Line Treatment Of Multiple Myeloma Research Articles

Smoldering Multiple Myeloma Progressing to Active Multiple Myeloma Vs De-Novo Active Multiple Myeloma - a Comparison of Disease Characteristics, Organ Involvement and Outcomes in a Real-Life Multicenter Retrospective Cohort Study

Background Smoldering Multiple Myeloma (SMM) is an intermediate precursor phase in Multiple Myeloma (MM) evolution. SMM patients are monitored for progression to active disease, supposing such surveillance will identify myeloma-defining events (MDEs) early and consequently hasten treatment, prevent complications and improve outcomes. To what extent this approach is successful is not well established. We aimed to compare disease characteristics, end organ involvement and outcomes between SMM patients who progressed to active MM vs newly diagnosed MM (NDMM) patients. Methods We performed a two-center real-world case-control retrospective cohort study. Consecutive patients receiving first line treatment for MM after progressing from SMM were identified; each was matched by age and year of diagnosis (±2 years) to a patient first presenting as NDMM. SMM, MM, MDEs and response were defined by the International Myeloma Working Group (IMWG) criteria (2014, 2016); progression-free survival (PFS) and overall survival (OS) were calculated from active MM diagnosis. Data was extracted in 07/2023. Results We identified two cohorts of newly diagnosed MM patients, presented between 09/2008and 02/2023: Post SMM (P-SMM, N=57) and De novo MM patients (D-MM, N=57). Median follow up time was 38.6 months (IQR 23.3 - 72.7). There were no differences in baseline demographics between gender (p=.19), and median age: 73.4 (range 42 - 88) in the P-SMM group and 72.9 (range 42 - 92) in the D-MM (p=.75). Comparing MDEs using SLiM-CRAB criteria between groups, more patients in the D-MM group presented with hypercalcemia (p=.02) and lytic lesions (p=.03). Other domains were similar between groups: anemia (p=.68), renal failure (p=.59), FLC ≥100 (p=.76), % bone marrow plasma cells (BMPC) ≥ 60 (p=.11). D-MM patients had higher ISS/R-ISS at presentation: ISS ≥ II (30 vs 11, p=.004) and R-ISS ≥ II (31 vs 13, p=.002). Additional disease characteristics were balanced at diagnosis of active MM: heavy chain (p=.53), light chain type (p=.69), M-Protein level (p=.23), extra medullary disease (p=.14), Al amyloidosis (p=.13), and high-risk cytogenetics (p=.65). Bone involvement was more frequent in D-MM vs P-SMM patients, with significantly more pathological fractures (p=.006), bone pain (p=.001), and a detrimental bone disease (p=.001) (defined as combination of pathological fracture and/or ≥ 3 lytic lesions) (Figure 1B). Significantly higher rates of hospital admissions for upfront therapy initiation were seen in the D-MM group compared with P-SMM, 18 vs 7 (p=.008), as well as more potentially irreversible MDEs (pathological fractures and/or renal injury): 43 (p=.009) vs 31 (41.9%) respectively. Treatment patterns were balanced excluding bortezomib used more often in the D-MM (p=.009) and daratumumab in the P-SMM group (p=.03). Best response rates to upfront therapy were comparable between groups, (p=.71) as well as ≥ very good partial response (VGPR) rates (p=.88), 52.4% vs 47.6% in P-SMM and D-MM respectively. Frequency of skeletal imaging tests up-to 2-year period prior to active MM diagnosis were associated with lower rates of detrimental bone disease (p=.006). Despite the similar ≥ VGPR rates between cohorts, PFS was longer in the P-SMM group vs D-MM group, 39.6 vs 21.6 months, respectively (log-rank 0.01). A superior PFS in P-SMM group vs D-MM remained after correction for % BMPC at diagnosis (46.2% vs 58.8%, p=.03). OS was also longer, not reached vs 93.7 months (log-rank=.047) (Figure 1A). Conclusions Patients who develop active MM post SMM clinic surveillance presented with a lower disease burden, as well as reduced rates of detrimental bone disease and potentially irreversible MDEs. P-SMM patients had favorable PFS and OS rates. This may reflect effectiveness of SMM monitoring resulting in lower disease burden at time of treatment onset; favorable long-term outcomes may also be affected by variability in treatment patterns between groups. Another possible explanation is that patients with more indolent MM biology may have extended periods of precursor condition, hence increasing their likelihood to be diagnosed by incidental laboratory tests during their SMM phase.

Initial Safety and Efficacy of Daratumumab (DARA) in Combination with Bortezomib, Lenalidomide, and Dexamethasone in the Treatment of Transplant-Eligible Newly Diagnosed Multiple Myeloma (TE-NDMM) Patients with Standard Risk Who Refused to Accept ASCT As First Line in China

