The study was approved by Institution Ethics Committee and written informed consent was obtained. Response was assessed according to the IMWG criteria after 4 cycles. QOL was assessed by EORTC QOL questionnaire C30. Responders (CR or VGPR) received maintenance dex 20 mg PO from day 1-4 every month until progression. All patients received inj zoledronic acid 4 mg IV every month for 6-9 months. Eligible patients were offered ASCT. Median follow-up is 9.5 months (range 1-21). Analysis was by intention to treat. Results: 23 patients (Len-dex, n=12 and Thal-dex, n=11) have completed at least 4 cycles of therapy. 16 patients responded; VGPR-7, PR-9, 2-stable disease. Two patients died of progressive disease (1 in each group). Response was similar in both arms. 6 patients have proceeded to ASCT. In Len-dex arm, the major toxicities were grade III-IV neutropenia-2, thrombocytopenia-1 and anemia in 1 pt. Other toxicities were: fatigue-4, URTI- 3, constipation-2, dizziness-2, autoimmune thrombocytopenia-1 and rest tremors in 1 patient. In Thal-dex arm, toxicities were sensory neuropathy-5 (all grade I), constipation-4 (grade I-3, grade III-1), skin infection-2, fatigue-1 and coarse tremors in 1 patient. QOL analysis showed improvement in physical functioning among patients of Len-dex arm (p<0.008). Conclusions: For newly diagnosed myeloma patients, induction treatment with Lenalidomide-dexamethasone is associated with better toxicity profile and improved QOL compared to thalidomide-dexamethasone.

Genetic Associations with Bortezomib Mediated Neuropathy in Multiple Myeloma.

Abstract 1794Poster Board I-820The proteasome inhibitor bortezomib has demonstrated high antitumor activity in multiple myeloma (MM). Peripheral neuropathy (PNP) is a dose-limiting toxicity of bortezomib, which typically occurs within the first cycles of bortezomib in 30-40% of MM patients. Although bortezomib induced PNP is manageable and reversible in most MM patients, no effective prophylactic treatment against PNP is available and bortezomib discontinuation is frequently required. Identifying patients at risk of neuropathy and understanding its pathogenesis is therefore of great importance.The mechanism underlying bortezomib induced PNP is unknown. To investigate whether genetic variation is associated with bortezomib induced PNP, a custom-built molecular inversion probe (MIP) based single nucleotide polymorphism (SNP) chip, designed by “Bank on a Cure” (BOAC)) was used, containing 3404 SNPs selected in “functional regions” within 983 genes representing cellular functions and pathways that may influence disease response, toxicities, complications, and survival. To explore SNP associations with bortezomib induced PNP we compared cases and controls in two phase 3 clinical trials. In the Dutch-German HOVON-65/GMMG-HD4 trial 3 cycles of Bortezomib/Doxorubicin/Dexamethason were given for induction, and 52 PNP grade 2,3,4 cases (37 %) were identified during this treatment against 84 controls. In the French IFM 2005-01 trial 4 cycles of Bortezomib/Dexamethasone were given, and 74 PNP grade 2,3,4 cases (34 %) versus 144 controls were identified. A Cochran-Armitage trend test was applied on the combined data set using the program PLINK. To account for multiple testing we carried out label swapping procedures. A set of SNPs was identified that was highly associated with bortezomib induced PNP. The 5 most significant SNPs are rs3136516 in F2 (thrombin) (p=2.0×10-4; Odds Ratio (OR)=0.53, 95% confidence interval (CI)=0.38-0.72), rs2686184 in FDFT1 (p=2.1×10-4; OR=1.6, 1.17-2.19), rs2137975 in DPYD (p=2.3×10-4; OR=1.60, 1.17-2.20), rs2857605 in TNF (p=3.0×10-3; OR=0.53, 0.35-0.79), rs12198787 in TNF (p=4.9×10-3; OR=0.48, 0.30-0.79). In addition, 3 significant SNPs (rs10979601, rs10759326 and rs838827) were located in IKBKAP, a gene involved in hereditary sensory neuropathies. Another interesting associated SNP, rs7096206 (p=8.5×10-3; OR=1.60, 1.10-2.32), is known to lead to reduced MBL2 serum levels. Significant associations were also seen in ADME genes (drug absorption, distribution, metabolism, and excretion) such as ABCC1, CYP2C9, CYP1A1, CYP1A2, CYP11B1, CYP17A1, CYP3A4, ABCB11, FMO2 and SLC22A4. Overall, the set of associated SNPs were enriched for genes in pathways involved in DNA replication, DNA repair, cell-to-cell signaling and drug metabolism. In conclusion, we identified a set of SNPs which are highly associated with bortezomib mediated PNP. Both ADME and critical biological pathways are implicated, which suggests a critical role for bortezomib metabolism and biological effects in PNP development. Our results open the way to develop a classifier predicting PNP in MM patients. DisclosuresOff Label Use: Use of Bortezomib in first line treatment of Multiple Myeloma. Goldschmidt:Johnson and Johnson: Research Funding, Speakers Bureau. Lokhorst:Celgene: Consultancy. Sonneveld:Johnson and Johnson: Research Funding, Speakers Bureau.

