Chimeric antigen receptor and bispecific T-cell engager therapies in multiple myeloma patients with prior allogeneic transplantation.

Chimeric antigen receptor T-cell (CAR-T) therapy and bispecific T-cell engagers (BsAb) have emerged as promising immunotherapeutic modalities in patients with relapsed and/or refractory multiple myeloma (RRMM). However, there is limited data on the safety and efficacy of CAR-T and BsAb therapies in MM patients with a prior history of allogeneic transplantation (allo-HCT). Thirty-three MM patients with prior allo-HCT received CAR-T (n = 24) or BsAb (n = 9) therapy. CAR-T therapy demonstrated an ORR of 92% (67% ≥ CR), and 73% were MRD negative. BsAb therapy resulted in an ORR of 44% (44% ≥ CR) and 44% MRD negative. Safety analysis showed grade ≥3 AEs in 92% of CAR-T and 56% of BsAb patients. Cytokine release syndrome (CRS) occurred in 83% of CAR-T and 78% of BsAb recipients, while immune effector cell-associated neurotoxicity syndrome (ICANS) was observed in three CAR-T patients. Infections of grade ≥3 were reported in 50% of CAR-T and 44% of BsAb recipients. No exacerbation of graft-versus-host disease occurred except in one BsAb recipient. CAR-T and BsAb therapies appear to be feasible, safe and provide deep and durable responses in MM patients with prior allo-HCT.

The changing spectrum of infection with BCMA and GPRC5D targeting bispecific antibody (bsAb) therapy in patients with relapsed refractory multiple myeloma.

There is a paucity of granular data on infection risk with B-cell maturation antigen (BMCA) and GPRC5D bispecific antibodies (bsAb) in relapsed/refractory multiple myeloma (RRMM). The aim of our multi-institutional study was to characterize the incidence, etiologies, and risk factors of infections from the start of therapy to the last follow-up or 90 days after study exit. A total of 66 patients received BCMA bsAb monotherapy, 15 GPRC5D bsAb monotherapy, and 15 GPRC5D bsAb combination therapy with daratumumab and/or pomalidomide. While the infection rate per 100 days was 0.57 for BCMA bsAb, it was 0.62 for GPRC5D bsAb combination and 0.13 for GPRC5D bsAb monotherapy; P=0.05. The proportion of infections that were grade ≥3 was higher in the BCMA bsAb group compared to the GPRC5D groups (58% vs. 36%; P=0.04). Grade 5 events were observed in 8% (n=8) of the patients, all treated with BCMA bsAb. The 9 month cumulative incidence of any grade of infection was similar in the BCMA and GPRC5D-combination groups (57% and 62%) and significantly higher than in the GPRC5D-mono group (16%); P=0.012. The cumulative incidence of grade ≥3 infections was highest in the BCMA group reaching 54% at 18 months; P=0.06. Multivariate analysis showed that BCMA bsAb therapy or GPRC5D combination therapy, history of previous infections, baseline lymphopenia, and baseline hypogammaglobulinemia were significantly associated with a higher risk of grade ≥3 infections. Our results indicate that BCMA bsAb and GPRC5D-combination therapies in RRMM are associated with higher cumulative incidence of infection and grade ≥3 infection compared to GPRC5D bsAb mono.

IL6Myc mouse is an immunocompetent model for the development of aggressive multiple myeloma.

Multiple Myeloma (MM) is a plasma cell neoplasm originating in the bone marrow and is the second most common blood cancer in the United States. One challenge in understanding the pathogenesis of MM and improving treatment is a lack of immunocompetent mouse models. We previously developed the IL6Myc mouse that generates plasmacytomas at 100% penetrance that phenotypically resemble aggressive MM. Using comprehensive genomic analysis, we found that the IL6Myc tumors resemble aggressive MM by RNA and protein expression. We also found that IL6Myc tumors accumulated fusions and missense mutations in genes that overlap significantly with human myeloma, indicating that the mouse is good model for studying disease etiology. Lastly, we derived cell lines from IL6Myc tumors that express cell surface markers typical of MM and readily engraft into mice, home to the bone marrow, and induce osteolytic disease. The cell lines may be useful in developing immunotherapies directed against BAFF-R and TACI, though not BCMA, and may also be a good model for studying dexamethasone resistance. These data indicate that the IL6Myc model is useful for studying development of aggressive MM and for developing new treatments against such forms of the disease.

