Response Rates In Multiple Myeloma Research Articles

Preclinical discovery and initial clinical data of WVT078, a BCMA × CD3 bispecific antibody.

B-cell maturation antigen (BCMA) is an ideal target in multiple myeloma (MM) due to highly specific expression in malignant plasma cells. BCMA-directed therapies including antibody drug conjugates, chimeric antigen receptor-T cells and bispecific antibodies (BsAbs) have shown high response rates in MM. WVT078 is an anti-BCMA× anti-CD3 BsAb that binds to BCMA with subnanomolar-affinity. It was selected based on potent T cell activation and anti-MM activity in preclinical models with favorable tolerability in cynomolgus monkey. In the ongoing first-in-human phase I dose-escalation study (NCT04123418), 33 patients received intravenous WVT078 once weekly at escalated dosing. At the active doses of 48-250 µg/kg tested to date (n = 26), the overall response rate (ORR) was 38.5% (90% CI: 22.6-56.4%) and the complete response rate (CRR, stringent complete response + complete response) was 11.5%, (90% CI: 3.2-27.2%). At the highest dose level tested, the ORR was 75% (3 of 4 patients). 26 (78.8%) patients reported at least one Grade ≥3 AE and 16 of these AEs were suspected to be drug related. 20 patients (60.6%) experienced cytokine release syndrome. WVT078 has an acceptable safety profile and shows preliminary evidence of clinical activity at doses tested to date.

Minimal Residual Disease in Multiple Myeloma: Something Old, Something New.

Simple SummaryCurrently, response rates in multiple myeloma (MM) have increased dramatically, with more than 50% otablef those who respond satisfying complete response criteria. Achieving frequent deep responses has necessarily led to test conceptual advantages for assessing and treating MM patients with only minimal residual disease (MRD). In this review, we present and discuss the clinical relevance, methodology, and challenges for measuring MRD in MM.The game-changing outcome effect, due to the generalized use of novel agents in MM, has cre-ated a paradigm shift. Achieving frequent deep responses has placed MM among those neoplasms where the rationale for assessing MRD is fulfilled. However, its implementation in MM has raised specific questions: how might we weight standard measures against deep MRD in the emerging CAR-T setting? Which high sensitivity method to choose? Are current response criteria still useful? In this work, we address lessons learned from the use of MRD in other neoplasms, the steps followed for the harmonization of current methods for comprehensively measuring MRD, and the challenges that new therapies and concepts pose in the MM clinical field.

Reduced Intensity Stem Cell Transplantation Followed By Adjunctive Lenalidomide Is Tolerable and Safe and Improves Complete Response Rate in Multiple Myeloma:a UK NCRI Phase 2 Feasibility Study (LenaRIC)