Background: Despite the advent of numerously new drugs, multiple myeloma (MM) remains an incurable plasma cell malignancy. Autologous hematopoietic stem cell transplantation (ASCT) remains an important first line treatment for MM. In China, rate of utility of ASCT in front line was as low as 10%. There are many transplant-eligible (TE) patients who refuse ASCT for a variety of subjective and objective reasons,. Bortezomib, lenalidomide and dexamethasone (VRd) combination has been reported to demonstrate high efficacy in these patients (SWOG S0777), And recently, daratumumab combinations, such as D-VRd (GRIFFIN) and D-VTd (CASSIOPEIA), have shown good results in TE-NDMM patients who received ASCT as initial therapy. The observed benefits of these combination therapies have led us to explore the potential efficacy of D-VRd in standard risk TE-NDMM patients without ASCT. In addition, there were no studies assessing minimal residual disease (MRD) data after treatment with the D-VRd regimen in TE-NDMM patients who are unwilling to undergo ASCT in Chinese population , thus we chose MRD as the primary endpoint. This is the first open-label, single arm study to evaluate the efficacy and safety of D-VRd in TE-NDMM in standard risk without ASCT in China (NCT 05088330). Methods: This is a single-center prospective ongoing clinical study, planning to recruit 76 patients. NDMM patients as documented per IMWG criteria who were evaluated as transplant-eligible, but voluntary not to accept ASCT were enrolled. And t(4;14) or Del(17p) or t(14;16) or R-ISS stage III patients were excluded from this study. D-VRd regimen includes ‘daratumumab’ 16 mg/kg I.V. every week for 2 cycles, 16 mg/kg I.V. every 3 weeks for 6 more cycles, and then 16 mg/kg I.V. for 13 more cycles (Total: 21 cycles); ‘lenalidomide’: 25 mg, P.O., Days 1-14/1-8 cycles; ‘Bortezomib’: 1.3 mg/m2, SC, Days 1, 4, 8, 11/1-8 cycles; dexamethasone: 20 mg, P.O., Days 1, 2, 4, 5, 8, 9, 11, 12/1-8 cycles. The primary endpoint of this study was to evaluate the negativity of NGS MRD at 10-5 after 8 cycles of D-VRd. The secondary objectives of this study were to determine the ORR, sCR, ≥CR ≥VGPR, AE, TTR and DOR of treatment. Patients were recommended to have stem cells collection after 4 cycles of D-VRd treatment. Result: As of 30 June 2023, 24 patients including 6 safety-run-in patients were enrolled. The median (range) age of these 24 patients was 65 (50-74) years. 54.2% (13/24) were male. 62.5% of patients had a 1q gain. 16.7% (4/24) of patients had renal insufficiency with 30mL/min <CCR <60mL/min (Table 1). The median follow-up time was 3 (1-11) months, 8 patients completed 4 cycles and 2 patients completed 2 cycles. Among the 17 patients who had response evaluation, the ORR was 94.1%, 87.5% (7/8) of patients had VGPR or better after 4 cycles (Figure 1). All patients (6/6) above VGPR and CR had NGS MRD negativity. Both 2 patients who have completed the 8 cycles treatment achieved CR and MRD negativity. All patients had bone pain relief. The main treatment-related adverse events were hematological toxicity, which occurred in 22 patients including neutropenia (n=14, Grade 1-2 for 10 patients and Grade 3-4 for 4 patients), lymphopenia (n=13, Grade 1-2 for 10 patients and Grade 3-4 for 3 patients) and thrombocytopenia (n=19, Grade 1-2 for 15 patients and Grade 3-4 for 4 patients). One patient had to discontinue lenalidomide due to serious adverse event (SAE) of pulmonary embolism. Other toxicities to date include pneumonia (n=3, Grade 1 for 2 patients and Grade 2 for 1 patient), ALT/AST increase (n=10, all Grade 1), and rash (n=3). The infusion related reactions were reported in 25% of patients (n=6, Grade 1 for 4 patients and Grade 2 for 2 patients). Conclusion: In the safety-run-in phase, D-VRd induction therapy was well tolerated in the Chinese population in 6 patients. This preliminary study of D-VRd demonstrated excellent efficacy with rapid response even in a population with high 1q gain. The most common adverse events were hematological toxicities that were manageable after 2 cycles. The updated results will be presented in the following phase.

P-158 Experience at Son Espases University Hospital with daratumumab, bortezomib, lenalidomide and dexamethasone (D-VRd) as first line treatment in multiple myeloma

P-158 Experience at Son Espases University Hospital with daratumumab, bortezomib, lenalidomide and dexamethasone (D-VRd) as first line treatment in multiple myeloma

Neurofilament light chain levels indicate acute axonal damage under bortezomib treatment

IntroductionBortezomib (BTZ) is a selective and reversible proteasome inhibitor and first line treatment for multiple myeloma (MM). One of the side effects is BTZ-induced peripheral neuropathy (BIPN). Until now there is no biomarker which can predict this side effect and its severity. Neurofilament light chain (NfL) is a neuron specific cytoskeletal protein, of which higher levels can be detected in peripheral blood in case of axon damage. In this study, we aimed to evaluate the relationship between NfL serum levels and characteristics of BIPN.MethodsWe performed a first interim analysis of a monocentric, non-randomized, observational clinical trial including 70 patients (DRKS00025422) diagnosed with MM in the inclusion period of June 2021 until March 2022. Two groups of patients—one with ongoing BTZ treatment at the time of recruiting, and one with BTZ treatment in the past—were compared to controls. NfL in serum was analyzed via the ELLA™ device.ResultsBoth patients with previous and ongoing BTZ treatment had higher serum NfL levels than controls, and patients with ongoing BTZ treatment had higher NfL levels than patients with BTZ treatment in the past. Serum NfL levels correlated with electrophysiological measures of axonal damage in the group with ongoing BTZ treatment.ConclusionElevated NfL levels indicate acute axonal damage under BTZ in MM patients.

