Newly Diagnosed Multiple Myeloma (MM) Patients Treated With Lenalidomide Induction and Maintenance Show a Low Incidence Of Second Primary Malignancies (SPMs)

Abstract Introduction New drugs have significantly improved the outcome of MM patients (pts) increasing both progression free survival (PFS) and overall survival (OS). Among new drugs lenalidomide (LEN) due to its oral availability and favourable toxicity profile is an attractive option both as an induction and as a maintenance treatment, with different studies demonstrating its effectiveness. Long term therapy with LEN, however, has been associated with an increased risk of developing SPMs. Aims We are conducting a large phase III study to evaluate the use of LEN as induction and/or as maintenance therapy. The primary end points of the study are OS and PFS. Secondary end points are response and toxicity. Methods Pts are treated following an intensive or a non intensive pathway based on their eligibility for high dose Melphalan (HDM) and stem cell transplantation (ASCT) and are randomised to receive induction therapy with cyclophosphamide and dexamethasone combined with either LEN (CRD) or thalidomide (CTD). Pts failing to achieve an optimal response are randomised to receive additional therapy with cyclophosphamide, dexamethasone and bortezomib (CVD) or no extra therapy. Pts with minimal or no response will automatically receive further therapy with CVD. A randomisation between LEN maintenance and no maintenance is also performed. Data on the occurrence of SPMs are being routinely collected as part of safety assessment during all protocol phases and follow up. Analyses were performed on treatment actually received. Results As per cut off of the 23rd July, 2371 pts have undergone the induction randomisation, of which 2368 are eligible for the safety analysis; 794 pts entered maintenance randomisation. The median follow up is 1.36 years from initiation of the study and 1.06 years from maintenance randomisation. Localised skin cancer other than melanoma were considered as non-invasive SPMs. At the time of the present analysis 17 SPMs have been reported with a cumulative incidence rate of 0.7% (cumulative rate of 0.6% for invasive SPMs and 0.1% for non-invasive SPMs); four additional patients, reported as having a SPM, were excluded, after central review of the data, either due to a previous history of malignancy or because of the evidence of a pre-existing tumour other than MM at the time of study entry. The median age at the time of SPMs development is 72 years (range 61-92), and the median time from trial entry to development of SPMs is 11 months (range 2.1-27.0). The most common SPMs reported were squamous cell carcinoma (4 pts, 2 invasive and 2 non invasive), breast cancer (3 pts), colon cancer (2 pts) and prostate cancer (2 pts). No haematological SPM has so far been reported. One patient, treated according to the intensive arm with LEN both as induction and maintenance, was reported as having a suspect myelodysplasia (MDS) due to anaemia and thrombocytopenia 2.7 months after entering the maintenance randomisation. No clear histological sign of MDS was found and the values improved after stopping maintenance treatment; these data fit with treatment related toxicity and not with the development of a MDS, and the patient was excluded from this analysis. Ten out of 17 SPMs developed during maintenance treatment or follow up phase, with 7 patients having received LEN maintenance. Median time from maintenance randomisation to SPMs development is 7 months (range 2-20.6 months). The remaining 7 were diagnosed during or immediately after induction. About half of the patients (8/17) were randomised to receive LEN induction; 3 patients received LEN both as induction and as maintenance. Interestingly only one of those 3 pts had been treated according to the intensive arm. With a median follow up of 1.36 years the estimated incidence rate at 1 and 2 years are 0.70% (95% CI .40-1.22)and 1.17% (95% CI .70-1.96) respectively (Figure 1). Conclusions Our data do not confirm previous findings of an excess risk of SPMs in association with the use of LEN and HDM in presenting patients, with 12/17 pts developing SPMs treated on the non intensive pathway that does not contain HDM. Most importantly only 0.4% of the patients enrolled within the intensive pathway developed a SPM, with only 2 of them receiving LEN maintenance. Longer follow up will help to further elucidate the risk of LEN associated SPMs. On behalf of the NCRI Haemato-Oncology subgroup Disclosures: Brioli: Celgene: Honoraria. Off Label Use: The presentation include the use of Lenalidomide as induction and as maintenance treatment for newly diagnosed multiple myeloma patients. Cook:Janssen: Honoraria, Research Funding, Speakers Bureau. Cavo:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Janssen: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Onyx: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Bristol-Meyer Squibb: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees. Morgan:Celgene: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Millenium: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Novartis: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Merck: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees; Johnson and Johnson: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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Consolidation with Vtd Significantly Improves the Complete Remission (CR) Rate Following Vtd Induction and Single Autologous Stem Cell Transplantation (auto) in Multiple Myeloma (MM).

Blood ◽

10.1182/blood.v120.21.3096.3096 ◽

2012 ◽

Vol 120 (21) ◽

pp. 3096-3096

Author(s):

Xavier Leleu ◽

Benjamin Hebraud ◽

Guillemette Fouquet ◽

Murielle Roussel ◽

Denis Caillot ◽

...

Keyword(s):