New Strategy for Allogeneic Peripheral Blood Stem Cell Transplantation After Reduced Intensity Conditioning in Multiple Myeloma: Interim Analysis of the IFM2005-03 Study.

Abstract 4321 IntroductionThe development of new agents with potent anti-tumor activity has considerably improved the survival of multiple Myeloma (MM) patients. However, there is still a high risk of relapse mainly due to the inability of these agents to cure and eliminate definitively the MM cells. Allografting remains the only available curative treatment particularly for patients with high risk factors. Material and methodsThis is an interim analysis of a prospective multicenter study for MM patients of age ≤ 65 years receiving reduced intensity conditioning (RIC) followed by allogeneic peripheral blood stem cell transplantation (allo-PBSCT) after achieving at least a partial response (PR) to auto-transplantation in first line. Patients previously received either VAD or VD as induction treatment followed by Melphalan 200 mg/m2. Patients must have an HLA identical donor either from siblings or unrelated 10/10 HLA donors, and at least one of the following poor prognostic factors (PPF) : β2 microglobulin >3mg/L, Del 13, t(4;14) and Del 17p. The conditioning regimen combined Fludarabine 30 mg/m2/d (d-5□d-1), Busilvex IV 3,2 mg/kg/d (d-4, d-3) and ATG 2,5 mg/kg/d (d-2, d-1). By day 90 post-allograft, a response assessment was done, patients not in CR received 4 cycles of Velcade 1.3 mg/kg, and after Velcade, if the CR was not achieved, increasing doses of donor lymphocyte infusions (DLI) were administered. This analysis included 11 patients, 9 males and 2 females, median age was 46 years [40-60], there were 8 IgG stageA (7κ & 1λ) and 3 IgA (1κ stage B & 2λ stage A). There were 3 patients with 1 PPF, 5 patients with 2 PPF and 3 patients with 3 PPF. ResultsSeven patients received 4 cycles of VAD (4 patients VAD+DCEP), 1 patient received 4 cycles of Velcade + dex. and 3 patients received other combinations (1PAD, 2VAD then Velcade). After induction, 7 patients were in PR and 4 in stable disease (SD). Patients received auto-HSCT after a median time of 6.6 months [4.5-8.7] from diagnosis. All patients were in PR after auto-HSCT and before allo-PBSCT. The median number of infused CD34+ cells was 6.5 ×106/kg [2.6-13.7] from 4 identical siblings and 7 matched unrelated donors. Sex matching was: F□M:4, F□F:1, M□F: 1 and MμM:5. At D90, 3 patients were in CR and 8 patients received Velcade after absence of CR (2 VGPR and 6 PR). After Velcade, the 2 VGPR evolved to CR and patients in PR became 1 CR, 1 VGPR and 4 remained in PR). One patient in VGPR and 3 in PR received DLI after Velcade, responses were: 1 VGPR and 3 patients progressed. There were 6 acute GVHD (5 grade II and 1 grade III) and 6 chronic GVHD (5 limited and 1 extensive), all GVHD were resolved at the last follow-up. After a median follow-up of 30 months, all patients are alive [100% overall survival (O.S.)], 3 patients are in CR, 3 in VGPR, 4 in PR and one in relapse without any active chronic GVHD even after DLI administration. ConclusionWe showed completely different results from the IFM99-03 study in terms of O.S. and toxicity, this difference was due to the better conditioning with the introduction of Busilvex, also the impact of Velcade in eliminating the residual disease. According to these very promising results, we should reconsider the allo-HSCT as a first line treatment for MM especially for patients with PPF using either RIC or standard conditioning depending on age. Disclosures:No relevant conflicts of interest to declare.