AFM26 - Targeting B Cell Maturation Antigen (BCMA) for NK Cell-Mediated Immunotherapy of Multiple Myeloma

Significant progress in multiple myeloma (MM) treatment has been made in recent years and achieving sustained minimal residual disease (MRD) negativity now constitutes a major goal of treatment. High dose melphalan combined with autologous stem cell transplantation (ASCT) is currently regarded the standard of care in 1st line treatment of MM in eligible patients, but fails to eradicate MRD in the majority of patients ultimately leading to disease relapse. Consequently, additional therapies are needed to target residual disease to delay or potentially prevent relapse.The cell surface antigen B cell maturation antigen (BCMA, CD269) constitutes a highly attractive target antigen for immunotherapy because of its restricted expression in non-malignant tissue but almost universal expression on MM cells.AFM26 is a BCMA-targeted tetravalent bispecific antibody that selectively engages natural killer (NK) cells to induce myeloma cell lysis. Through its high-affinity bivalent binding to CD16A (FcγRIIIa), AFM26 possesses prolonged cell retention times, and has been shown to be less prone to interference by high levels of circulating IgG than antibody Fc-domains. Thus, AFM26 can be used to “arm” NK cells for effective killing of tumor cells. AFM26 also induces markedly lower levels of pro-inflammatory cytokines in peripheral blood mononuclear cell (PBMC) cultures in the presence of target cells compared to BCMA-directed T cell activating approaches. In contrast to other monoclonal antibodies (mAbs) such as daratumumab and elotuzumab, AFM26 does not confer target-independent NK cell activation or NK cell depletion.NK cells are promising effectors to target MRD. Due to their early reconstitution following ASCT and their ability to rapidly destroy malignant cells through direct cytotoxicity. Redirecting NK cells through AFM26 may therefore offer an effective treatment of MM patients early after ASCT.Employing a wide range of functional assays, we demonstrate here that AFM26 exhibits potent cytotoxic activity against primary myeloma cells using patient (autologous) and donor-derived (allogeneic) NK cells as well as against a panel of high and low BCMA expressing cell lines. In particular, we show that AFM26 induces NK cell cytotoxicity towards cells expressing almost undetectable surface levels of BCMA, suggesting the potential for broad and deep anti-MM activity. In summary, AFM26 is well-differentiated from other mAbs and a promising therapeutic candidate to address the unmet medical need of MRD positivity in MM. DisclosuresGantke:Affimed: Employment. Reusch:Affimed: Employment. Kellner:Affimed: Research Funding. Klausz:Affimed: Research Funding. Haneke:Affimed: Employment. Knackmuss:Affimed: Employment. Müller:Affimed: Employment. Ellwanger:Affimed: Employment. Fucek:Affimed: Employment. Schniegler-Mattox:Affimed: Employment. Koch:Affimed: Employment. Kerber:Affimed: Employment. Peipp:Affimed: Research Funding. Treder:Affimed: Employment.

Impact of Prior Therapies on the Safety and Efficacy of Once Weekly Selinexor, Bortezomib, and Dexamethasone Compared with Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Results from the Boston Study

Impact of Prior Therapies on the Safety and Efficacy of Once Weekly Selinexor, Bortezomib, and Dexamethasone Compared with Twice Weekly Bortezomib and Dexamethasone in Relapsed or Refractory Multiple Myeloma: Results from the Boston Study

Pharmacoeconomics of bortezomib - a cochin cancer research centre evaluation and review

Bortezomib also known as Velcade is indicated as a parenteral agent in the treatment of multiple myeloma. In noncomparative trials in multiple myeloma patient’s early treatment was associated with a greater rate of success. Treatment with Bortezomib-based regimens was associated with improvements in health-related quality of life. Orthopaedic surgery for spinal cord compression in patients with multiple myeloma was generally predicted to be cost saving, relative to not having surgery, over the medium to long term in modelled cost analyses from a healthcare payer perspective in the UK and US. The initial cost of surgery was high, but the difference in costs between patients undergoing or not undergoing surgery was predicted to decline over time, as savings were realised from the decrease in the number of thrombocytopaenic episodes requiring treatment in patients who underwent surgery. Available pharmacoeconomic data from several countries including the Cochin Cancer Research Centre in Kerala State, India despite inherent limitations, support the use of Bortezomib in the first line treatment of multiple myeloma.

Carfilzomib, Daratumumab, Lenalidomide and Dexamethasone as First Line Treatment in Multiple Myeloma

Carfilzomib, Daratumumab, Lenalidomide and Dexamethasone as First Line Treatment in Multiple Myeloma

Bortezomib-Based Induction and Maintenance Overcomes the Negative Prognostic Impact of Renal Impairment and del17p in Transplant-Eligible Myeloma Patients: Long Term Results from the Phase III HOVON-65/GMMG-HD4 Study after Median 137 Months Follow up