BackgroundThe role of allogeneic stem cell transplantation in the management of myeloma remains uncertain as it is a procedure with significant mortality and low long term rates of disease control. We sought to evaluate the feasibility of using adjunctive Lenalidomide (Revlimid®) to augment long term myeloma response following Reduced-Intensity Conditioned (RIC) allograft in the UK NCRI trial LenaRIC (Lenalidomide in Reduced Intensity Conditioned Transplant)-ISRCTN:16228367.Material & MethodsForty (40) patients were recruited in this single arm phase II trial at ten UK stem cell transplant centres from June 2011-June 2015. All patients were in CR/VGPR 1 or 2 and had undergone a Melphalan conditioned autologous transplant in the previous 6 months. They then underwent a RIC allograft using Fludarabine & 2Gy TBI with ATG (Fresenius) as in vivo T-cell depletion (planned tandem SCT programme). Patients were scheduled to receive Lenalidomide (10mg until 2013, reduced to 5mg thereafter on DMEC advice) from day +35 if stable donor engraftment was present in the absence of GvHD. Lenalidomide was planned to be discontinued 12 months post-transplant with donor lymphocyte infusions given to patients with evidence of residual disease, relapse or mixed chimerism.ResultsOf the thirty nine(39) patients transplanted within 42 days of study entry, 8 were in CR1, 16 in VGPR1, 7 in CR2 and 8 in VGPR2. The median age was 49 years (range 35-65) with peripheral blood as the graft source in the 39 patients, from either sibling (n=16) or 10/10 matched unrelated donor (n=23). 1 patient failed to proceed to transplant. Of thirty four (34) evaluable patients, 28 (82.4%) achieved full donor T-cell chimerism and 32 (94.1%) full donor in whole blood. 34 patients completed at least one cycle of Lenalidomide. Mean number of cycles received was 7.4 (range 1-12, median 9.0). Mean dose was 5.2mg, median 5mg. 16 patients completed at least 10 cycles and 5 patients completed 12 cycles as per protocol treatment; of those completing >= 10 cycles, 5/16 received DLI.Safety dataThere were eight (8) patients who had biopsy-proven aGVHD (4 of grade 1-2 and 4 of grade 3- all 4 within 3 cycles of Lenalidomide) and 3 patients with cGVHD (2 extensive and 1 limited). No Grade 3/4 aGVHD was seen following DMEC advice to reduce the Lenalidomide dose to 5mg daily. 8 patients experienced grade 3 or 4 non-Haem toxicity. The majority of AEs were grade 1-2. Significant (Grade 3/4) non-Haem SAEs in this transplant population included Gastro-intestinal (4 patients), metabolism (4 patients), infection (13 patients) and vascular (4 patients). One year relapse-free survival was 84.3%.Clinical OutcomesEfficacy was assessed at a median follow-up of 445 days. The pre-transplant CR rate of 38.4% was improved to 67.6% at best response post-transplant. PFS at 2 years was 43.1% (figure 1a), OS at years 75.7% with a 2 year disease-free survival of 59.1% (figure 1b). Of the 10 patients who have died, 6 have been recorded as disease-related.Conclusions1) Based on the pre-defined safety stopping rules, the LenaRIC study shows that post-graft Lenalidomide is safe and tolerated in a T-depleted RIC setting at a dose of 5mg daily- this results in a tolerable AE profile with an acceptable GVHD rate.2) Acute GVHD only occurred in the first 3 cycles of exposure to Lenalidomide- consideration should be given to examining the longer term use of Lenalidomide beyond 12 months following a T-depleted RIC allograft to augment long term outcomes3) CR rates were nearly doubled by this approach4) Further work correlating Lenalidomide exposure with clinical events and immune reconstitution is ongoing.An unrestricted educational grant was provided to support the trial & adjunctive science by Cancer Research UK and by Celgene. Lenalidomide provided free of charge by Celgene. Lenograstim provided free of charge by Chugai. The support and time of participating patients and their families is gratefully acknowledged. [Display omitted] DisclosuresCook:Janssen: Honoraria, Other: Travel support, Research Funding; Amgen: Honoraria, Other: Travel support; Takeda: Honoraria; Myeloma UK: Membership on an entity's Board of Directors or advisory committees; Celgene: Honoraria, Other: Travel support, Research Funding; Jazz Pharmaceuticals: Honoraria. Brock:Merck: Other: travel expenses; Roche: Honoraria, Other: travel expenses; GlaxoSmithKline: Equity Ownership; Astra-Zeneca: Equity Ownership. Snowden:Sanofi: Honoraria. Hunter:Celgene: Other: Travel Support. Cavenagh:Takeda: Consultancy; Novartis: Consultancy; Janssen: Honoraria; Celgene: Consultancy. Cook:BMS: Consultancy, Honoraria; Sanofi: Consultancy, Honoraria, Speakers Bureau; Janssen: Consultancy, Honoraria, Research Funding, Speakers Bureau; Takeda: Consultancy, Honoraria, Research Funding, Speakers Bureau; Glycomimetics: Consultancy, Honoraria; Amgen: Consultancy, Honoraria, Speakers Bureau; Celgene: Consultancy, Honoraria, Research Funding, Speakers Bureau.

Plasma cell-free DNA chromosomal instability score as early predictor to monitor tumor burden in response to therapeutic in multiple myeloma patients.

8036 Background: Multiple myeloma (MM) is a plasma cell malignancy characterized by chromosomal instabilities (CIN). Here we investigate the potential of cell-free DNA CIN as non-invasive biomarker to predict early response for MM treatments. Methods: In this prospective study, we recruited 11 relapsed/refractory (RRMM) and 19 newly diagnosed (NDMM) patients at Changzheng Hospital. Plasma samples were collected after finished two cycles or one month (RRMM) of therapy, with matched ones before the current regimen. cfDNA was extracted, followed by CIN analyses by using a customized bioinformatics workflow, ultrasensitive chromosomal aneuploidy detector (UCAD). Criteria for response and progression were according to the IMWG (Durie BG et al. 2006). Results: 7 (23%) patients (5 RRMM and 2 NDMM) showed high cfDNA CIN regard as strong positive after two cycles of treatment. Plasma cfDNA CIN profiling found complex clonal evolution compared two cycles to baseline. Multiple genomic regions, including chr7, 17p (TP53), 12q and 3p, were involved in clonal evolution. The degree of cfDNA CIN correlated with myeloma stage and overall survival. Remarkably, of the 5 heavily treated RRMM patients and 1 primary refractory newly diagnosed patient, 3 died within 60 days after the last time of cfDNA detection. Nine patients (30%) of patients showed positive cfDNA CIN after two cycles of treatment, which response rate was 11% (n=1) with SD, 33% (n=3) with MR, and 56% with PR, respectively. Fourteen patients with 5 RRMM and 9 NDMM were detected marginal or negative cfDNA CIN after two cycle’s treatment. The overall response rate in 14 patients was 100%, including 14.3% with a complete response, 14.3% with a very good partial response (VGPR), 57.1% with a PR, and 14.3% with a MR. Of these patients, 3 RRMM who received with more than six lines of therapy, showed positive cfDNA CIN. Subsequently, these three heavily treated RRMM patients have chance to enroll the chimeric antigen receptor T-Cell immunotherapy (CAR-T) therapy (enrolled NCT03093168). Surprisedly, all of them benefit from the CAR-T therapy to improve responses dramatically, meanwhile, the dynamics of total cfDNA concentration correlated with tumor burden to negative. Conclusions: We provide evidence that cfDNA level correlates with tumor burden and response rate in MM. For heavily pre-treated advanced RRMM patients with cfDNA CIN positive were benefit from the CAR-T therapy. Therefore, serial plasma cfDNA analysis is a robust and sensitive tool for monitoring response to therapy.