Need of Reconsideration of Mobilization Strategy in Autologous Stem Cell Transplantation for Multiple Myeloma: Results of the Positive Impact of High Number of CD34+ Infused Cells.

Abstract 3225Poster Board III-162 BackgroundAutologous Stem Cell Transplantation (ASCT) with Peripheral Blood Stem Cells (PBSC) is widely used in first line treatment for Multiple Myeloma (MM) patients. The rapidity and stability of cell engraftment may correlate with the number of CD34+ cells in the autograft. However, the impact of this number on hematologic recovery and long term outcomes is not very well defined yet. Having a higher number of collected CD34+ cells seems to be a very important and accessible objective in 2009 (availability of mobilization agents), also it has in the same time cost and efficacy results. Materials and methodsThis study concerned 130 MM patients who underwent ASCT in our center between years 2000 and 2007. There were 79 males and 51 females with a median age of 56.8 years (34-72). At diagnosis there were 71 IgG (49κ, 22λ 26 IgA (15κ,11λ 2 IgD (1κ, 1λ 27 light chain (18κ,9λ 2 plasma cell leukemia and 2 nonsecretory. According to the IMWG classification, there were 11 patients in stage I (10A and 1B), 12 IIA, 96 III(75A and 21B) and 11 not classified. At diagnosis, 24 patients had a del(13), and 65 had high levels of β2microglobulin. The median interval between diagnosis and ASCT was 7.8 months (3.5-131). Before transplantation, all patients received granulocyte-colony stimulating factor (G-CSF) 5μg/kg/day, PBSC were mobilized in steady state in 135 cases, 62 after G-CSF + cyclophosphamide. As conditioning, all pts received melphalan alone with a median total dose of 304mg (130-440). Sixty six patients received a single ASCT and 64 patients received 2 ASCT in a double ASCT program. After transplantation, there were 2 graft failure, 40% of patients received red blood cell (RBC) transfusions (median number: 0 [0-23]), and 64% received platelet transfusions (median number: 1 [0-20]). The median number of days with neutrophils <0.5G/L was 6 (0-33) and with platelets <20G/L was 17 (2-104). The median length of hospitalization for auto transplantation was 18 days (14-54). To assess the impact of the infused CD34+ cells number, we have analyzed 2 groups: group 1 (n=86) for ASCT with a number of CD34+ ≤3×106/kg and group 2 (n=107) for ASCT with a number of CD34+ >3×106/kg. ResultsWe found a high significant impact of the high number of infused CD34+(group 2) on platelets recovery (p=0.002). The univariate analysis using Cox model, showed a trend for the high number of infused CD34+ cells (group2) on leukocyte recovery O.R= 0.748 [0.5-1.0] (p=0.0568) and a high significant impact of the same group on neutrophils recovery O.R= 0.670 [0.5-0.9] (p=0.009). These results were not changed even after adjustment on age also on the sequential number of the ASCT in the double auto ASCT program. The multivariate analysis using Cox model, studying the impact of CD34+ group, age, gender, poor prognostic factors [high level of β2microglobulin and del(13)], mobilization (G-CSF alone or G-CSF + cyclophsphamide), showed a significant impact only of poor prognostic factors on overall survival O.R.= 7.94 [1.0-59.2] (p=0.04) and also on progression free survival (PFS) O.R.= 2.55 [1.1-5.7] (p=0.024). ConclusionHigh level of infused CD34+ appeared to be very optimal for hematological recovery after ATSC in MM, without any significant impact on O.S and PFS. An economical study is running on this population to assess the impact of this level on hospitalization and treatment costs, results will communicated in the future. DisclosuresNo relevant conflicts of interest to declare.

Genetic Associations with Therapy Response in the HOVON-65/GMMG-HD4 Trial in Patients with Multiple Myeloma.