Background: Novel agents such as IMIDs and proteasome inhibitors have substantially changed the therapeutic landscape in the first line treatment of multiple myeloma (MM). Better response rates and prolonged progression-free survival have lead to an improvement in overall survival (OS) with median values well beyond 5 years. Therefore to assess whether first line therapy strategies have an impact on the prognosis for patients with MM, long-term results of clinical trials with follow up covering >10 years are necessary. Methods: The HOVON-65/GMMG-HD4 study is a prospective randomized trial testing bortezomib+adriamycin+dexamethasone (PAD) for 3 cycles as induction prior to high-dose chemotherapy (HDT) and autologous stem cell transplantation compared to vincristine+adriamycin+dexamethasone (VAD) in the control arm. After one (HOVON) or two (GMMG) HDT maintenance was given for 2 years consisting of bortezomib every 2 weeks in the PAD arm and thalidomide 50 mg daily in the VAD arm. The study results were initially reported in 2012 (1) and with a median follow up of 91 months in 2018 (2). In this analysis we present OS results after a median follow up of 137 months. All hazard ratios (HR) are given with 95% confidence intervals (CI). Results: Overall survival at 12 years was 32% (CI 27-37%) in the VAD arm versus 36% (CI 31-41%) in the PAD arm without significant difference in the univariate Cox model (HR 0.87, CI 0.73 - 1.03, p=0. 11 or in multivariate Cox model including ISS stage and treatment arm (HR 0.87, CI 0.73 - 1.04, p=0.12; the primary analysis) as specified in the study protocol. When other factors including age, sex, ISS stage, WHO performance status, Immunoglobulin-type, Durie and Salmon-stage, LDH, del 13q, study group and renal impairment (RI, defined as serum creatinine ≥ 2 mg/dl) were added to the Cox model, treatment in the PAD arm was a significant factor for improved OS (HR 0.84, CI 0.7 - 1.0, p=0.048). Of the remaining factors age (HR 1.02, CI 1.01 - 1.03, p=0.002), female sex (HR 0.83, CI 0.69 - 0.99, p=0.044), ISS stage (HR 1.19, CI 1.04 - 1.35, p=0.01), WHO performance status (HR 1.32, CI 1.17 - 1.48, p<0.001), IgA (HR 1.56, CI 1.18 - 2.06, p=0.002), LDH>ULN (HR 1.44, CI 1.14 - 1.82, p=0.002), del 13q (HR 1.42, CI 1.17 - 1.73, p<0.001) and RI (HR 1.42, CI 1.04 - 1.95, p=0.026) were significantly associated with OS. Tests for heterogeneity revealed two factors as significant: RI and del17p (only fully evaluated for the GMMG cohort). For patients with RI the OS probability at 12 years was 39% in the PAD arm versus 5% in the VAD arm (HR 0.34, CI 0.20 - 0.59, p<0.0001, Fig. 1). 12 year OS in patients without RI was 36% in the PAD arm and 35% in the VAD arm without significant difference (HR 0.97, CI 0.81 - 1.17, p=0.77, Fig,1). In the GMMG cohort (receiving tandem-HDT) del17p results were available and patients with del17p had a significantly better OS in the PAD arm than in the VAD arm (HR 0.36, CI 0.17 - 0.77, p=0.006), while no significant difference between treatment arms was found in patients without del17p (HR 1.01, CI 0.75 - 1.37, p=0.92). Discussion: Long-term results of the HOVON-65/GMMG-HD4 trial show that one third of patients receiving HDT with either thalidomide-based or bortezomib-based maintenance are still alive at 12 years. In contrast to earlier analyses with shorter follow up (1,2) the use of bortezomib in the induction and maintenance treatment provided a significant OS benefit when adjusting for other risk in a multivariate Cox model, although not in the primary analysis. A particular OS benefit was found in patients with RI receiving bortezomib before and after HDT and this could completely abolish the negative prognostic impact of RI. Similarly bortezomib used in combination with tandem-HDT improved OS in patients with del17p so that more than a third of these patients with high-risk MM survived more than 10 years. Our results underline that despite the growing options for treatment at relapse the choice of an optimal first-line therapy is of critical prognostic importance, in particular for patients with high-risk myeloma.

Native aortic valve endocarditis with Morganella morganii in a patient with multiple myeloma and valvular amyloidosis: a case report

BackgroundPatients with multiple myeloma (MM) are known to be immune incompetent and experience higher incidences of infectious diseases. However, infective endocarditis (IE) is rarely observed in patients with MM and Morganella morganii (M. morganii) has rarely been associated with IE.Case presentationA 72-year-old female receiving 4th line treatment for MM presented with fever and concomitant confusion. Urinary culture revealed growth of Escherichia coli, wherefore broadspectrum penicillin and high-dose corticosteroids were initiated. However, blood cultures showed growth of M. morganii. Fluoroquinolone was added due to penicillin-resistance of the Morganella species. Two days after admission, the patient acutely deteriorated with hemodynamic instability. Gentamicin and high dose corticosteroids were added. Echocardiography showed marked aortic valve vegetation with severe aortic valve regurgitation, leading to the diagnosis of bacterial endocarditis of the native aortic valve. Shortly after diagnosis, the patient died. At autopsy, vegetation with gram-negative rods in the native aortic valve was observed, confirming the diagnosis of M. morganii-endocarditis. Additional staining for amyloid confirmed advanced light-chain (AL) amyloidosis with extensive amyloid depositions of the aortic valve and valvular damage as complications of her MM.ConclusionsOur case suggests that IE with M. morganii was facilitated by the combination of the cardiac amyloidosis with valvular impairment and the profound immune deficiency caused by the several chemo-immunomodulatory treatment lines and the MM itself. This case further illustrates that awareness for rare opportunistic infections in an era with growing potential of combined chemoimmunotherapy is warranted.

Multiple Myeloma (MM) in First Relapse Patients: Role of the Second Autologous Stem-Cell Trasplant (ASCT): Experience of Two Centers

the 2nd ASCT is considered as a salvage therapy in the 2016 IMWG guidelines for patients with MM in the 1st relapse, provided that the duration of the response to the 1st ASTC is ≥ 18 months. Currently, the increasing effectiveness of the available therapies as 2nd line treatment for MM, could challenge the role of the 2nd ASCT in this setting.

The Prognostic Impact of t(14;16) in Multiple Myeloma: A Multicenter Retrospective Study of 213 Patients. Is It Time to Revise the Revised ISS?

The Prognostic Impact of t(14;16) in Multiple Myeloma: A Multicenter Retrospective Study of 213 Patients. Is It Time to Revise the Revised ISS?