Immunohistochemical expression of cereblon and MUM1 as potential predictive markers of response to lenalidomide in extranodal marginal zone B-cell lymphoma of the mucosa-associated lymphoid tissue (MALT lymphoma).

Lenalidomide is an active agent for the treatment of MALT lymphoma. Recently, high expression levels of cereblon (CRBN) and MUM1 have been associated with better response rates in multiple myeloma treated with lenalidomide. However, there are no data on CRBN and MUM1 expression in MALT lymphoma. In the current study, we have systematically investigated a potential correlation of CRBN/MUM1 immunohistochemical expression and response to lenalidomide-based therapy in a series of 46 patients with MALT lymphoma treated at the Medical University Vienna 2009 to 2014. In total, 28% (13/46) of biopsy specimens derived from gastric tissues, while 72% (33/46) originated from extragastric MALT lymphoma. In terms of CRBN, 54% showed high expression (CRBN+, ≥50% positive cells); the remaining 46% were classified as low expression (CRBN-). In contrast to other reports, there was a non-significant trend towards worse response rates in CRBN+ (68% versus 86%, P=0.161). Relapse rates (P=0.592) and PFS (P=0.306) did not differ between CRBN+/CRBN-, but all 3 patients progressing on lenalidomide were CRBN+ and both patients completely lacking CRBN expression responded to treatment. Concerning MUM1, 62% were MUM1-negative (MUM1-) and 38% positive (MUM1+). There was no difference in response to lenalidomide by MUM1-status (MUM1+ 71% versus MUM1- 79%, P=0.546) and also relapse rates (P=0.828) and PFS (P=0.681) did not differ. Interestingly, a subgroup analysis of gastric lymphoma revealed a significantly better PFS for CRBN- and MUM1- patients, respectively (both P<0.05). To conclude, there was no significant difference in response to lenalidomide between patients with low or high expression of CRBN/MUM1 in a general population of MALT lymphoma, and immunohistochemical CRBN/MUM1 assessment cannot be recommended in the clinical routine.

The Co-Occurrence of MAF Translocations in RAS Mutated Multiple Myeloma Confers Resistance to MEK Inhibition