Board Of Directors ◽

Incidence Rate ◽

Relapse Rate ◽

Research Funding ◽

The Other ◽

Newly Diagnosed ◽

Phase 3 ◽

Advisory Committees ◽

Induction Regimen

Abstract Abstract 3096 Background. Several studies have demonstrated the impact of VTd on response rates and PFS either as induction or consolidation regimen. However there are limitations to these studies, especially that no data is available regarding the role of VTd consolidation in the context of bortezomib-triple based VTd induction regimen followed by a single auto. At completion of therapy, the response rate (ORR, PR and better) was 89%, VGPR+CR rate 74%, CR rate 29%, relapse rate and median PFS was 53% and 26 months (median F-up 32 months) in the VTd arm of the phase 3 IFM2007-02 trial conducted for newly diagnosed MM (Moreau et al, Blood 2012). In this study, only a minority of patients had received a consolidation or maintenance. On the other hand, Cavo et al. (Blood 2012) reported 97.5%, 92%, 61%, 39% 3-year progression and 62% estimated 5-year PFS (F-up 43 months) respectively in the VTd arm. VTd was given as induction before and consolidation after double auto in this upfront GIMEMA phase 3 trial (Cavo et al, Lancet 2010). We aimed to assess the efficacy and safety of VTd as consolidation therapy in the context of VTd as induction regimen followed by a single auto (VTd-auto-VTd regimen). Method. This study has included a first group of 121 newly diagnosed MM from 2009 to 2011 across 9 IFM centers. Patients were to be eligible for auto upfront, aged less than 65 and treated with VTd-auto-VTd regimen. The second cohort included MM treated with VTd-auto without consolidation from the IFM2007-02 trial (n=76). A third cohort comprised MM that received upfront a triplet Vd-based combination induction (VCd, VRd) -auto without consolidation (n = 40). Results. In the whole study, the median age was 56 years, the sex ratio was 1,49, 50% had ISS 2 and 3, 22% had adverse FISH [t(4;14); del17p] (similar in the 3 groups). Overall, the ORR was identical in the 3 cohorts at completion of therapy, 104 (86%), 72 (94%) and 32 (80%) for the cohort 1 to 3, respectively. Nevertheless, the CR rate was significantly greater in patients that received a consolidation (cohort 1), as compared to the cohorts 2 and 3 that did not receive any consolidation, 59 (53%) vs. 26 (34%) and 13 (32.5%), respectively (p=0.0001). Interestingly, the CR rates were identical at the end of the induction in the 3 cohorts, 13%, 15% and 22.5%, respectively. With a median follow-up of 25 months, the incidence rate of relapse was significantly greater in the cohort 2 and 3 versus 1, further demonstrating the importance of the consolidation, 25 (21%), 42 (55%) and 13 (32.5%) patients (p=0.0001), respectively; and 9 (8%), 6 (8%) and 8 (20%) had died in cohorts 1 to 3 (p=0.07). The median (95%CI) PFS was not reached in cohort 1, and was 32 (28;36) months and 30 (26;33) months in cohort 2 and 3, respectively. Importantly, 54.5%, 32% and 32% of patients were free of relapse at 32 months in the 3 cohorts, respectively. Similar data were obtained for TTP. The median (95%CI) OS was not significantly different in cohorts 1 to 3, although not reached for the first 2 cohorts and 38 (33;43) months for the 3rdcohort. The 3-year survival was 84%, 91% and 76%, respectively (p=ns). A longer follow up will certainly demonstrate greater survival end points benefit in favor for consolidation. The safety profile of the cohort that contained a consolidation was superimposable to that of the remaining 2 cohorts without consolidation. The incidence rate of hematological EIs of grade 3 and 4 was 4%, 6% and 8% in the 3 cohorts (p=ns), respectively. The incidence rate of neuropathy grade 1–2 and 3–4 was 5% and 2% in the cohort 1 with consolidation, but only 1% occurred during the consolidation. This data compares favorably to the 3% reported in the cohort 2 (Moreau et al. Blood 2012). We have also observed 9 (9%) thromboembolic events (TE), 8 of venous type and 1 arterial. None of them happened during the consolidation, and again, this incidence rate if superimposable to that reported in the IFM2007-02 vTd cohort. Conclusion. This study showed an impressive increase in CR rate in relation to the consolidation that translated into a lower relapse rate. This study also demonstrated that the VTd regimen, used both as induction and consolidation, in the context of a single auto upfront in MM, significantly contributed to improve clinical outcomes with an acceptable toxicity profile. VTd-auto-VTd compared very favorably to the other upfront protocols, and may become in the near future a standard of care in newly diagnosed patients with Myeloma. Disclosures: Leleu: Celgene: Honoraria, Research Funding, Speakers Bureau; Janssen: Honoraria, Research Funding, Speakers Bureau; Novartis: Honoraria, Research Funding; Amgen: Honoraria, Research Funding; Sanofi: Honoraria; Onyx: Honoraria, Speakers Bureau; LeoPharma: Honoraria, Speakers Bureau. Off Label Use: Pomalidomide. Roussel:celgene: Honoraria; janssen: Honoraria. Facon:onyx: Membership on an entity's Board of Directors or advisory committees; celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees; millenium: Membership on an entity's Board of Directors or advisory committees. Attal:celgene: Membership on an entity's Board of Directors or advisory committees; janssen: Membership on an entity's Board of Directors or advisory committees.

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A Phase III Study Of ASCT Vs Cyclophosphamide-Lenalidomide-Dexamethasone and Lenalidomide-Prednisone Maintenance Vs Lenalidomide Alone In Newly Diagnosed Myeloma Patients

Blood ◽

10.1182/blood.v122.21.763.763 ◽

2013 ◽

Vol 122 (21) ◽

pp. 763-763 ◽

Cited By ~ 16

Author(s):

Antonio Palumbo ◽

Francesca Gay ◽

Andrew Spencer ◽

Francesco Di Raimondo ◽

Adam Zdenek ◽

...

Keyword(s):

Stem Cell ◽

Board Of Directors ◽

Research Funding ◽

Phase Iii ◽

Study Endpoint ◽

Newly Diagnosed ◽

Advisory Committees ◽

Grade 3 ◽

To Receive

Abstract Background High-dose chemotherapy followed by autologous stem cell transplantation (ASCT) improves survival in multiple myeloma (MM). The introduction of novel agents challenged the role of ASCT at diagnosis. We conducted a multicenter 2X2 randomized trial comparing conventional chemotherapy plus lenalidomide with ASCT followed by maintenance with lenalidomide-prednisone (RP) or lenalidomide (R) alone in newly diagnosed young MM (NDMM) patients. Methods Eligible patients with NDMM ≤ 65 years were enrolled. All patients received Rd induction (four 28-day cycles of lenalidomide 25 mg day 1–21 and low-dose dexamethasone 40 mg day 1,8,15,22) followed by stem cell mobilization. Patients were randomized to receive consolidation with CRD [six 28-day cycles of cyclophosphamide (300 mg/m2 day 1,8,15), dexamethasone (40 mg days 1,8,15,22) and lenalidomide (25 mg days 1–21)] or MEL200-ASCT (melphalan 200 mg/m2 with stem-cell support). Patients were randomly assigned to receive subsequent maintenance with RP (28-day cycles of lenalidomide 25 mg days 1–21 plus prednisone 50 mg every other day) or R alone (28-day cycles of lenalidomide 25 mg days 1–21). Primary study endpoint was progression-free survival (PFS); secondary endpoints included safety, responses and overall survival (OS). Data cut off was May 30th, 2013. Results Three-hundred and eighty-nine patients were enrolled in the trial. Patient characteristics were well balanced between CRD (n=194) and MEL200-ASCT (n=195), and between R (n=195) and RP (n=194) arms. Median follow-up was 31 months. In the intent to treat (ITT) analysis, the median PFS was not reached with MEL200-ASCT and 28 months with CRD (the respective 3-year PFS was 60% vs. 38%, HR=0.62, 95%CI: 0.49-0.85, P=0.003). Median time from enrolment to maintenance was 14 months. In the population of patients eligible for maintenance, 2-year PFS from the start of maintenance was 73% for RP and 56% for R patients (HR= 0.57, 95%CI: 0.34-0.93; P=0.03). In the subgroup of patients who received MEL200-ASCT, 2-year PFS from the start of maintenance was 83% for patients who received RP and 64% for those who received R alone (HR=0.36 95%CI: 0.15-0.87, P=0.02). In the subgroup of patients who received CRD, 2-year PFS from the start of maintenance was 64% for patients who received RP and 47% for those who received R alone (HR=0.75, 95%CI: 0.40-1.39, P=0.36). At present, no differences in OS were noticed between patients randomised to received CRD or MEL200-ASCT, and between patients who received RP or R maintenance. As expected, the rates of grade 3-4 hematologic (85% vs. 26%, P<0.001) and non-hematologic (35% vs. 19%, P=0.003) adverse events (AEs) were higher in the MEL200-ASCT arm compared with the CRD arm. The main non-hematologic AEs were infections (18% vs. 5%, P=0.001) and gastrointestinal AEs (18% vs. 3%, P<0.001). Rates of grade 3-4 hematologic (8% vs. 7%, P=0.85) and non-hematologic (12% vs. 13%, P=0.88). AEs were similar in the RP and R arms. The main non-hematologic AEs in both RP and R groups were infections (3% vs. 3%). At present, 6 second primary malignancies and 3 cases of cutaneous basalioma have been reported. Conclusions MEL200-ASCT significantly prolonged PFS in comparison with CRD. At present no difference in OS was reported, this may be due to the low number of events and to the length of follow-up. The increase in toxicity with MEL200-ASCT did not adversely impact on efficacy. The addition of prednisone to lenalidomide maintenance significantly reduced the risk of progression in comparison with lenalidomide alone, without increasing the toxicity. Updated data with longer follow-up will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Gay:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Spencer:Celgene: Honoraria, Membership on an entity’s Board of Directors or advisory committees. Larocca:Celgene: Honoraria. Caravita:Celgene: Honoraria, Research Funding. Petrucci:Celgene: Honoraria. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding.