The Prognostic Impact of t(14;20) in Multiple Myeloma - a Multicenter Retrospective Study of 26 Patients

IntroductionThe prognosis in multiple myeloma (MM) is based upon complex biological and clinical features. One of the strongest predictors of outcome are the intrinsic genetic abnormalities in the malignant plasma cells. t(14;20), as other chromosome 14 abnormalities, deregulates the c-musculoaponeurotic fibrosarcoma (c-MAF) oncogene. Due to the relative rarity of t(14;20) [<1.5% of newly diagnosed MM; slightly higher in monoclonal gammopathies of unknown significance- about 5%], there are no large databases which provide the natural history of this abnormality. Its meaning remains controversial due to the small sample sizes in previously published reports in contrast to t(4;14) and 17p- abnormalities which have been described independently in the literature.MethodsWe retrospectively analyzed the clinical features and outcomes of patients t(14;20) from 5 clinical centers in Germany, Italy and the United States. Newly diagnosed MM patients according to the International Myeloma Working Group (IMWG) criteria were enrolled. The t(14;20) was detected by double color fluorescence in situ hybridization (FISH) using bone marrow samples. Baseline characteristics at diagnosis, comorbidities, patient treatment regimens and clinical outcomes were collected using unified case report forms. Clinical responses were assessed according to the IMWG uniform response criteria. Overall survival (OS) was defined as the period between the date of initial diagnosis and the date of death or the date of the last observation. Progression-free survival (PFS) was defined as the period between the date of initial diagnosis and either the date of the first relapse or death of any causes or the date of the last observation. Cox proportional hazard regression analysis was applied to assess risk factors of death. Survival curves were plotted by the Kaplan-Meier method and compared using log-rank and Breslow-Gehan-Wilcoxon tests.Results26 patients were included in analysis including 11 males (42.3%). Median age at MM diagnosis was 68.5 years (range 56-71). Immunoglobulin isotype included: IgG (n=14, 53.8%), IgA (n=9, 34.6%), light chain (n=3, 11.5%). R-ISS stage at diagnosis included: stage III (n=8, 30.8%); stage II (n=9, 34.6%) and stage I (n=1, 3.8%)- the staging for remaining 8 patients is unknown. Anemia (<10g/dl) was observed in 13 (50%), impaired renal function (creatinine clearance <40 mL per minute or serum creatinine >2 mg/dl) in 3 (11.5%). In 14 (53.8%) cases osteolytic lesions were present. In 15 patients (57.7%) the t(14;20) was associated with other cytogenetic aberrations, including del17p in 2 patients (7.7%), t(4;14) in 5 patients (19.2%) and t(14;16) in 4 patients (15.4%). First line treatment for MM included mostly PIs + IMIDs in 8 patients (30.8%), PIs + IMIDs + chemotherapy in 7 patients (26.9%) or PIs alone in 3 cases (11.5%). Auto-PBSCT was performed in 8 cases (30.7%).Median PFS was 30 months (CI 95% 17.8 months; Figure 1, panel A). Median OS was not reached (Figure 1, panel B). 5-year OS from MM diagnosis was 77.5% (±10.6%).ConclusionIn this study of 26 patients with t(14;20) the median PFS and 5-year OS were 30 months and not reached, respectively. Historically, the presence of a t(14;20) is considered to be a very poor prognostic factor-this was not observed in this multi-institutional retrospective analysis. In comparison to the recent studies (Ross et al, Haematologica, 2010; n=27; median survival 14.4 months), the PFS and OS of patients with t(14;20) in our analysis are better than expected. It should be highlighted that most probably in the Ross et al. study patients were not treated with novel drug therapies. Nonetheless, this controversy remains to be elucidated in the future studies. DisclosuresCastillo:Genentech: Consultancy; Pharmacyclics: Consultancy, Research Funding; Millennium: Research Funding; Abbvie: Consultancy, Research Funding; Janssen: Consultancy, Research Funding; Beigene: Consultancy, Research Funding. Hari:Celgene: Consultancy, Honoraria, Research Funding; Amgen Inc.: Research Funding; Spectrum: Consultancy, Research Funding; Bristol-Myers Squibb: Consultancy, Research Funding; Takeda: Consultancy, Honoraria, Research Funding; Kite Pharma: Consultancy, Honoraria; Sanofi: Honoraria, Research Funding; Janssen: Honoraria. Goldberg:COTA Inc.: Employment, Equity Ownership.

Real-World Treatment Patterns, Time to Next Treatment, and Economic Outcomes in Relapsed or Refractory Multiple Myeloma Patients Treated with Pomalidomide or Carfilzomib.