IntroductionMutant NRAS and KRAS lead to the activation of the RAS/RAF/MEK/ERK pathway in approximately 50% of multiple myeloma (MM). Blocking this pathway with MEK1/2 inhibitors (MEKi) such as trametinib (Tram) is a therapeutic option but the response rate in MM varies between 30-50% (Heuck et al, Leukemia 2015). In MM it is unknown whether RAS mutation status correlates with sensitivity to Tram. The purpose of this study was to characterize factors which predict response to Tram and to identify mechanism mediating resistance.MethodsWe established the IC50 of Tram using MTT assays in 32 MM cell lines (HMCL) including 16 RAS mutant positive (RASm+), and 15 wildtype RAS (RASm-), and 1 BRAF mutant (BRAFm+) line which acted as a positive control. HMCLs were classified according to the IC50 value as sensitive (<0.05μM); intermediate sensitive (IMS) (0.05 and 10μM); and resistant (>10μM). All lines underwent immunoblotting for pERK at baseline and following treatment with serial concentrations of Tram to identify correlation of activation with sensitivity. BrdU incorporation analyzed by FACS was performed to determine the molecular action of Tram. A lentiviral mediated expression system was used to engineer a MAF overexpressing cell line in a RASm+ HMCL lacking MAF (MMRASm+MAF) and silencing MAF in two lines with co-occurring MAF and RASm+ (MMRASm+shMAF). The clinical characteristics of 84 relapsed RASm+ patients who received Tram either as a single agent or in combination with other anti-MM therapies were also examined.Results6/16 (37.5%) of RASm+ HMCLs were sensitive to Tram, 5/16 (31.1%) were IMS and 5/16 (31.1%) resistant. There was no difference in sensitivity to Tram between KRASm+ (IC50 = 9.5μM, n = 11) and NRASm+ (IC50 =12.5μM, n=4, p=0.65). In contrast, 13/15 (87%) RASm- HMCLs were resistant to Tram. Mechanistically, Tram blocked cell cycle progression in Tram-sensitive RASm+ cells with an increase in G0/G1 phase (22.25%) and a decrease in S phase (16.76%) compared with untreated controls (p<0.01). These in-vitro findings correlated with our clinical experience where there was no difference in progression free or overall survival (OS) between KRASm+ (n=46) or NRASm+ (n=38) patients treated with Tram.Given that RASm+ lines exhibit a range of sensitivity (IC50 0.005-30μM), we further defined additional molecular modifiers that influence sensitivity by comparing KRASm+ alone with KRASm+ co-occurring with t(14;16) (n=4) or t(4;14) (n=3). The mean IC50 value of Tram (0.025μM) in 5 RASm+ was significantly lower than those with a co-occurring t(14;16) (IC50 =16μM; P<0.001) or a t(4;14) (IC50 =11.6μM, P<0.05). Among 15 RASm- HMCLs, the IC50 (37.5μM, n=9) of Tram was much higher in t(14;16) HMCL than in t(4;14) (IC50=9.16μM, n=3, P<0.01). A similar pattern was seen in patients, with a shorter OS when RASm+ co-occurred with t(14;16) or t(4;14) (n=17 OS=0.99yrs) than those with RASm+ alone (n= 67, OS=1.85yrs, P=0.01). These findings provide evidence that co-occurring MAF expression renders RAS+ MM less sensitive to MAKP inhibition.To determine if activation of MAPK pathway caused by RAS mutation was associated with sensitivity to MEKi, we assess baseline and post Tram treatment levels of p-ERK1/2, a downstream substrate of MEK1/2 activation. MM HMCLs displayed variable basal levels of pERK. There was no correlation between basal levels of pERK and RASm+, with the highest baseline levels of pERK being seen in HMCLs with a t(14;16) or t(14;20) and wildtype RAS, intermediate levels in RASm+ with a t(14;16) and lowest in RASm+ alone. The concentrations of Tram for complete inhibition of pERK were higher in HMCLs with co-occurring t(14;16) ( >or = 500 nM) than for RASm+ alone.To further confirm the ability of MAF to confer resistance of RASm+ cells to MEKi, we examined the sensitivity of MMRASm+/MAF to Tram.MTT assay showed that the IC50 of MMRASm+/MAF cells was 50% higher than that of MMEV cells (P <0.001). Similar results were observed in two other HMCLs with transient ectopic expression of MAF indicating that increase in MAF protein in RAS mutant cells reduces sensitivity to MEKi. In contrast, silencing of MAF in two RASm+ HMCLs significantly increased sensitivity (75% decrease in IC50) to Tram, compared with MMRASm+shCont (P<0.001).ConclusionOur results demonstrate that RASm+ MM is sensitive to Tram but the co-occurrence of t(14;16) leading to MAF overexpression confers resistance both in-vitro and in patients. DisclosuresMorgan:Univ of AR for Medical Sciences: Employment; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Consultancy, Honoraria; Bristol Meyers: Consultancy, Honoraria; Janssen: Research Funding. Davies:Celgene: Consultancy, Honoraria; Takeda: Consultancy, Honoraria; Janssen: Consultancy, Honoraria.

Light chains removal by extracorporeal techniques in acute kidney injury due to multiple myeloma: a position statement of the Onconephrology Work Group of the Italian Society of Nephrology.

Acute kidney injury (AKI) is a frequent complication of multiple myeloma and is associated with increased short-term mortality. Additionally, even a single episode of AKI can eventually lead to end-stage renal disease (ESRD), significantly reducing quality of life and long-term survival. In the setting of multiple myeloma, severe AKI (requiring dialysis) is typically secondary to cast nephropathy (CN). Renal injury in CN is due to intratubular obstruction from precipitation of monoclonal serum free light chains (sFLC) as well as direct tubular toxicity of sFLC via stimulation of nuclear factor (NF)κB inflammatory pathways. Current mainstays of CN treatment are early removal of precipitating factors such as nephrotoxic drugs, acidosis and dehydration, together with rapid reduction of sFLC levels. Introduction of the proteasome inhibitor bortezomib has significantly improved the response rates in multiple myeloma due to its ability to rapidly reduce sFLC levels and has been referred to as "renoprotective" therapy. As an adjunct to chemotherapy, several new extracorporeal techniques have raised interest as a further means to reduce sFLC concentrations in the treatment of CN. Whether addition of extracorporeal therapies to renoprotective therapy can result in better renal recovery is still a matter of debate and there are currently no guidelines in this field. In this positon paper, we offer an overview of the available data and the authors' perspectives on extracorporeal treatments in CN.