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Clinical Outcomes of Patients with Newly Diagnosed Multiple Myeloma Receiving Triplet Therapy in the Connect MM® Disease Registry

Blood ◽

10.1182/blood.v126.23.4229.4229 ◽

2015 ◽

Vol 126 (23) ◽

pp. 4229-4229

Author(s):

Jatin J. Shah ◽

Rafat Abonour ◽

Mohit Narang ◽

Jayesh Mehta ◽

Howard R. Terebelo ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Employment Equity ◽

Advisory Committees ◽

Risk Of Death ◽

Equity Ownership ◽

Triplet Regimen

Abstract Introduction: Triplet therapies are used for treatment (Tx) of both transplant-eligible and -ineligible patients (pts) with newly diagnosed multiple myeloma (NDMM). Actual patterns and outcomes of Tx are not fully understood. Connect MM® is the first and largest multicenter, US-based, prospective observational cohort study designed to characterize Tx patterns and outcomes for pts with NDMM. This analysis describes demographic and disease characteristics of pts who received triplet Tx as an induction regimen and for whom transplant was or was not intended. The analysis explores the relationship of these factors with overall survival (OS) and other efficacy endpoints. Patients and Methods: Pts aged ≥ 18 y with NDMM within 60 days of diagnosis were eligible for enrollment regardless of disease severity, medical history, or comorbidities. Data including transplant intent (yes/no) was collected at baseline; follow-up data was collected quarterly thereafter. Based on the initial intent, 2 groups were identified: patients with intent to transplant who received transplant (TT) and pts with no intent to transplant who did not receive a transplant (NT). Triplet Tx was defined as the combination of ≥ 3 concurrent therapeutic agents in the first course of Tx (within 56 days of study entry). KM analysis adjusted for age was conducted for OS. Because decisions on use of transplant and triplet therapy are influenced by multiple factors, a multivariable Cox regression analysis was performed to evaluate the contribution of the triplet therapy (yes/no) to OS and was adjusted for other variables, including age, comorbidities, and ISS staging. Results: Between September 2009 and December 2011, 1493 pts were enrolled. This analysis was on 1436 pts: 650 pts with transplant intent and 786 pts without transplant intent. The data cutoff date was November 30, 2014, and the median follow-up for overall survival (OS) was 33.8 mos. Of pts with transplant intent, 451 (69%) received transplant (TT) and 199 (31%) did not. Of pts without transplant intent, 62 (8%) received transplant and 724 (92%) did not (NT). The abstract focuses on TT and NT groups only. NT pts tended to be older and have more advanced ISS staging and higher β2-microglobulin levels than TT pts (Table). The most common triplet regimen given during the first course treatment (within 56 days) was lenalidomide, bortezomib, and dexamethasone (RVd). RVd was administered to 34% of the NT pts (76/225) and 59% of the TT pts (152/257). The most common non-triplet regimen was bortezomib and dexamethasone (Vd), which was given to 31% of NT pts (156/499) and 38% of TT pts (73/194). Within the NT group, pts given triplet Tx had a lower risk of death than those who did not receive triplet Tx (P = .0013). The multivariable analysis found triplet Tx to be associated with a 36% reduced risk of death (hazard ratio [HR] = 0.64 [95% CI, 0.50-0.82]; P = .001). ISS disease stage (HR = 1.43 [95% CI, 1.21-1.69]; P < .001) and history of diabetes (HR = 1.38 [95% CI, 1.08-1.78]; P = .012) were negative prognostic factors for OS. Within the TT group, pts who received triplet Tx did not attain an OS benefit (P = .8993), and no baseline characteristics were significantly associated with OS. These results may be limited by other factors not considered that may have influenced physicians' choice of treatment, including the use of maintenance therapy and a short follow-up period of 33.8 months. Conclusions: Triplet Tx as a first regimen is associated with longer OS in pts without transplant intent who did not receive a transplant. RVd and Vd were the most common first Tx regimens, respectively. Continued follow-up of these pts and enrollment of an additional cohort will provide additional data with mature follow-up. Table 1. Table 1. Disclosures Shah: Bristol-Myers Squibb: Research Funding; Array: Research Funding; Novartis: Membership on an entity's Board of Directors or advisory committees, Research Funding; Onyx: Membership on an entity's Board of Directors or advisory committees, Research Funding; Celgene: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millenium: Research Funding; Merck: Membership on an entity's Board of Directors or advisory committees. Abonour:Celgene: Research Funding, Speakers Bureau. Narang:Celgene: Speakers Bureau. Mehta:Celgene Corporation: Speakers Bureau. Terebelo:Millenium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Pharmacylics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Gasparetto:Celgene Corporation: Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Millennium: Honoraria, Other: Export Board Committee, Speakers Bureau. Toomey:Celgene: Consultancy. Hardin:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees. Srinivasan:Celgene Corporation: Employment, Equity Ownership. Larkins:Celgene Corporation: Employment, Equity Ownership. Nagarwala:Celgene Corporation: Employment, Equity Ownership. Rifkin:Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Millennium Pharmaceuticals, Inc., Cambridge, MA, USA, a wholly owned subsidiary of Takeda Pharmaceutical Company Limited: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees.

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Development of an Inclusive Risk Prognostic Index for Newly Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood-2021-149213 ◽

2021 ◽

Vol 138 (Supplement 1) ◽

pp. 3789-3789

Author(s):

Ben A Derman ◽

Andrew J. Belli ◽

Ching-Kun Wang ◽

Eric Hansen ◽

Spencer S Langerman ◽

...