Negligible real-world evidence exists for later line treatment of multiple myeloma (MM) to assist treatment decisions or reimbursement models, such as episode-based payments. To describe the treatment patterns and clinical/economic outcomes when pomalidomide or carfilzomib is used for relapsed/refractory MM. A U.S. claims database was used to identify MM patients with an initial pomalidomide or carfilzomib claim (index date) between February 1, 2013, and February 28, 2015, which was assumed to be relapse therapy. Treatment regimens were defined as all MM chemotherapy observed within 60 days of index. Patients receiving pomalidomide and carfilzomib within 60 days of index were excluded. Time to next treatment (TTNT), a progression proxy, was defined as the addition of a new agent > 60 days from index or as treatment restart following a > 90-day therapy gap. Cost estimations used plan-allowed amounts. Descriptive statistics were used to compare outcomes between treatment groups, and regression models were used to adjust for baseline patient characteristics. There were 454 patients initiating treatment with pomalidomide (n = 264) or carfilzomib (n = 190) during the index period. The most frequent initial regimens for pomalidomide patients included pomalidomide + dexamethasone (47.0%) and pomalidomide alone (33.0%); the most frequent regimens for carfilzomib patients were carfilzomib alone (45.3%) and carfilzomib + dexamethasone (14.7%). The most frequent next line treatment for pomalidomide patients who progressed was the addition of (14.0%) or switch to (15.0%) carfilzomib ± dexamethasone and for carfilzomib patients, the most frequent next line treatment was pomalidomide + dexamethasone (9.3%) and carfilzomib alone or carfilzomib + dexamethasone + cyclophosphamide (6.7% each). The median (95% CI) TTNT for pomalidomide patients was 11.9 (10.7-14.8) compared with 9.4 (7.7-10.0) months for carfilzomib (P = 0.060). For patients followed to progression (pomalidomide: n = 100, 37.9%; carfilzomib: n = 75, 39.5%), mean TTNT was longer for patients initiating therapy with pomalidomide (6.9 months) versus carfilzomib (5.3 months, P = 0.016). When adjusted for baseline confounders, pomalidomide patients had a nonsignificant longer time to a subsequent treatment line. Inpatient encounters observed during the index line were very low (mean = 1) for both groups; outpatient encounters were fewer in pomalidomide patients. Adjusted analyses revealed inpatient encounters were higher (P = 0.005), while outpatient use was lower in pomalidomide patients (P = 0.006). Unadjusted median costs incurred during the initial line were similar between the 2 groups (pomalidomide: $102,805; carfilzomib: $127,203; P = 0.110) but significantly lower in pomalidomide patients after adjusting for baseline characteristics (P = 0.013). Unadjusted per patient per month (PPPM) costs incurred over the entire follow-up period were lower in pomalidomide-initiated patients ($18,298 vs. $24,734, P = 0.001) but not statistically significant in adjusted analyses (P = 0.230). A longer time to a subsequent line of therapy was observed in pomalidomide patients compared with carfilzomib patients, although the difference lost significance in adjusted analyses. Compared with carfilzomib, pomalidomide patients were observed to have lower unadjusted median PPPM costs over the entire post-index period and lower adjusted mean monthly costs during initial therapy. Funding for this study was provided by Celgene. Chen, McGuiness, and Wade are employees of QuintilesIMS, which was contracted by Celgene to undertake this research. McGuiness also owns stock in Pfizer. Parikh, Abouzaid, Purnomo, and Hussein are employees of Celgene and participated fully in the development and approval of the manuscript. Portions of the results of this research were previously presented at the American Society of Clinical Oncology (ASCO) 2016 Annual Meeting; June 3-7, 2016; Chicago, Illinois. Study concept and design were contributed by Chen, Parikh, Abouzaid, McGuiness, and Wade. Chen and McGuiness took the lead in data collection, along with Wade, and data interpretation was performed by Hussein and Wade, with assistance from the other authors. The manuscript was written by McGuiness, Chen, and Wade, with assistance from Parikh and Abouzaid, and revised by McGuiness and Hussein, along with the other authors.

Abstract 4720: Synergistic antitumor effect of selinexor, a selective inhibitor of nuclear export (SINE) compound and panobinostat in a mouse model of multiple myeloma

Abstract Introduction: Selinexor is an oral, first-in-class SINE compound that binds to the primary nuclear exporter XPO1/CRM1. XPO1 exports over 200 cargos, including major tumor suppressor proteins (TSPs) leading to their inactivation. Inhibition of XPO1 results in nuclear retention of TSPs and restores their normal functions. XPO1 also mediates the export of key signaling molecules in multiple myeloma (MM) including c-MYC mRNA and NF-κB. Selinexor is currently being investigated in phase 2 clinical trials in MM in combination with dexamethasone, pomalidamide, lenalidomide, bortezomib and carfilzomib. In preclinical studies selinexor has been shown to synergize broadly with these anti-MM drugs making it an excellent candidate partner for combination therapies in MM. To identify additional synergistic pairings, we investigated the use of selinexor in combination with panobinostat, a pan-histone deacetylase inhibitor (HDAC) recently approved by the FDA in combination with bortezomib for 3rd line treatment of MM, as a potential treatment for MM both in-vitro and in-vivo. Methods: The effects of selinexor and panobinostat alone or in combination on cell viability were tested on MM1.S and NCI-H929 cell lines using MTT assays. Total RNA and whole protein cell lysates were extracted and analyzed by qPCR and by immunoblots. In-vivo, MM.1S cells were used to derive a xenograft mouse model. Mice were treated with sub-therapeutic doses of selinexor and panobinostat alone or in combination and with the therapeutic dose of selinexor. Tumor growth was monitored for 17 days and% Tumor Growth Inhibition (%TGI) was determined. Xenografts were harvested and analyzed microscopically and by immunohistochemestry (IHC). Results: Selinexor-panobinostat combination was highly effective both in-vitro and in-vivo. In MTT assays, both selinexor and panobinostat demonstrated low IC50 values (nanomolar) and when combined, they synergistically/ additively inhibit proliferation. Gene expression and western blot analyses showed that the combination treatment leads to a synergistic reduction in c-MYC mRNA and protein levels. In addition, an overall reduction in expression of anti-apoptotic signaling molecules including NF-κB and p21 and an increase of expression of pro-apoptotic molecules including cleaved caspase 3 and BAX were observed. Importantly, in-vivo, while%TGI of sub-therapeutic doses of selinexor and panobinostat measured 58% and 52% respectively, the combination showed a synergistic effect, measuring 93%. Importantly this high%TGI exceeded the effect of the therapeutic dose of selinexor alone 79%. Conclusion: Selinexor-panobinostat combination synergizes to induce apoptosis in MM cells and amplifies anti-tumor effect in a MM xenograft model. These data provide rational support for study of selinexor/ panobinostat combination in clinical trials. Citation Format: Sivan Elloul, Hua Chang, Boris Klebanov, Trinayan Kashyap, Maxwell Werman, Margaret Lee, Yosef Landesman, Sharon Shacham, Michael Kauffman, Sharon Y. Friedlander. Synergistic antitumor effect of selinexor, a selective inhibitor of nuclear export (SINE) compound and panobinostat in a mouse model of multiple myeloma. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 4720.