Long-term outcomes of different bortezomib-based regimens in Chinese myeloma patients

Bortezomib has significantly increased the response rates in multiple myeloma (MM), but optimal bortezomib-based regimens for initial MM therapy have not yet been defined. We retrospectively compared the outcomes of 128 patients newly diagnosed with symptomatic MM who received either bortezomib combined with dexamethasone (PD) or three-drug combinations of PD with liposomal doxorubicin (PAD) or thalidomide (PTD). The overall response rate (ORR), very good partial response (VGPR) rate, and complete remission CR/near-complete remission (nCR) results were better for the PAD and PTD regimens than for the PD group. Three-year overall survival (OS) was 80.1%, 72.5%, and 61.8% with PAD, PTD, and PD regimens, respectively. The 3-year OS rate of PAD and PTD was significantly higher than that of PD (80.1% vs 61.8%, P=0.024; 72.5% vs 61.8%, P=0.035), but the difference was not statistically significant between PAD and PTD (80.1% vs 72.5%, P=0.843). Similarly, the PAD and PTD regimens resulted in significantly superior 3-year progression-free survival (PFS) rates. The patients in the PTD arm were more frequently observed with grade 1–3 peripheral neuropathy (PN), compared to those in the PAD and PD groups, especially grade 2–3 PN. PN developed less frequently without sacrificing the efficacy when bortezomib was administered subcutaneously rather than intravenously. Our experience suggests that the three-drug combinations PAD and PTD produce a better outcome than PD, especially with respect to PAD, with fewer adverse events.

Impact Of Response Duration and Maintenance Therapy After Autologous Stem Cell Transplantation On Long-Term Survival In Multiple Myeloma Patients

BackgroundThe introduction of novel agents has significantly improved response rates in multiple myeloma (MM) patients. The exact impact of quality and duration of response on long-term survival, however, remains controversial. MethodsWe retrospectively analyzed MM patients who underwent high-dose chemotherapy and autologous stem cell transplantation (ASCT) as first-line therapy at our center between June 1992 and February 2012. Treatment response was assessed according to IMWG criteria both immediately before and 100 days after ASCT. Overall survival (OS) was calculated from day 100 after first ASCT. In addition, in a landmark analysis OS was calculated starting from 3 years post first ASCT. Log-rank tests were used to assess the impact of response on OS. P-values < 0.05 were regarded as statistically significant. Results1155 patients with symptomatic MM (683 males, 472 females) were evaluated for this analysis. Median age was 56 years (y) (range 24 to 74y). 751 received single, 404 tandem ASCT. Maintenance therapy with interferon, thalidomide, or bortezomib was administered after ASCT to 629 patients. 37 proceeded to allogeneic transplantation and were censored at that time. Median OS was 5.2y (range 4.8 to 5.8y).The achievement of complete response (CR) or near CR (nCR) before ASCT was associated with a superior OS of 7.0y, significantly longer than for those achieving either a partial response (PR) or very good PR (VGPR) (p < 0.01 and p = 0.04, resp.). Evaluating response on day 100 after ASCT, patients in CR/nCR continued to show superior OS in comparison to those in PR (p < 0.01). However, VGPR post-transplant had similar prognostic value to CR/nCR (p = 0.17). Interestingly, patients remaining in stable disease or minimal response after ASCT also had a favorable OS of 6.4y (range 4.8 to 9.7y), potentially indicating a distinct biological entity.To assess whether timing of response is of prognostic relevance, we compared outcome of patients reaching CR/nCR before ASCT with those of patients achieving CR/nCR only after ASCT. Early and late responders showed a similar OS (7.0y vs 6.4y, p = 0.2) with no significant difference between the two groups.For the 3-year landmark analysis 709 patients were evaluable. Remarkably, the depth of response before or after ASCT did not exert any significant effect on survival for those patients still alive 3y after ASCT (p = 0.8 and 0.3 resp.). However, the implementation of maintenance therapy after ASCT was associated with a strong survival benefit (OS 5.6 vs 2.9y, p < 0.01).To assess the importance of response duration, we compared the OS of patients with sustained CR/nCR at 3yrs after ASCT to patients in all other response groups (non-CR/nCR) and patients who had relapsed in the interval (lost CR/nCR and lost non-CR/nCR, respectively). Remarkably, OS was excellent for patients with sustained CR/nCR (10.2y) as well as with sustained non-CR/nCR (7.8y), with no significant difference between both groups. However, patients with lost CR/nCR or lost non-CR/nCR had an unfavorable OS of 2.4 and 2.7y, resp. (fig. 1). Combining the effects of sustained response and application of maintenance therapy showed a significant benefit for maintenance therapy in patients with both sustained and lost response without annihilating the clear difference in survival between the two latter groups (fig. 2). ConclusionIn this large, retrospective single-center study, achievement of CR/nCR before and after ASCT was prognostic in regard to OS. Yet, for patients evaluable 3y after ASCT, no further significant influence of the quality of response achieved by ASCT was detectable. While patients with sustained CR/nCR as well as those with inferior yet sustained responses showed similar survival, both groups had a markedly better outcome than those patients losing a once obtained response. This effect was independently improved by the implementation of maintenance therapy, indicating that intervention to sustain achieved responses appears to be a key factor for long-term survival. [Display omitted] [Display omitted] Disclosures:Ho:Sanofi-Aventis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees; Genzyme: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees.