Keyword(s):

Older Adults ◽

Multiple Myeloma ◽

Board Of Directors ◽

Real World ◽

Prognostic Index ◽

Newly Diagnosed ◽

Advisory Committees ◽

C Statistic ◽

Equity Ownership

Abstract Background: Multiple myeloma (MM) risk stratification schemata such as the International Staging System (ISS) and Revised-ISS (R-ISS) were derived from clinical trial subjects made up predominately of younger White individuals with adequate renal function. It is unknown whether these prognostic indices are applicable to all patients with newly diagnosed (ND) MM, especially among Black individuals, older adults, and those with renal dysfunction. The R-ISS expanded on the ISS by including and serum lactate dehydrogenase (LDH) and high-risk cytogenetic abnormalities (HRCA) identified by fluorescence in-situ hybridization (FISH), but HRCA may not translate into poor prognosis for older adults and for Black individuals. We sought to create an inclusive risk prognostic index for NDMM using real-world data derived from electronic health records. Methods: De-identified NDMM patient-level data in the real-world setting was provided by COTA, Inc. 3000 patients were identified who met the inclusion criteria of NDMM between 2005 and 2020. Baseline diagnostic parameters available within 60 days before or after diagnosis were included. Progression free survival (PFS) was defined as the time from diagnosis to disease progression or death of any cause. Overall survival (OS) was defined as the time from diagnosis to death of any cause. Proportional hazards models were used to calculate hazard ratios (HR) and 95% confidence intervals for all-cause mortality. Age-adjusted univariate analyses identified variables significantly associated with OS, and continuous variables were dichotomized based on accepted cutoffs. Multivariate Cox models to identify the variables with the strongest association with OS were performed adjusting for age, sex, Black race, receipt of proteasome inhibitor and immunomodulatory imide during induction, autologous stem cell transplant within 1 year of diagnosis, ECOG performance status, and creatinine. An additive risk score was created with one point given to each significant variable. The risk score was then validated for PFS using the Multiple Myeloma Research Foundation's (MMRF) CoMMpass database (version IA15). Results: 3000 NDMM pts from the COTA, Inc. real-world database were initially evaluated, and a total of 689 NDMM pts had sufficient level of data to be included. The median follow-up time was 49.9 months (interquartile range (IQR) 29.1-76.2 months). Median age was 64 (IQR 32-86), including 44% age 65+. Of the 607 with reported race, 474 (78%) were White, 86 (14%) Black, 17 (3%) Asian, and 30 (5%) other. Of the 676 pts with reported serum creatinine (mg/dL), the median was 1 mg/dL (IQR 0.8-1.3) with 85 (13%) measuring >2 mg/dL. Examined peripheral blood variables were: calcium (corrected for albumin), albumin<3.5 mg/dL, beta2-microgloublin (B2M) >3.5 mcg/mL, LDH >250 U/L, hemoglobin <10 g/dL, M-spike >3 g/dL, and IgA isotype. Variables with significance using multivariate analysis at p<0.1 were: LDH>250 U/L, B2M >3.5 mcg/mL, hemoglobin <10 g/dL, and IgA isotype. These variables were simultaneously present in 558 patients. Patients were stratified into 3 groups: standard (std score = 0, n=186), intermediate (int score = 1-2, n=295), and high (score 3-4, n=77) risk. For this inclusive risk prognostic index (IRPI), the c-statistic was 0.61 for OS (HR 2.0, 95% CI 1.5-2.6, p<0.001) which compared favorably to the c-statistic for ISS (c=0.64, HR 1.8, 95% CI 1.5-2.2, p<0.001) and for R-ISS (c=0.63, HR 2.0, 95% CI 1.6-2.6). For the IRPI, median OS was 218 (std) vs 121.5 (int) vs 79.5 months (high). In comparison, median OS by ISS was 198.9 (stage I) vs 121.6 (stage II) vs 80.6 months (stage III), and by R-ISS: 198.9 (I) vs 121.6 (II) vs 79.5 months (III). Validation of the inclusive risk prognostic index (IRPI) using the MMRF CoMMpass database in 938 patients with all four criteria showed median PFS was 44 (std) vs 33 (int) vs 20.5 months (high). In comparison, median PFS by ISS was 45.9 (I) vs 31.5 (II) vs 20.5 (III) months. Median PFS by R-ISS was 50.1 (I) vs 32.7 (II) vs 19.1 (III) months. Conclusions: Employing real-world datasets that incorporate a more diverse patient population led to the generation of an inclusive risk prognostic index incorporating beta2-microgloublin, LDH, hemoglobin, and IgA isotype. This IRPI does not require bone marrow sampling, performs similarly to ISS and R-ISS in predicting PFS, and with datasets with longer follow-up may prove to predict OS. Figure 1 Figure 1. Disclosures Derman: Sanofi: Membership on an entity's Board of Directors or advisory committees. Belli: COTA, Inc.: Current Employment, Other: Equity ownership. Wang: COTA, Inc.: Current Employment, Other: Equity ownership. Hansen: COTA, Inc.: Current Employment. Jakubowiak: Amgen: Membership on an entity's Board of Directors or advisory committees; Karyopharm: Membership on an entity's Board of Directors or advisory committees; Gracell: Membership on an entity's Board of Directors or advisory committees; BMS: Membership on an entity's Board of Directors or advisory committees; GSK: Membership on an entity's Board of Directors or advisory committees; Abbvie: Membership on an entity's Board of Directors or advisory committees; Sanofi: Membership on an entity's Board of Directors or advisory committees; Janssen: Membership on an entity's Board of Directors or advisory committees; Celgene: Membership on an entity's Board of Directors or advisory committees.

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EARLY Results of TOTAL Therapy 7 (TT7): High Response Rates of NEWLY Diagnosed High Risk Myeloma to Daratumumab

Blood ◽

10.1182/blood-2019-131887 ◽

2019 ◽

Vol 134 (Supplement_1) ◽

pp. 4569-4569 ◽

Cited By ~ 1

Author(s):

Frits van Rhee ◽

Sharmilan Thanendrarajan ◽

Carolina D. Schinke ◽

Jeffery R. Sawyer ◽

Adam Rosenthal ◽

...