Abstract 1790Poster Board I-816Multiple Myeloma (MM) is a plasma cell malignancy, characterized by significant heterogeneous disease progression and response to therapy. It is very likely that genetic polymorphisms of genes involved in drug absorption, distribution, metabolism and excretion may affect a patient's response to therapy.To explore whether genetic variation is associated with therapeutic outcome in the Dutch-German HOVON-65/GMMG-HD4 trial, a custom-built molecular inversion probe (MIP) based single nucleotide polymorphism (SNP) chip, designed by “Bank on a Cure” (BOAC)) was used, containing 3404 SNPs selected in “functional regions” within 983 genes representing cellular functions and pathways that may influence disease response, toxicities, complications, and survival. In the HOVON-65/GMMG-HD4 trial patients were treated with either 3 induction cycles of Vincristine/Adriamycin/Dexamethason (VAD, arm A) or 3 cycles of Bortezomib in combination with Doxorubicin and Dexamethason (PAD, arm B) after which response to treatment was determined. In 189 out of the initial 40% of patients (n=350) being included in the HOVON-65/GMMG-HD4 trial germ-line DNA was collected. To explore SNP associations with treatment response, an analysis was performed on both treatment arms separately and a comparison was made between good responders (CR, VGPR) (VAD n=17; PAD n=50) and patients who responded less well (PR or less) (VAD n=67; PAD n=55). A Cochran-Armitage trend test was applied on both data sets using the program PLINK. To account for multiple testing we carried out label swapping procedures.The association analysis identified highly significant SNPs uniquely associated with VAD or bortezomib treatment response. The 3 most significant SNPs associated with CR/VGPR on VAD are rs2725362 in WRN (p=8.0×10-4; Odds Ratio (OR)=4.13, 95% confidence interval (CI)=1.71-9.97) rs891507 in ABCB8 (p=1.2×10-3; OR=4.44, 1.81-10.88) and rs755622 in MIF (p=1.4×10-3; OR=4.35, 1.79-10.55). Different SNPs were associated with CR/VGPR on PAD: rs2293616 in SLC15A2 (p=5.0×10-4; OR=0.43, 0.25-0.75), rs1062372 in PMS2 (p=9.0×10-4; OR=0.31, 0.15-0.66) and rs90925 in LTA (p=1.0×10-3; OR=0.41, 0.22-0.75). Pathway analyses showed that the two sets of associated SNPs were enriched for genes involved in DNA repair, immune response/inflammation and drug metabolism. In addition, overlapping SNP associations in the ADME genes (drug absorption, distribution, metabolism, and excretion) ABCC1, CYP2C9, ABCC4 and ABCA1 were seen in both treatment arms.Our findings demonstrate a trend of genetic polymorphisms associated with treatment response. Genetic variations were found that were uniquely associated with each treatment. The associations found will be validated in an independent dataset. DisclosuresOff Label Use: Use of Bortezomib in first line treatment of multiple myeloma. Goldschmidt:Johnson and Johnson: Research Funding, Speakers Bureau. Sonneveld:Johnson and Johnson: Research Funding, Speakers Bureau.

Indirect Comparison of the Efficacy of Melphalan-Prednisone-Bortezomib Relative to Melphalan-Prednisone-Thalidomide and Melphalan-Prednisone for the First Line Treatment of Multiple Myeloma