Combination Therapy Based on Bortezomib for Newly Diagnosed Multiple Myeloma Patients

AbstractAbstract 5048 Introduction:Novel drugs, such as bortezomib, have significantly improved the response rates in multiple myeloma (MM), but little has been reported on bortezomib-based therapies in Chinese patients. Methods:In the initial eight 28-day cycles, newly diagnosed ymptomatic patients were treated with combination therapy including bortezomib plus dexamethasone (PD) and the triplet combinations of PD with adriamycin (PAD), cyclophosphamide (PCD), thalidomide (PDT) between February 1, 2006 and May 31, 2012. Among the above regimens, bortezomib (1. 3 mg/m2) was given intravenously on days 1, 4, 8, 11, while dexamethasone (20 mg/m2/day) was given intravenously on days 1–2, 4–5, 8–9, 11–12, adriamycin (10 mg/m2) was given intravenously on days 1–4, cyclophosphamide (200 mg/m2) was given intravenously on days 1–4 and thalidomide (100 mg) was administered orally each day. Results:The overall response rate (¡Ý partial response, PR) of all the 151 eligible patients was 88. 7% (including 29. 8% very good partial response (VGPR) and 25. 8% complete response/near complete response (CR/nCR). The responses per IMWG criteria for patients are shown in Table 2. The median PFS was 20. 3 months (95% CI: 14. 8–25. 8 months) in the patients who received PDT, 24. 8 months (95% CI: 20. 0–30. 0 months) in the patients who received PCD, 22. 9 months (95% CI: 17. 6–28. 2 months) in patients who received PAD and 21. 8 months (95% CI: 15. 3–28. 3 months) in the patients who received PD with no significant differences between the groups. The median OS for PD arm was 42. 0(95% CI: 20. 1–63. 9 months) months while other arms were not reached, but the median OS for PDT, PCD and PAD was significant longer than PD (P=0. 042, 0. 039, 0. 010). PFS and OS for patients with favorable cytogenetics were significantly longer than those with unfavorable cytogenetics by FISH. The frequently observed hematologic toxicities (Grade 3/4) were: thrombocytopenia (17. 00%), neutropenia (15. 00%) and anemia (8. 61%). The most common non-hematologic toxicities included (all Grades) peripheral neuropathy(57. 61%), fatigue(27. 15%), infection(23. 84%), constipation(22. 52%), herpes zoster(17. 22%) and diarrhea(15. 23%). Conclusions:Our experience indicated that bortezomib-based regimens were active and well-tolerated for MM patients, and triplet combinations were superior to PD. Serious Adverse events were rare in the Chinese patients with MM who received bortezomib-based chemotherapy. [Display omitted] [Display omitted] Disclosures:No relevant conflicts of interest to declare.

Longitudinal Evaluation of 110 Bone Marrow Aspirates of Multiple Myeloma Patients Treated with Lenalidomide Alone or in Combination with Autologous Stem Cell Transplantation or Alkylators for Early Dysplastic Signs