Keyword(s):

Multiple Myeloma ◽

High Risk ◽

Board Of Directors ◽

Research Funding ◽

Response Rates ◽

Newly Diagnosed ◽

Advisory Committees ◽

Early Results ◽

Research Grant

Background. The TT approach has significantly improved the outcome of multiple myeloma (MM) by combining new drugs with a regimen that comprises induction, tandem autologous stem cell transplantation (ASCT), consolidation and maintenance. However, a group of 15% of patients with high risk multiple myeloma (HRMM) have derived little benefit despite similar response rates to induction chemotherapy and ASCT when compared to low risk MM. The poor outcome of HRMM is explained by early relapse post ASCT resulting in a short progression free survival (PFS) with only 15-20% of patients surviving long-term. Daratumumab (Dara) is a human IgG1k anti-CD38 monoclonal antibody that has shown favorable results in early single-arm studies and more recently in phase III studies for relapsed/refractory and newly diagnosed MM. In TT7, we introduced Dara during all phases of therapy, including immune consolidation early post ASCT, to improve responses rate and PFS in HRMM. Methods. Patients had newly diagnosed HRMM as defined by high risk cytogenetic abnormalities, presence of extramedullary disease, >3 focal lesions on CT-PET, elevated LDH due to MM, or ISS II/III with cytogenetic abnormality. Dara (16mg/kgx1) was added to induction with KTD-PACE (carfilzomib, thalidomide, dexamethasone; and four-day continuous infusions of cisplatin, doxorubicin, cyclophosphamide, etoposide). Conditioning for tandem autologous stem cell transplantation (ASCT) was with fractionated melphalan (50mg/m2x4) (fMEL) based on prior observations that patients with adverse cytogenetics fare better with fMEL rather than single high dose MEL200mg/m2.In the inter tandem ASCT period immunological consolidation with Dara (16mg/kg) alone for 2 doses was followed by Dara (16mg/kg) on day 1 combined with K (36mg/m2) and D (20mg) weekly for 2 cycles. DaraKD was administered to avoid treatment free periods allowing for myeloma regrowth. The 2nd ASCT was followed by further immunological consolidation with Dara (16mg/k) for 2 doses, and maintenance therapy for 3 yrs with 3-months block of alternating Dara-KD (dara 16mg/kg day 1; K 36mg/m2 and dex 20mg weekly) and Dara-lenalidomide (R)D (dara 16mg/kg day 1; R 15mg day 1-21 q28 and D 20mg weekly). Results. TT7 enrolled 43 patients thus far. The median follow-up was 11 months (range: 1-22). The median age was 61 yrs (range 44-73). Sixteen patients were ≥65 yrs (37.2%). A mean of 29.4x106 CD34+ cells/kg (range: 4.6-86.4) were collected. 36 patients completed ASCT #1 (83.7%) and 18 (41.9%) ASCT #2, whilst 14 patients have proceeded to the maintenance phase. R-ISS II/III or metaphase cytogenetic abnormalities were present in 85.1 and 58.1% of patients, respectively. Elevated LDH or >3FL on CT-PET were noted in 30 and 41.8%. The 1-yr cumulative incidence estimates for reaching VGPR and PR were 87 and 83%, respectively. A CR or sCR was achieved in 68 and 46%. The 1-yr estimates of PFS and OS were 91.6 and 87.2%. 40 subjects are alive, whilst 5 progressed on study therapy and 3 subsequently died. 38 patients are progression free at the time of reporting. Dara was well-tolerated and no subjects discontinued therapy due to dara-related side effects. The CR and sCR rates compared favorably to the predecessor HRMM TT5 protocol where CR and sCR rates were 59 and 27%. Conclusion. The early results of TT7 point to increased response rates of HRMM to a dara-based TT regimen with especially higher rates of CR and sCR. Longer follow-up is required to determine if these early results translate into superior PFS and OS. Figure Disclosures van Rhee: Karyopharm Therapeutics: Consultancy; Kite Pharma: Consultancy; Adicet Bio: Consultancy; Takeda: Consultancy; Sanofi Genzyme: Consultancy; Castleman Disease Collaborative Network: Consultancy; EUSA: Consultancy. Walker:Celgene: Research Funding. Morgan:Amgen, Roche, Abbvie, Takeda, Celgene, Janssen: Honoraria, Membership on an entity's Board of Directors or advisory committees; Celgene: Other: research grant, Research Funding. Davies:Amgen, Celgene, Janssen, Oncopeptides, Roche, Takeda: Membership on an entity's Board of Directors or advisory committees, Other: Consultant/Advisor; Janssen, Celgene: Other: Research Grant, Research Funding.

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Thalidomide Maintenance Significantly Improves Progression-Free Survival (PFS) and Overall Survival (OS) of Myeloma Patients When Effective Relapse Treatments Are Used: MRC Myeloma IX Results

Blood ◽

10.1182/blood.v116.21.623.623 ◽

2010 ◽

Vol 116 (21) ◽

pp. 623-623 ◽

Cited By ~ 11

Author(s):

Gareth J Morgan ◽

Faith E. Davies ◽

Walter M. Gregory ◽

Sue E. Bell ◽

Alex J. Szubert ◽

...

Keyword(s):

Mathematical Model ◽

Multiple Myeloma ◽

Maintenance Therapy ◽

Board Of Directors ◽

Induction Treatment ◽

Newly Diagnosed ◽

Advisory Committees ◽

Relapse Treatment ◽

Fish Group

Abstract Abstract 623 Background: Although a meta-analysis has suggested that a consistent PFS benefit is seen with maintenance thalidomide therapy in multiple myeloma (MM) patients, the impact on OS remains unclear (Hicks LK, et al. Cancer Treat Rev 2008;34:442-452). This could be due to a lack of effect, differing biological subgroups in relatively small studies with short follow-up, or lack of effective relapse treatment. Aims: The study was set up to evaluate the effect of thalidomide maintenance therapy in newly diagnosed MM patients aged ≥ 18 years with OS and PFS as end points, and to examine differential effects in fluorescence in situ hybridization (FISH) identified molecular subgroups. Methods: Following induction treatment in an intensive pathway for younger fitter patients and a non-intensive pathway for the remaining patients, eligible patients were randomized to open-label thalidomide maintenance until progression (50 mg/day escalating to 100 mg/day after 4 weeks assuming good tolerance) or no maintenance. Patients of all ages were included in the randomization. FISH was performed using standard approaches. Adverse FISH groups were defined as any of t(4;14), t(14;16), t(14;20), 1q+, 17p−, or 1p32− (in the intensive pathway only); the remainder were defined as favorable. Results: Overall, 820 patients were eligible of which 818 were evaluable. Median patient age was 65 years (range, 31−89). Median follow-up from maintenance was 38 months (range 12−66 months). Median time on maintenance was 7 months (range 0−50 months). Maintenance thalidomide significantly improved PFS, with a difference between the curves of 13% (95% confidence interval [CI] 6%−20%) established by 24 months and maintained till the current maximum follow-up at 66 months (hazard ration [HR] 1.36; 95% CI 1.15−1.61; logrank P < 0.001). However, in the initial analysis there was no apparent impact on OS (P = 0.40). These findings were consistent regardless of prior intensive or non-intensive induction treatment. At 66 months follow-up, a PFS benefit was seen in the favorable FISH group (P = 0.004) with no effect on OS (P = 0.6). In the adverse FISH group there was no effect on PFS (P = 0.48) and a negative effect on OS (P = 0.009). Subsequently, we evaluated the effect of relapse treatment on outcomes and used this data in a mathematical model to determine if OS benefit would have accrued from the prolonged PFS if all patients had received effective treatment at relapse. A total of 523 patients have progressed to date and of these, 47% received thalidomide as initial relapse treatment (either as a single agent or in combination), 30% received novel agents (either bortezomib or lenalidomide), and 27% received alkylating agents or steroids. Median survival after progression was significantly worse in patients who received thalidomide maintenance than those who did not (P < 0.005); this could, at least partly, be attributed to patients who received thalidomide at progression. In those patients, the median OS after progression was significantly greater in the no maintenance group versus the thalidomide maintenance group (P = 0.004). Among patients treated with novel agents at progression, prior thalidomide maintenance therapy had no impact on OS and these patients were effectively salvaged. The mathematical model employed to examine the effect of effective salvage therapy at progression suggested that a significant survival benefit of 5.5% at 3-years in favor of thalidomide maintenance would have accrued if all patients had received effective therapy at progression (HR 0.77; 95% CI 0.60–0.99; P = 0.04). Next, we examined whether continuous thalidomide therapy was associated with a consolidation or maintenance effect. Upgrading of response with thalidomide maintenance was not common. Importantly, there was no difference in response over time between maintenance therapy and no maintenance. In contrast to what has been reported previously, these findings suggest a maintenance effect. Conclusions: Maintenance thalidomide significantly improves PFS and if effective relapse treatment is available this translates into an OS advantage. The median duration of maintenance thalidomide therapy of 7 months in the present study was short. The clinical impact of maintenance would be improved if patients could remain on therapy for longer, suggesting that the use of other agents such as lenalidomide, with better tolerability profiles, may produce better results. Disclosures: Off Label Use: THALOMID (thalidomide) in combination with dexamethasone is indicated for the treatment of patients with newly diagnosed multiple myeloma. Davies:Celgene: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Ortho Biotech: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Novartis: Membership on an entity's Board of Directors or advisory committees.