Melphalan-prednisone (MP) combination has been considered a standard of care for front line treatment of multiple myeloma in patients non eligible for transplant. Melphalan-prednisone-bortezomib (MPV) combination has been approved in the United States in patients non eligible for high-dose chemotherapy (HD-C) and has recently received a positive opinion from the CHMP in Europe. Melphalan-prednisone-thalidomide (MPT) was approved in Europe in patients >65 or not eligible for HD-C. There is no head-to-head trial directly comparing MPV to MPT. The objective of the current study was to compare the efficacy of MPV to MP and MPT as first line treatment of multiple myeloma in patients non eligible for transplant. Six randomized placebo controlled trials investigating the efficacy of MPT (5) and MPV (1) relative to MP were identified with a systematic literature review. The endpoints of interest were overall survival (OS), progression free survival (PFS) and overall and complete response. Relative efficacy estimates of MPT versus MP as obtained from the MPT-MP trials were combined with meta-analysis techniques and simultaneously indirectly compared with the relative efficacy of MPV versus MP from the MPV-MP trial (VISTA). This adjusted indirect comparison was performed with Bayesian fixed and random effects models. As compared to frequentist approach, Bayesian meta-analysis offers a more informative summary of the likely value of efficacy after observing the data and allows for direct probabilistic inferences. Of the three interventions compared, there was an 81% probability that MPV was the most efficacious intervention in terms of overall response and a >99% probability in terms of complete response. With MPV a patient was two times more likely to show a complete response than with MPT (Relative Risk=2.15; 95%Credible Interval (CrI): 0.99–4.45). Both MPV and MPT showed greater OS than MP (HR=0.61; 95%CrI: 0.42–0.88 and HR=0.61; 95%CrI: 0.47–0.78 respectively); the indirect comparison showed similar efficacy in terms of OS between MPV and MPT (MPV vs MPT: Hazard Ratio=1.00; 95%CrI 0.64–1.57). Both MPV and MPT also displayed greater PFS than MP (MPV versus MP: HR=0.61; 95%CrI 0.49–0.76 and MPT versus MP HR=0.51; 95%CrI 0.41–0.63 respectively) and showed similar efficacy (MPV vs MPT: HR=1.19; 95%CrI: 0.87–1.63). In this study, both MPV and MPT are more efficacious than MP in terms of response, PFS and OS. MPV is expected to result in a greater complete and overall response than MPT. No difference in OS or PFS was displayed. Further analyses will need to be undertaken once evidence base data is more mature.

Bortezomib Plus Dexamethasone as Second Line Therapy after Vincristine, Adriamycin and Dexamethasone in Multiple Myeloma

BACKGROUND: Bortezomib is an useful drug for the second line treatment of Multiple Myeloma (MM). This reversible proteasome inhibitor obtains durable responses in relapsed or refractory MM, given as monotherapy or in combination, with acceptable toxicity.AIM: To analyse the overall response of bortezomib plus dexamethasone in patients with relapsed or refractory MM after treatment with vincristine, adriamycin and dexamethasone (VAD) regimens. The time to progression (TTP), time to alternative treatment (TTAT), overall survival (OS) and toxicity profile were also studied.PATIENTS AND METHODS: We conducted a retrospective study of 58 patients with relapsed or refractory MM from seven Andalusian hospitals since March 2005 until June 2008. Patients received bortezomib and dexamethasone as second line therapy after a prior treatment with VAD regimens. The patients were treated with standard bortezomib dose (1.3 mg/m2 IV bolus on days 1, 4, 8 and 11) plus dexamethasone (40 mg/d PO the same days) every 21 days, for up to 8 cycles. The mean age of our series was 57 years (range 39–66) and included 53% males. The prognostic variables at the time of diagnosis were: beta2-microglobuline >3,5 mg/l (57 %), albumine <3,5 g/dl (41%), mean of plasma cells in bone marrow (37 ± 3,6%) and ISS stages at diagnosis (stage I 29%, stage II 28% and stage III 43%). The incidence of plasmacytoma was 22%. Response was evaluated according to the modified EBMT criteria after 4th and 8th courses. Adverse events were graded based on WHO toxicity scale.RESULTS: Fifty-eight patients with refractory/relapsed MM after VAD were analysed with a median follow-up of 11.6 months (1.5–40.5). Forty-eight patients (83%) were evaluated after 4 cycles and the overall response (OR), considered as partial response (PR) or better, was 70.9%; complete response (CR) 18.8%; near complete response (CnR) 18.8%; PR 33.3%; minimal response (MR) 2.1%; stable disease (SD) 12.5% and progression 8.3%. Thirty-three patients (57%) received 8 cycles and the analysis showed the following responses: OR 63.7%, CR 9.1%, CnR 27.3%, PR 27.3%, SD 6.1% and progression 12.1%. In patients who progressed, the median of TTP was 9 months (4–20) and the median of TTAT was 9 months (5–22). Grade 3–4 anemia, neutropenia and gastrointestinal toxicity were not observed in our series. Thrombocytopenia and neuropathy (grade 3–4) appeared in 3% and 11% respectively. Thirty percent of patients required dose reduction of bortezomib whereas dexamethasone was ajusted in 11% of patients, because of toxicity or intolerance. The overall survival of the series was 76%.CONCLUSION: The combination of bortezomib and dexamethasone is an effective alternative of second line treatment without severe toxicity in patients with refractory/relapsed Multiple Mieloma.