Inhibition of the neuronal NFκB pathway attenuates bortezomib-induced neuropathy in a mouse model

Bortezomib is a proteasome inhibitor with a remarkable antitumor activity, used in the clinic as first line treatment for multiple myeloma. One hallmark of bortezomib mechanism of action in neoplastic cells is the inhibition of nuclear factor kappa B (NFκB), a transcription factor involved in cell survival and proliferation. Bortezomib-induced peripheral neuropathy is a dose-limiting toxicity that often requires adjustment of treatment and affects patient’s prognosis and quality of life. Since disruption of NFκB pathway can also affect neuronal survival, we assessed the role of NFκB in bortezomib-induced neuropathy by using a transgenic mouse that selectively provides blockage of the NFκB pathway in neurons. Interestingly, we observed that animals with impaired NFκB activation developed significantly less severe neuropathy than wild type animals, with particular preservation of large myelinated fibers, thus suggesting that neuronal NFκB activation plays a positive role in bortezomib induced neuropathy and that bortezomib treatment might induce neuropathy by inhibiting NFκΒ in non-neuronal cell types or by targeting other signaling pathways. Therefore, inhibition of NFκB might be a promising strategy for the cotreatment of cancer and neuropathy.

Novel Therapy May Be the First Line Treatment for Multiple Myeloma but Should Not Be the Last Word: Two Cases Illustrated

Novel Therapy May Be the First Line Treatment for Multiple Myeloma but Should Not Be the Last Word: Two Cases Illustrated

VTD (Bortezomib Plus Thalidomide Plus Dexamethasone) Followed By Autologous Stem Cell Transplantation As First Line Treatment for Multiple Myeloma: Real Life Results from a Single Institution

BACKGROUND. In recent years, new classes of drugs have been introduced for the treatment of Multiple myeloma (MM). Several randomized trials have investigated, in the setting of first line treatment of patients eligible for autologous transplant (ASCT), the efficacy of the combination of two to four new and old drugs given as induction. Among these, VTD combination (bortezomib plus thalidomide plus dexamethasone) provided impressive results, so that it is now considered at different Institutions the standard of care as pretransplant therapy. However, data of VTD derive from clinical trials and should be verified in the "real life" setting, in terms of either efficacy or toxicity.AIMS. Here we present our experience in 76 MM patients treated between 2008 and 2014 with VTD as part of a first line treatment including also mobilization, single or double ASCT, and consolidation with two additional VD courses. No patient had been enrolled into a clinical trial.CHARACTERISTICS OF PATIENTS/METHODS. There were 39 males and 37 females, with a median age of 57 years (range 38-67). MM subtype was IgG=44 cases, IgA=15, IgD=1, micromolecular=13, non secreting=2, and solitary plasmocytoma=1. Stage according to Durie & Salmon was II-A=29, II-B=2, III-A=34 and III-B=10. In 8 cases single or multiple vertebroplasty was also necessary, while 7 patients had concomitant extramedullary plasmocytoma. In absence of CRAB criteria, patients were treated when progressive increase of M-component was observed. Treatment was given according to GIMEMA-MM-BO2005 protocol (Cavo et al, Lancet 2010) except for the following: from September 2012, bortezomib was given subcutaneously (in a total of 37 patients) and 4 instead of 3 induction cycles were given; mobilization therapy consisted of vinorelbine 30mg/sqm day 1 plus cyclophosphamyde 1500 mg/sqm day 2 (for further details, Annunziata et al, Ann Hematol 2006); consolidation did not include thalidomide and was given only from 2011; no maintenance therapy with dexamethasone was administered.RESULTS. Overall response rate after induction was 92% (70/76 patients), with 35 complete remission (CR), 25 very good partial remission (VGPR), 9 partial remission (PR) and one minimal response (MR). One patient was considered as stable disease and continued with the therapeutic program, 3 patients were refractory and were switched to salvage therapy, and 2 patients died during induction (due to fatal sepsis from H1N1 virus infection and multiorgan failure in a severely ill subject, respectively). After successful mobilization in 70/71 patients, single (n=34) or double (n=36) ASCT were given, depending on quantity of CD34+ cell collection, toxicity of first ASCT and response achieved. High dose melphalan was the conditioning regimen in all cases. After ASCT, response was upgraded in 24 cases (in 17 cases VGPR to CR, 4 PR to VGPR, 2 PR to CR, 1 MR to PR). Consolidation was given in all 47 programmed cases. Hematologic toxicity of VTD was negligible. Reduction of thalidomide schedule was necessary in 60 patients, while only 16 patients (21%) were able to complete the programmed days of therapy at 200 mg/day. In the remaining cases, 39 completed the therapy at 100 mg, 2 at 50 mg, while 19 had to definitely discontinue therapy after a median of 33 days (15-68). More frequent reasons of discontinuation or reduction were neuropathy, constipation, fatigue and skin rash; only 1 case of thrombosis was recorded in a non responding patient. Reduction of bortezomib dose was necessary only in 5 patients (all ev cases), all because of neuropathy. At the time of writing 57/76 patients (75%) are alive, with a median follow up of 27 months. The median duration of response was 38 months, 25/70 patients (36%) having progressed or relapsed. Depending on time to relapse (> or < 18 months), bortezomib or lenalidomide based salvage therapy was used. Overall and progression free survival (OS and PFS) are shown in figure 1.DISCUSSION. Our data demonstrate that the VTD combination in the real life is an extremely effective regimen in terms of response rate. Most patients after VTD are able to mobilize CD34+ cells as well as to receive ASCT. In a considerable proportion of cases reduction of thalidomide dose is required and in 25% of cases the drug needed to be discontinued. As compared to data from clinical trials, PFS in our series seems to be shorter, however our patients were unselected and in this series follow up is significantly longer. [Display omitted] DisclosuresNo relevant conflicts of interest to declare.