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Car-Bird [Carfilzomib, Clarithromycin(Biaxin(R)), Lenalidomide/(Revlimid(R)), Dexamethasone) For Newly-Diagnosed Multiple Myeloma

Blood ◽

10.1182/blood.v122.21.3216.3216 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3216-3216 ◽

Cited By ~ 2

Author(s):

Tomer M Mark ◽

John N. Allan ◽

Geoffrey Marano ◽

Adriana C Rossi ◽

Roger N Pearse ◽

...

Keyword(s):

Multiple Myeloma ◽

Partial Response ◽

Board Of Directors ◽

Research Funding ◽

Newly Diagnosed ◽

Advisory Committees ◽

Disease Response ◽

M Spike ◽

Grade Iii

Abstract Background Carfilzomib (Cfz) synergizes with lenalidomide and dexamethasone (Len-dex) to provide impressive response rates as upfront treatment of multiple myeloma (MM) (Jakubowiak et al 2012). The addition of clarithromycin to Len-dex has shown superior time to progression compared to Len-dex alone (Gay et al 2010). We hypothesized that sequential treatment with Cfz-dex and BiRD would lead to enhanced efficacy, response duration, and tolerability. We thus tested a sequential approach of upfront carfilzomib / dexamethasone, consolidation with BiRd, and lenalidomide maintenance to evaluate overall response and safety as first line therapy for MM. Methods Twenty-four patients (pts) with symptomatic untreated MM were enrolled in a single institution study to evaluate the efficacy and tolerability of Car-BiRd. Car-BiRd therapy is: Cfz IV over 30 minutes on Days 1, 2, 8, 9, 15, 16 of a 28-day cycle at a dose of 20mg/m2 on days 1, 2 of the 1st cycle only and 45mg/m2 for each successive dose thereafter and dex 40mg on D1, 8, 15, 22. Cfz-dex was continued until plateau in disease response defined as unchanged M-protein for 2 cycles. Elective autologous stem cell collection was then performed per physician and patient discretion and consolidation with BiRd initiated. Transplant ineligible pts proceeded directly to BiRd. BiRd is: Clarithromycin 500mg BID, lenalidomide 25mg daily on D1-21, and dex 40mg daily D1, 8, 15, 22 of 28-day cycle. Therapy was continued until a 2nd plateau in disease response after which lenalidomide maintenance at a dose of 10mg daily D1-21 of 28 day cycle was continued until disease progression or intolerability. Results 24 pts have currently been enrolled; 23 have completed at least 1 cycle of therapy and were evaluable for response. Sixteen pts (67%) harbored high-risk cytogenetics, as defined by the presence of one or more of the following on iFISH: del 17p, gain 1q, del 1p, t(4;14), t(14;16), or complex karyotypic abnormalities. Median study follow-up was 30.8 weeks (range 4.5-62.2). Response to the Car-BiRD regimen was: overall response rate (ORR) 87%, stringent complete response (sCR) 13%, very good partial response (VGPR) 48%, partial response (PR) 26%, stable disease (SD) 13%. Maximum response to the Cfz-dex induction was: ORR 87%, sCR 9%, VGPR 39%, PR 35%, SD 13%. Median time to PR and maximum response with Cfz-dex was 2 cycles (range 1-2) and 4 cycles (range 1-5) respectively. Median M-spike percentage decrease with Cfz-dex was 92% (range 13-100%). Twelve pts thereafter received BiRD consolidation with 5 pts (41%) further decreasing the M-spike by a median of 8% (range 1-45%). A median of 3 cycles (range 2-7) of BiRD was given until a 2nd response plateau was achieved. Seven pts subsequently received lenalidomide and all have maintained their response after a median of 5 cycles (range 1-8) of follow-up. Seven pts (30%) have come off study, 2 (8%) secondary to disease progression (1 during Car-Dex and 1 during BiRD) and 5 pts (22%) due to toxicity (2 pts due to Grade III renal failure, both attributable to Cfz, and 2 pts due to Grade III CHF during Cfz-Dex, 1 attributable to Cfz; 1 pt with Grade III Thromboembolic event during BiRD, attributable to Len-dex). Discussion This is the first prospective study evaluating the response to induction Cfz/Dex in treatment-naïve MM. Cfz/Dex therapy appears safe and effective in newly diagnosed myeloma patients. Responses deepen with subsequent IMiD(R)-based consolidation and maintenance. Toxicities due to each component of the regimen were manageable. The ORR of 87% and rate of VGPR or better of 61% in group with a high percentage of unfavorable cytogenetics compares favorably to similar studies using 1st generation proteasome inhibitor combinations, and may continue to improve with longer study follow-up. Disclosures: Mark: Onyx: Research Funding, Speakers Bureau; Millennium: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Off Label Use: Carfilzomib is not approved for front line use in myeloma. Rossi:Celgene: Speakers Bureau. Zafar:Onyx: Speakers Bureau; Millennium: Speakers Bureau; Celgene: Speakers Bureau. Pekle:Millennium: Speakers Bureau; Celgene: Speakers Bureau. Niesvizky:Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Onyx: Consultancy, Honoraria, Research Funding, Speakers Bureau; Millennium: The Takeda Oncology Company: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau.