Neuropathy in Multiple Myeloma Patients Treated with Bortezomib: A Multicenter Experience.

INTRODUCTION: Bortezomib (B) is the first proteasome inhibitor to be used in clinical practice and has been recently approved for second line treatment of multiple myeloma (MM) patients(pts). Several trials demonstrated that Bortezomib is relatively well tolerated; however, manageable non-hematologic and hematologic toxicity has been reported. The dose limiting toxicity is peripheral neuropathy (PN), reported up to 35% of the patient population.AIM: We evaluated the incidence and severity of PN in 179 MM patients that received B as single agent or in combination.MATERIAL AND METHODS: Patients characteristics were as follows: median age was 66.7 years (range: 32–82) with 52% male; 55 patients were at the onset of the disease, 124 were pre-treated. Median time from diagnosis to treatment with B was 25.4 months (range 0–111), median value of β2-microglobulin was 3.02 (0.2–20). Risk factors for PN included prior use of thalidomide in 68 patients (38%), vincristine in 75 patients (41.8%) and 15 patients (8.8%) had diabetes mellitus.RESULTS: Patients received bortezomib alone (?) or in combination with either dexamethasone (n=52), or chemotherapy (n=114) or thalidomide (n=38). Overall, the response rate (≥PR) was 86%. PN of grade ≥2 was observed in 73 pts (41%); grade 3–4 occurred in 32 (18%). Median time to the onset of bortezomib-related PN was 84 days (range, 10–449) after bortezomib initiation. In most cases (93%), patients had sensory symptoms, while 5 patients (7%) experienced both sensory and motor symptoms. Bortezomib-related PN led to therapy discontinuation in 31 pts (17%). For PN treatment, pts received mostly supportive therapy (analgesics, gabapentin, pregabalin, amitriptyline and vitamin supplements). Of the 31 patients with bortezomib-related PN that required discontinuation, resolution or improvement occurred in 16 (51.6%), at a median time of 140 days (range, 27–346) from B discontinuation. Data analysis of the PN risk factors (age, diabetes, sex, β2M, neurotoxic pre-treatment) showed a significant association with age >75 years (p<0.013) and a trend with thalidomde pre-treatment (p=0.07); noteworthy, PN risk was not increased in pts treated with bortezomib and thalidomide in combination. Furthermore, responses were independent to PN.CONCLUSIONS: In our experience, PN is a relatively frequent side effect of bortezomib treatment, generally manegeable by dose reduction or discontinuation and reversible in the majority of pts. Patients with advanced age can be considered at higher risk, while the combination of thalidomide and bortezomib did not increase the risk of PN. Further studies are needed to better define the PN pathogenesis and develop optimal strategies to improve the B related PN management.

Tratamento de primeira linha no Mieloma Múltiplo

A presente revisão tem por objetivo avaliar o estado atual do tratamento de primeira linha dos pacientes com MM. O paciente com MM assintomático não deve receber tratamento ao diagnóstico, mas apenas quando surgirem indicações. Para o paciente sintomático (anemia, hipercalcemia, alteração da função renal, presença de lesões líticas ou plasmocitoma extramedular, aumento progressivo do componente-M no soro e/ou urina), o tratamento deverá ser rapidamente instituído. Aqueles pacientes com menos de 65-70 anos, com bom performance status, sem comorbidades e com função renal próxima do normal são potencialmente candidatos à consolidação com altas doses de quimioterapia seguidas de transplante autólogo de células-tronco hematopoéticas. Portanto, não devem utilizar drogas alquilantes para evitar prejuízos à mobilização das células-tronco. São opções: dexametasona, VAD e talidomida (com ou sem dexametasona). Os pacientes com mais de 65-70 anos, com performance status ruim, comorbidades e com função renal alterada podem receber tratamento com agentes alquilantes (por exemplo, melfalano e prednisona, com ou sem talidomida) pois não serão submetidos a transplante. O principal objetivo nesses casos é atingir resposta com mínima toxicidade.