18 research outputs found
Reuse of Neural Modules for General Video Game Playing
A general approach to knowledge transfer is introduced in which an agent
controlled by a neural network adapts how it reuses existing networks as it
learns in a new domain. Networks trained for a new domain can improve their
performance by routing activation selectively through previously learned neural
structure, regardless of how or for what it was learned. A neuroevolution
implementation of this approach is presented with application to
high-dimensional sequential decision-making domains. This approach is more
general than previous approaches to neural transfer for reinforcement learning.
It is domain-agnostic and requires no prior assumptions about the nature of
task relatedness or mappings. The method is analyzed in a stochastic version of
the Arcade Learning Environment, demonstrating that it improves performance in
some of the more complex Atari 2600 games, and that the success of transfer can
be predicted based on a high-level characterization of game dynamics.Comment: Accepted at AAAI 1
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Object-model transfer in the general video game domain
Reinforcement learning agents often benefit from learning models that predict their
environment. However, learned models may not generalize well to novel situations. This
thesis investigates the potential for a transfer learning approach to address the challenge in
the video game domain. The approach helps agents learn models of new games by transferring
knowledge from previously learned games. Transfer is facilitated by decomposing
games into the objects they contain. The assumption is that it is easier to relate features
between objects from different games than features between whole environments of different
games. Experiments show that predictions made by this method are more accurate than
predictions made without transferred knowledge, and this improvement is demonstrated to
result in increased efficiency in a task where an agent explores a maze-like game. The
conclusion is that model learning can be enhanced by transferring object models from previously
learned environments.Computer Science
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Avelumab, a PD-L1 Inhibitor, in Combination with Hypofractionated Radiotherapy and the Abscopal Effect in Relapsed Refractory Multiple Myeloma
Despite the initial optimism for using immune checkpoint inhibition in the treatment of multiple myeloma, subsequent clinical studies have been disappointing. Preclinical studies have suggested that priming the immune system with various modalities in addition to checkpoint inhibition may overcome the relative T-cell exhaustion or senescence; however, in this small data set, radiotherapy with checkpoint inhibition did not appear to activate the antitumor immune response.
Extramedullary disease (EMD) is recognized as an aggressive subentity of multiple myeloma (MM) with a need for novel therapeutic approaches. We therefore designed a proof-of-principle pilot study to evaluate the synergy between the combination of the anti-PD-L1, avelumab, and concomitant hypofractionated radiotherapy.
This was a single-arm phase II Simon two-stage single center study that was prematurely terminated because of the COVID-19 pandemic after enrolling four patients. Key eligibility included patients with relapsed/refractory multiple myeloma (RRMM) who had exhausted or were not candidates for standard therapy and had at least one lesion amenable to radiotherapy. Patients received avelumab until progression or intolerable toxicity and hypofractionated radiotherapy to a focal lesion in cycle 2. Radiotherapy was delayed until cycle 2 to allow the avelumab to reach a study state, given the important observation from previous studies that concomitant therapy is needed for the abscopal effect.
At a median potential follow-up of 10.5 months, there were no objective responses, one minimal response, and two stable disease as best response. The median progression-free survival (PFS) was 5.3 months (95% confidence interval [CI]: 2.5-7.1 months), and no deaths occurred. There were no grade ≥3 and five grade 1-2 treatment-related adverse events.