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A Randomized Phase 3 Trial Of Melphalan-Lenalidomide-Prednisone (MPR) Or Cyclophosphamide-Prednisone-Lenalidomide (CPR) Vs Lenalidomide Plus Dexamethsone (Rd) In Elderly Newly Diagnosed Multiple Myeloma Patients

Blood ◽

10.1182/blood.v122.21.536.536 ◽

2013 ◽

Vol 122 (21) ◽

pp. 536-536 ◽

Cited By ~ 10

Author(s):

Antonio Palumbo ◽

Valeria Magarotto ◽

Sara Bringhen ◽

Massimo Offidani ◽

Giuseppe Pietrantuono ◽

...

Keyword(s):

Multiple Myeloma ◽

Board Of Directors ◽

Research Funding ◽

Alkylating Agents ◽

Second Primary ◽

Newly Diagnosed ◽

Advisory Committees ◽

Significant Difference ◽

Grade 3 ◽

To Receive

Abstract Background Rd and MPR are effective treatments in newly diagnosed multiple myeloma (NDMM) patients (pts). In this study we compared a non-alkylating containing regimen (Rd) vs alkylating-based regimens (MPR/CPR) in elderly transplant ineligible NDMM pts. Methods Patients were randomized (2:1) to receive nine 28-day cycles of MPR/CPR or Rd. MPR: lenalidomide 10 mg/day for 21 days; melphalan orally 0.18 mg/Kg for 4 days in pts 65-75 years old and 0.13 mg/Kg in >75 years pts; prednisone 1.5 mg/Kg for 4 days; CPR: cyclophosphamide orally 50 mg/day for 21 days in pts 65-75 years old and 50 mg every other day (eod) in >75 years pts; lenalidomide 25 mg/day for 21 days; prednisone 25 mg every other day. Rd: lenalidomide 25 mg/day for 21 days; dexamethasone 40 mg on days 1,8,15 and 22 in pts 65-75 years old and 20 mg in those >75 years. After induction, patients were randomized to receive maintenance with lenalidomide alone (10 mg/day for 21 days) or with prednisone (25 mg eod on days 1-28), until disease progression. The primary endpoint was progression-free survival (PFS). Results Between October 2009 and October 2012, 659 pts were enrolled ( MPR/CPR:439 and Rd:220), and 641 pts were evaluable (MPR/CPR:430 and Rd:211). Patient characteristics were well balanced in the 2 groups: median age was 73 years in both groups, 38% of pts were older than 75 years, 27% had ISS stage III in both groups, 21% of patients both in the MPR/CPR and in the Rd groups had unfavorable FISH profile [t(4;14) or t (14;16) or del17p]. After induction, the response rates were similar in the 2 groups: at least PR rate was 75% versus 79% (p=0.52) and CR rate was 9% versus 7% (p=0.35), in the MPR/CPR and Rd group, respectively. No significant difference in response rate were reported between two alkylating containing regimens. After a median follow-up of 21 months, the 2-year PFS was 55% in MPR/CPR and 49% in Rd (HR=0.86, 95% CI: 0.66-1.12, p=0.26), and 2-year OS was 84% in MPR/CPR and 80% in Rd (HR= 0.93, 95% CI: 0.60-1.41, p=0.71) At least one grade ≥3 hematological adverse event was reported in 51% with MPR/CPR and 29% with Rd (p<0.001), with a significant difference between the two alkylating agents (67% MPR and 31% CPR, p<0.001). At least one grade ≥3 extra-hematologic toxicities were similar in the two groups (31% with MPR/CPR and 28% with Rd, p=0.77). with no difference between two alkylating agents (31% both in MPR and CPR group). Second primary malignancies (SPM) were reported in 5 MPR patients (1 hematologic and 4 solid) in 1 CPR patient (hematologic) and in 2 Rd patients (both solid). Conclusion In a community-based population, triplet alkylating combinations did not lead to different PFS or OS clinical benefits over doublet therapy. Updated results will be presented at the meeting. Disclosures: Palumbo: Amgen: Consultancy, Honoraria; Bristol-Myers Squibb: Consultancy, Honoraria; Celgene: Consultancy, Honoraria; Janssen Pharmaceuticals: Consultancy, Honoraria; Millenium: Consultancy, Honoraria; Onyx: Consultancy, Honoraria. Bringhen:Celgene: Honoraria. Giuliani:Celgene: Research Funding. Cavallo:Celgene: Honoraria; Celgene: Membership on an entity’s Board of Directors or advisory committees. Hajek:Celgene: Honoraria; Celgene: Consultancy. Boccadoro:Celgene: Consultancy, Membership on an entity’s Board of Directors or advisory committees, Research Funding; Janssen-Cilag: Consultancy, Honoraria, Membership on an entity’s Board of Directors or advisory committees.

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Prognostic Factors Affecting Progression Free Survival For Multiple Myeloma Patients Receiving Lenalidomide Maintenance After Autologous Transplantation. Follow-Up Analysis Of The IFM 2005-02 Trial

Blood ◽

10.1182/blood.v122.21.3312.3312 ◽

2013 ◽

Vol 122 (21) ◽

pp. 3312-3312

Author(s):

Gerald Marit ◽

Valérie Lauwers-Cances ◽

Denis Caillot ◽

Thierry Facon ◽

Cyrille Hulin ◽

...

Keyword(s):