Abstract 2885 Introduction:Lenalidomide (LEN) is structurally similar to thalidomide and induces high response rates in multiple myeloma (MM). Recently several randomized trials (IFM 2005–02, CALGB 100104) have shown that LEN maintenance given after autologous stem cell transplant (ASCT) in newly diagnosed MM patients resulted in significant prolongation of the progression-free survival. Unfortunately in both trials an increased rate of second cancers with a high concern for the development of MDS/AML was observed. Therefore the goal of this study was to evaluate the bone marrow and corresponding cytogenetic data of patients treated with LEN alone or in combination for early signs of MDS. Methods:To investigate the role of ASCT and alkylators such as bendamustine in combination with LEN in the development of MDS we evaluated•newly diagnosed MM patients treated with LEN and dexamethasone alone (LD alone) (n=14)•○ pre treatment, after 6–9 cycles, at follow up•newly diagnosed MM patients treated with LEN and dexamethasone followed by ASCT (LD+ASCT) (n=18)•○ pre treatment, after 3–4 cycles, 3 months after ASCT, at follow up•relapsed MM patients treated with LEN, bendamustine and dexamethasone (BLD) (n=8)•○ pre treatment, at the end of treatment after median 6 cycles (4–8 cycles), at follow upWe evaluated 110 bone marrow specimens (aspirate smears and biopsy) and the corresponding peripheral blood films and cytogenetic studies, including classical and myeloma-related FISH studies, in 40 MM patients. Review of morphology and cytogenetic studies were performed independently of each other. Results:In the LD alone arm, 5 out of 14 (36%) patients showed mild, non-specific erythropoietic and megakaryopoietic dyspoiesis pre-treatment. Those changes were also found in 6 of 14 (43%) and 4 of 6 (67%) of patients after 6–9 cycles and at further follow up (median follow up 14 months; range 12–28.5), respectively. One patient developed MDS 13 months after start of treatment that was characterized by frank megakaryocytic dysplasia, ring sideroblasts and an abnormal clone 46, XX, t(4;11)(q31;p15)[3]/46, XX[18]. This patient had no karyotypic abnormalities related to MDS prior to treatment.In patients treated with LEN for 4 cycles followed by ASCT (LD+ASCT), 1 of 16 patients (6%) showed mild megakaryocytic dyspoiesis pretreatment. Mild megakaryocytic dyspoiesis was present in 2 of 17 (12%) and 3 of 16 (19%) patients after 4 cycles of LEN and at 3 months post ASCT, respectively. At further follow up in 8 patients (median 12.5 months, range: 10–22), dysmegakaryopoietic signs were no longer detected. Only one patient was found to have a potentially significant clonal cytogenetic abnormality post LD+ASCT that could not be attributed to myeloma – 46, XY, t(2;17)(p23;q11.2)[2]/46, XY[17]. The t(2;17) persisted in the subsequent bone marrow evaluation, but was no longer present in the next evaluation.In relapsed and heavily pretreated MM patients (median 3 prior treatments; range 2–9) receiving BLD, 5 of 7 patients (71%) showed mild non-specific dyspoiesis prior to treatment involving either erythroid, megakaryocytic or granulocytic lineages. Mild non-specific erythropoietic and/or megakaryopoietic dyspoiesis was found in 7 of 8 (88%) and 2 of 4 (50%) of patients at end of treatment and at further follow up (median 14.5 months; range 12–23), respectively.Overall, frank morphologic dysplasia was not detected in any patient except the one (from LD alone) who developed MDS. Conclusion:In summary the careful longitudinal reevaluation of 110 bone marrow samples and corresponding cytogenetic studies treated with LEN alone, in combination with ASCT or bendamustine did not show increased signs of early or overt MDS. It is of note that many MM patients showed mild dyspoiesis even before treatment. The development of MDS in one patient (2.5%) suggests that longer follow up is needed for all patients. To our knowledge this is the first study that re-evaluated longitudinal bone marrow samples for early signs of MDS before clinical symptoms are overt. Disclosures:Lentzsch:Celgene Corp: Consultancy, Research Funding; Onyx: Consultancy; Genzyme: Consultancy; prIME Oncology: Honoraria; Imedex: Honoraria; Clinical Care Options: Honoraria.

Updated Results of Bortezomib-Naïve Patients in PX-171-004, An Ongoing Open-Label, Phase II Study of Single-Agent Carfilzomib (CFZ) in Patients with Relapsed or Refractory Myeloma (MM).