Avelumab in combination with radiotherapy for patients with RRMM and EMD was associated with very modest systemic clinical benefit; however, patients did benefit as usual from local radiotherapy. Furthermore, the combination was very well tolerated compared with historical RRMM treatment regimens
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Fixed Duration Combination Therapy with Carfilzomib, Lenalidomide, and Dexamethasone Followed By Lenalidomide Maintenance Leads to High Rates of Sustained MRD Negativity in Patients with High-Risk Smoldering Multiple Myeloma: Long Term Follow up of an Investigator Initiated Phase 2 Trial
Background: Patients with high-risk smoldering multiple myeloma (HR-SMM) have a 5-year risk of progression to symptomatic multiple myeloma of approximately 75% and a median time to progression of less than 2 years (Lakshman et al., Blood Cancer J 2018) (Rajkumar et al., Blood 2015). We previously reported the primary results of our phase 2 trial of carfilzomib, lenalidomide, and dexamethasone followed by lenalidomide maintenance (KRd-R) as prevention of symptomatic multiple myeloma in patients with HR-SMM (Kazandjian et al., JAMA Onc 2021). Herein, we present follow-up data after all patients have completed lenalidomide maintenance to evaluate the durability of responses off therapy. Methods: Patients with HR-SMM based on the Mayo Clinic, PETHEMA, and/or Rajkumar, Mateos, and Landgren criteria were eligible for enrollment in this single-center phase 2 investigator-initiated study. Patients received eight 28-day cycles (induction) of carfilzomib, 20/36 mg/m 2, with dexamethasone 20/10 (days 1,2, 8, 9, 15, 16) and lenalidomide 25 mg (days 1-21), followed by 2 years of maintenance therapy with lenalidomide 10 mg (days 1-21). The primary endpoint was the rate of minimum residual disease negative complete responses (MRD negative CR) at the end of induction as assessed by multicolor flow cytometry (MRD sensitivity 10 -5). Secondary objectives included progression to overt clinical multiple myeloma (end-organ damage or myeloma-defining event) or death (clinical PFS) and biochemical progression (PD) by IMWG criteria (biochemical PFS). Results: A total of54 patients were enrolled and started treatment between May 29, 2012 and July 23, 2020. Full patient demographics and baseline disease characteristics were previously reported. (Kazandjian et al., JAMA Onc 2021) At the data cut-off of July 17, 2023, the median follow-up time was 60.2 months (range: 33.7 - 127.8). As previously reported, 38 patients (70.4%) achieved MRD negative CR by the end of induction. The median duration of MRD negative CR was 57.4 months (95% CI: 44.6 - 97.2). To date, durability of MRD negative CR has been observed up to 120.6 months and 21 patients (39%) have remained MRD negative for over 2 years (95% CI: 25.9 - 53.1%). (Figure 1) All patients attained a PR or better and the median duration of response has still not been reached. At 60 months, 75.1% of patients maintained their response (95% CI: 59.9 - 85.2%). The median clinical PFS has also not been reached. Only 5 out of 54 (9.3%; 95% CI: 3.1-20.3%) patients have progressed to clinical multiple myeloma. At 60 months, 92.7% of patients were free from clinical progression (95% CI: 78.1 - 97.9%). The probability of being free of clinical progression at 100 months was 78.9% (95% CI: 51.9 - 91.8%). While the median biochemical PFS has not been reached, patients who were MRD negative by the end of induction had significantly less risk of having biochemical progression compared to patients who still had measurable disease at completion of induction (median biochemical PFS NR vs. 41.8 (HR 0.168 (95% CI: 0.060 - 0.474) (P value < 0.0001) (Figure 2). As previously reported, KRd-R was well tolerated, with no grade 4 non-hematologic adverse events and manageable low-grade toxicities. Discussion: Treatment of patients with HR-SMM with KRd-R has led to deep and durable remissions. At a median of 5 years of follow-up, this trial has yet to reach a median clinical PFS, indicating success in preventing serious end organ damage. However, it is still unclear if the beneficial outcomes seen in HR-SMM interventional studies are due to treatment of more susceptible disease or inherently less aggressive disease. An abstract evaluating the genomic profile of patients from this trial has been submitted to the meeting separately. Future prospective trials must capture and eventually select HR profiles based on validated genomic signatures. This study suggests that patients who achieve MRD negative remissions after induction therapy have prolonged biochemical PFS. However, further follow-up time is needed to fully understand the rates of clinical PFS and OS. To evaluate if additional treatment duration to achieve MRD negativity would be beneficial we have designed a trial using daratumumab, carfilzomib, and dexamethasone utilizing an adaptive treatment duration based on MRD status for patients with HR-SMM which is currently enrolling participants (NCT04933539)