Multiple Myeloma ◽

Prognostic Factors ◽

Board Of Directors ◽

Maintenance Treatment ◽

Autologous Transplantation ◽

Progression Free Survival ◽

Advisory Committees ◽

Free Survival ◽

Factors Affecting

Abstract Background Lenalidomide is an effective agent for the treatment of multiple myeloma (MM). The IFM Group conducted a randomized double-blind placebo controlled trial investigating the efficacy of lenalidomide maintenance treatment after autologous transplantation (IFM 2005-02 trial). The results showed that lenalidomide maintenance therapy significantly prolonged progression-free survival (PFS). Methods The aim of the present study was to identify prognostic factors affecting PFS in the 614 patients enrolled in this study. Analysis was performed using an extended Cox model, complete response (CR) was entered into the model as a time varying covariate. Results With a median follow-up of 60.6 months (54.5-68) PFS since randomization was shorter in the placebo arm (23.8 months, 95% CI 21-27.3) than in the lenalidomide arm (45.6 months, 95% CI: 40-55.1) (p<.001). Multivariate analysis showed that lenalidomide maintenance treatment arm, female sex, and obtention of CR were favourable prognostic factors for PFS. Conversely, beta2microglobuline, deletion of chromosome 13 and induction treatment reinforced by DCEP were associated with reduced PFS. For patients not in CR before initiation of maintenance therapy lenalidomide arm improved significantly PFS. This advantage is still observed in the 129 patients in CR at time of initiation of maintenance treatment. Conclusion These results confirm that obtention of CR at any time during treatment is a major factor for improving PFS in MM patients receiving first-line treatment including autologous transplantation. In this setting our data and those of other studies seems to support that lenalidomide maintenance treatment could be an intereresting option for delaying progression. At this time the gain in PFS did not translate into an OS improvement Disclosures: Marit: janssen-cilag: Honoraria, upport for travel to meeting, meeting expenses, upport for travel to meeting, meeting expenses Other; celgene: support for travel to meeting, meeting expenses Other. Off Label Use: lenalidomide maintenance treatment after autologous transplantation in myeloma patients. Facon:Amgen: Membership on an entity’s Board of Directors or advisory committees; Britsol-Myers Squibb: Membership on an entity’s Board of Directors or advisory committees; Onyx: Membership on an entity’s Board of Directors or advisory committees; Millennium: The Takeda Oncology Company: Membership on an entity’s Board of Directors or advisory committees; Celgene: Membership on an entity’s Board of Directors or advisory committees; Janssen: Membership on an entity’s Board of Directors or advisory committees; Novartis: Membership on an entity’s Board of Directors or advisory committees. Hulin:JANSSEN: Honoraria; CELGENE: Honoraria. Moreau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Roussel:JANSSEN: Honoraria; CELGENE: Honoraria. Avet-Loiseau:JANSSEN: Honoraria, Speakers Bureau; CELGENE: Honoraria, Speakers Bureau. Attal:CELGENE: Honoraria, Speakers Bureau; JANSSEN: Honoraria, Speakers Bureau.

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Minimal Residual Disease Detection By Multiparametric Flow Cytometry in Newly Diagnosed Multiple Myeloma Patients: A Preliminary Analysis of the EMN02/HO95 MM Study

Blood ◽

10.1182/blood.v126.23.1760.1760 ◽

2015 ◽

Vol 126 (23) ◽

pp. 1760-1760

Author(s):

Stefania Oliva ◽

Manuela Gambella ◽

Milena Gilestro ◽

Francesca Gay ◽

Alessandra Larocca ◽

...

Keyword(s):

Board Of Directors ◽

Residual Disease ◽

Newly Diagnosed ◽

Advisory Committees ◽

Off Label ◽

Depth Of Response ◽

To Receive ◽

Minimal Residual

Abstract Introduction: Multiple myeloma (MM) is still an incurable disease and patients may relapse despite achievement of complete remission (CR). Minimal residual disease (MRD) assessment by multiparameter flow cytometry (MFC) on bone marrow (BM) is a sensitive diagnostic tool to measure response and is highly predictive of outcome in MM as previously reported. The aim of this study is to evaluate the role of MRD monitoring by MFC in MM patients receiving novel agents with or without autologous stem cell transplantation (ASCT) and to investigate the efficacy of treatments by using MRD-negativity as a deeper response criteria. Methods: The RV-MM-COOP-0556 (EMN02/HO95 MM) study is a phase III, randomized, trial including newly diagnosed MM patients ≤ 65 years. All subjects received 4 cycles of Bortezomib-Cyclophosphamide-Dexamethasone (VCD) induction, followed by Cyclophosphamide chemotherapy and subsequent stem cell mobilization and collection. Afterward, patients were randomized to receive 4 cycles of Bortezomib-Melphalan-Prednisone (VMP) vs one or two cycles of High-Dose-Melphalan (HDM) followed by ASCT. After intensification patients were secondly randomized to receive two cycles of consolidation with Bortezomib-Lenalidomide-Dexamethasone (VRD) vs no consolidation, followed by Lenalidomide maintenance in both arms. Patients who achieved CR/sCR according to IMWG criteria (Rajkumar et al. Blood 2011) after intensification/consolidation treatment, were eligible for the MRD sub-study. MRD analysis by MFC was performed on BM samples after intensification/consolidation, after 6 courses of maintenance, and thereafter every 6 months until progression, to detect monoclonal plasma cells (PCs). Here, we used a double antibody combination (CD138Fitc/CD20PerCp-Cy5.5/CD117APC/CD45APC-H7/CD38PE-Cy7; cyKappaFitc/cyLambdaPE/CD19PerCp-Cy5.5/CD56APC/CD45APC-H7/CD38 PE-Cy7): one tube was employed to obtain PCs quantification, the other one to validate PCs clonality. MRD-negativity was defined when <20 clonal PCs were detected among ≥2.000.000 leukocytes (<0.001%). Results: One hundred-eleven Italian patients (58 male/53 female) with a median age of 56 years (IQR 52-62) entered MRD sub-study. Sixteen (14%) were ISS stage III, 24 (22%) had high-risk cytogenetic profile and 10 (9%) had LDH levels higher than the upper normal limit. Forty-five patients (40%) received VMP as intensification and 66 (60%) underwent ASCT, thereafter 65 (58%) received VRD consolidation, 24 after VMP and 41 after ASCT. The median follow-up were 28.7 and 17 months from starting treatment and from MRD enrollment, respectively. After intensification/consolidation, 4 patients were not evaluable for MRD due to unsuitable samples, MRD negativity rate was 79% (85 out of 107 evaluable patients) and was independent from the intensification therapy: actually 50/63 patients who received ASCT and 35/44 patients who received VMP achieved MRD negativity. Within MRD-negative patients, 48/85 (56%) received VRD consolidation without major differences between VMP and ASCT. With the limitation related to the shorter follow-up, depth of response further improved during maintenance: 11/22 (50%) of MRD-positive patients became MRD-negative, independently from previous intensification therapy. Conclusions: MRD detection by MFC is a feasible technique in MM and allows to detect residual tumor cells among CR and sCR patients. Preliminary MRD results show that, in patients achieving CR, intensification with VMP or ASCT induced comparable rates of MRD-negativity and maintenance with Lenalidomide further improved depth of response in both arms. Longer follow-up is needed to correlate MRD status to prognosis and clinical outcome and to evaluate the role of maintenance therapy in increasing the quality of response. Disclosures Off Label Use: Use off-label of drugs for the dose and/or schedule and/or association . Gay:Sanofi: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Honoraria. Larocca:Janssen-Cilag, Celgene: Honoraria. Caravita:Celgene: Honoraria. Gamberi:Janssen Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees; Mundipharma: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees. Rossi:Celgene: Research Funding. Offidani:Janssen-Cilag, Celgene, Sanofi, Amgen, Mundipharma: Honoraria. Boccadoro:Sanofi: Consultancy, Membership on an entity's Board of Directors or advisory committees; Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees; Onyx Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees; Janssen-Cilag: Consultancy, Membership on an entity's Board of Directors or advisory committees. Sonneveld:Janssen-Cilag, Celgene, Onyx, Karyopharm: Honoraria, Research Funding; novartis: Honoraria. Palumbo:Novartis, Sanofi Aventis: Honoraria; Celgene, Millennium Pharmaceuticals, Amgen, Bristol-Myers Squibb, Genmab, Janssen-Cilag, Onyx Pharmaceuticals: Consultancy, Honoraria.

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