Abstract 302 Background:Carfilzomib (CFZ) is a proteasome inhibitor with unique target selectivity and an irreversible binding mechanism that results in sustained proteasome inhibition. In preclinical studies, CFZ lacks non-proteasome off-target activities associated with bortezomib (BTZ) (Kapur et al, Blood 2008). This may account for observed differences in tolerability with CFZ (e.g. minimal neuropathy and myelosuppression), permitting consecutive day dosing and treatment over an extended period of time. We previously observed higher response rates in multiple myeloma (MM) patients without prior BTZ exposure (BTZ-naïve) compared to those with relapsed disease following BTZ therapy (BTZ-treated). Here we present updated data on the BTZ-naïve cohort from PX-171-004, an ongoing Phase 2 study of single-agent CFZ in MM patients with relapsed or refractory disease following 1–3 prior therapies. Methods:Patients with relapsed or refractory (e.g, < 25% response or disease progression during last treatment) MM were enrolled and stratified into two cohorts: BTZ-naïve and BTZ-treated. CFZ 20 mg/m2 IV was administered on Days 1, 2, 8, 9, 15 and 16 every 28 days, for up to 12 cycles. The primary endpoint was Overall Response Rate [≥ Partial Response (PR)] per International Uniform Response Criteria for Multiple Myeloma. Secondary endpoints included Clinical Benefit Response [CBR = ORR + Minor Reponse (MR)] and safety. Results:Fifty-seven BTZ-naive patients have been enrolled and 56 subjects have received at least one dose of CFZ. Prior therapies included alkylators (81%), stem cell transplant (SCT) (77%), thalidomide (THAL) (67%), lenalidomide (LEN) (42%), and anthracyclines (23%). Ten (18%) patients had received both LEN and THAL and 18 (32%) patients were refractory to their most recent regimen prior to study entry. At baseline, 30 (53%) patients had an ECOG score ≥ 1, 21 (37%) had neuropathy Grade ≥ 1, 12 (21%) had impaired renal function (CrCl < 60 mL/min) and 10 (18%) had diabetes. The mean time from diagnosis was 4 years (range 0.7–24). To date, the mean number of CFZ doses administered was 29.2 (∼5 four-week cycles; range 2–72 doses, 1–12 cycles). Fifty-one patients initiated therapy and were evaluable for response per protocol. The ORR was 45% (23/51 patients) and included 1 CR, 4 VGPR and 18 PR. An additional 9 (18%) patients had MR and 10 (20%) had stable disease (SD) for ≥ 6 weeks. The most common (>25%) adverse events (AEs) were fatigue (59%), nausea (41%), dyspnea (36%), and anemia (29%), and were primarily ≤ Grade 2. Grade 3/4 AEs occurring in ≥ 5% of patients were thrombocytopenia (9%), fatigue (9%), neutropenia (7%), lymphopenia (7%), anemia (5%), pneumonia (5%) and hyperglycemia (5%). One (1.7%) patient had febrile neutropenia. Dose modifications were rarely required. Peripheral neuropathy (PN) of any grade was infrequent (7 patients, 12%) with a single case of Grade 3 PN (2%) in a pt with a history of THAL-induced PN that lasted 41 days. The CFZ dose was reduced and the event resolved to Grade 1 while on CFZ and prior to study discontinuation. Of the12 patients with impaired renal function at baseline, none required dose modifications due to renal AE. Overall, 5 patients have completed the full 12-cycle protocol and another 5 (9%) have completed ≥ 9 cycles; 17 patients (30%) are continuing on study. Conclusions:The 45% ORR (CBR 63%) is noteworthy for a single-agent regimen in patients with tumor progression despite therapy with novel combinations. CFZ can be safely administered to patients with significant comorbidities (e.g. peripheral neuropathy, leukopenia, renal dysfunction, diabetes) when other anti-myeloma agents may not be well tolerated. Enrollment to PX-171-004 is continuing and, based on the safety profile, subjects are now permitted to dose escalate to 27 mg/m2. Disclosures:Wang:Proteolix: Honoraria, Research Funding. Off Label Use: testing testing. Siegel:Celgene: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Millennium: Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Jakubowiak:Millennium Pharmaceuticals, Inc.: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau; Celgene: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Centocor Ortho Biotech: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Exelixis: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Bristol-Myers-Squibb: Consultancy, Honoraria, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau. Kukreti:Celgene: Honoraria. Bahlis:Celgene: Honoraria, Speakers Bureau; Ortho Biotech: Honoraria, Speakers Bureau. McDonagh:Proteolix: Research Funding. Belch:Ortho Biotech: Honoraria, Research Funding. Le:Proteolix, Inc.: Employment. Bennett:Proteolix: Employment. Kunkel:Proteolix: Consultancy, Employment. Kauffman:Proteolix, Inc.: Employment. Vij:Proteolix, Inc.: Consultancy, Research Funding.

Concurrent B-cell chronic lymphocytic leukemia and multiple myeloma treated successfully with lenalidomide

The occurrence of multiple myeloma and chronic lymphocytic leukemia in the same patient is very uncommon. The immunomodulatory agent lenalidomide has been shown to have high response rates in multiple myeloma and appears to be quite active in advanced CLL. We report two patients with concurrent CLL and MM who were both treated successfully with lenalidomide.

774 Alternating VCMP/VBAP at standard doses (SD) vs. VCMP/VBAP at intermediate doses (ID) as initial treatment of multiple myeloma (MM)

In a previous PETHEMA study we have shown that VCMP/VBAP increases response rate in MM when compared with melphalan/prednisone. The aim of the present study was to ascertain whether treatment with VCMP/VBAP (ID) with a moderate increase in the cyclophosphamide (C) and adriamycin (A) doses could be superior to VCMP/VBAP at SD. From Jan 1, 1990 through May 31, 1994, 449 pts with symptomatic MM entered the study. All patients were randomized to receive: (A) alternating courses of VCMP (vincristine 1 mg iv on day 1, cyclophosphamide 500 mg/m 2 iv on day 1, melphalan 9 mg/m 2 p.o. on days 1–4 and prednisone 60 mg/m 2 on days 1–4) and VBAP (vincristine 1 mg iv; BCNU and adriamycin iv, 30 mg/m 2 each on day 1; and prednisone 60 mg/m 2 on days 1–4, or (B) the same VCMP/VBAP increasing the cyclo from 500 to 1200 mg/m 2 and adria from 30 to 50 mg/m 2 . The objective response rate among the already evaluable pts for response was 40.2% with SD vs 50.5% with ID ( P = 0.068) with no impact on survival (31 vs 30 mos). In summary, these results show a trend towards a higher response rate to VCMP/VBAP at higher doses of cyclo and adria, with no significant impact on survival. Supported in part by Grants from FIS 95/0828 and “Fundacio Josep Carreras per a la Lluita Contra la Leucemia”.