Toxic effects of bortezomib on primary sensory neurons and Schwann cells of adult mice.

The proteasome inhibitor bortezomib is nowadays first line treatment for multiple myeloma. One of the most significant adverse events is peripheral neuropathy, mainly involving sensory nerve fibers that can lead to withdrawal of treatment. Here we develop an in vitro model to compare the effects of bortezomib on primary sensory neurons and Schwann cells of adult mice. We observed that sensory neurons were more susceptible to bortezomib, and their viability was reduced at a concentration of 6 nM, that only affected Schwann cell proliferation but not survival. At concentration higher than 8 nM Schwann cell viability was also compromised. Already at low concentrations, surviving neurons presented alterations in neurite outgrowth. Neurites were shorter and had dystrophic appearance, with alterations in neurofilament staining. However, neurites were able to regrow after removing bortezomib from the medium, thus indicating reversibility of the neurotoxicity. We confirmed in vivo that bortezomib produced alterations in neurofilaments at early stages of the treatment. After an accumulated dose of 2 mg/kg bortezomib, dorsal root ganglia neurons of treated animals showed accumulation of neurofilament in the soma. To evaluate if this accumulation was related with alterations in axonal transport, we tested the ability of sensory neurons to retrogradely transport a retrotracer applied at the distal nerve. Treated animals showed a lower amount of retrotracer in the soma 24 h after its application to the tibial nerve, therefore suggesting that axonal transport was affected by bortezomib.

Bortezomib (BOR)-Thalidomide-Dexamethasone (VTD) and High-Dose Melphalan (HDM) As First Line Treatment for Multiple Myeloma (MM) Is Associated with a Lower Rate of Second Primary Malignancies (SPMs) Compared to TD Plus HDM

The availability of novel drugs such as immunomodulatory drugs, IMiDs, and proteasome inhibitors, PI, for the front line treatment of Multiple Myeloma (MM) has dramatically changed patients’ outcomes, significantly prolonging progression free survival (PFS) and translating into an extended overall survival (OS). Despite these impressive results, concerns have been raised regarding the possibility that IMiDs (lenalidomide and thalidomide) might increase the risk of developing SPMs, especially when associated with alkylating agents such as melphalan (MEL). It has long been known that the use of MEL can result in an increased incidence of SPMs, and this risk seems to be increased by the association with IMiDs. By the opposite, the use of PI in newly diagnosed MM (NDMM) patients (pts) was not associated with an increased risk of SPMs in a phase III study aimed at comparing BOR, MEL and prednisone (MP) vs MP.[1] Despite these results, the full impact of an upfront treatment containing both a PI and an IMiD in association with high dose MEL still has to be investigated.To address this issue, we have evaluated the incidence of SPMs in pts enrolled in the GIMEMA 26866138-MMY-3006 multicentre phase III study aimed at comparing BOR, thalidomide and dexamethasone (VTD) versus TD as induction before, and consolidation after, a double course of high dose MEL.The trial, conducted in Italy from 2006 to 2008, enrolled 480 transplant eligible NDMM, of which 474 received assigned treatment. Data on the incidence of SPMs are available for 299 pts (63%, 148 VTD and 151 TD).With a median follow up of 73 months, 25/299 pts (8%) developed a SPM: 7 (2%) SPMs were hematologic and 18 (6%) were non hematologic. The median time from trial entry to development of the SPM was 36 months (range 8.4-69.0). The number of pts developing a SPM was lower in VTD arm (5%) compared to TD arm (11%, p=0.068). Among pts developing a SPM, the proportion of solid malignancies was similar between treatment arms (75% and 71% in VTD and TD, respectively). Similarly, the percentages of hematologic SPMs was 25% for VTD pts and 29% for TD. On the overall population, the incidence rate (IR) of developing a SPM was 1% at 1 year and 9.9% at 6 years (yrs). This incidence was significantly lower for patients randomised to VTD compared with patients receiving TD (6% vs 13% at 6 yrs, p=0.037). When looking at the IR of solid tumours we noticed that only 5% of VTD-treated patients developed a solid SPM, as compared to 9.6% in TD; similarly, less hematologic SPMs were observed in the BOR arm (1% vs 4% at 6 yrs for VTD and TD, respectively). When the analysis was performed according to SPMs type, no statistical significance could be demonstrated.Our data compare favourably with data previously reported on the incidence of developing SPMs in NDMM treated with BOR frontline in association with MEL. With a follow up of 6 years, we were able to confirm that treatment with PI is associated with a low risk of developing SPM. Interestingly our data suggest that treatment with PI might decrease the risk of developing a SPM compared to IMiDs based treatment. Randomised trials with PI and IMiDs treatment should prospectively evaluate this issue.