Coactivation of NF-κB and Notch signaling is sufficient to induce B-cell transformation and enables B-myeloid conversion.

NF-κB and Notch signaling can be simultaneously activated in a variety of B-cell lymphomas. Patients with B-cell lymphoma occasionally develop clonally related myeloid tumors with poor prognosis. Whether concurrent activation of both pathways is sufficient to induce B-cell transformation and whether the signaling initiates B-myeloid conversion in a pathological context are largely unknown. Here, we provide genetic evidence that concurrent activation of NF-κB and Notch signaling in committed B cells is sufficient to induce B-cell lymphomatous transformation and primes common progenitor cells to convert to myeloid lineage through dedifferentiation, not transdifferentiation. Intriguingly, the converted myeloid cells can further transform, albeit at low frequency, into myeloid leukemia. Mechanistically, coactivation of NF-κB and Notch signaling endows committed B cells with the ability to self renew. Downregulation of BACH2, a lymphoma and myeloid gene suppressor, but not upregulation of CEBPα and/or downregulation of B-cell transcription factors, is an early event in both B-cell transformation and myeloid conversion. Interestingly, a DNA hypomethylating drug not only effectively eliminated the converted myeloid leukemia cells, but also restored the expression of green fluorescent protein, which had been lost in converted myeloid leukemia cells. Collectively, our results suggest that targeting NF-κB and Notch signaling will not only improve lymphoma treatment, but also prevent the lymphoma-to-myeloid tumor conversion. Importantly, DNA hypomethylating drugs might efficiently treat these converted myeloid neoplasms.

Athermal echelle grating and tunable echelle grating demultiplexers using a Mach-Zehnder interferometer launch structure.

We present a comparative experimental study of three silicon photonic echelle grating demultiplexers that are integrated with a Mach-Zehnder interferometer (MZI) launch structure. By appropriate choice of the MZI configuration, the temperature induced shift of the demultiplexer channel wavelengths can be suppressed (athermal) or enhanced (super-thermal) or be controlled by an on-chip micro-heater. The latter two configurations allow the channel wavelengths to be actively tuned using lower power than possible by temperature tuning a conventional echelle demultiplexer. In the athermal configuration, the measured channel spectral shift is reduced to less than 10 pm/°C, compared to the 83 pm/°C shift for an unmodified echelle device. In super-thermal operation an enhanced channel temperature tuning rate of 170 pm/°C is achieved. Finally, by modulating the MZI phase with an on-chip heater, the demultiplexer channels can be actively tuned to correct for ambient temperature fluctuations up to 20 °C, using a drive current of less than 20 mA.

CHEK1 and circCHEK1_246aa evoke chromosomal instability and induce bone lesion formation in multiple myeloma.

BACKGROUND: Multiple myeloma (MM) is still incurable and characterized by clonal expansion of plasma cells in the bone marrow (BM). Therefore, effective therapeutic interventions must target both myeloma cells and the BM niche. METHODS: Cell proliferation, drug resistance, and chromosomal instability (CIN) induced by CHEK1 were confirmed by Giemsa staining, exon sequencing, immunofluorescence and xenograft model in vivo. Bone lesion was evaluated by Tartrate-resistant acid phosphatase (TRAP) staining. The existence of circCHEK1_246aa was evaluated by qPCR, Sanger sequencing and Mass Spectrometer. RESULTS: We demonstrated that CHEK1 expression was significantly increased in human MM samples relative to normal plasma cells, and that in MM patients, high CHEK1 expression was associated with poor outcomes. Increased CHEK1 expression induced MM cellular proliferation and evoked drug-resistance in vitro and in vivo. CHEK1-mediated increases in cell proliferation and drug resistance were due in part to CHEK1-induced CIN. CHEK1 activated CIN, partly by phosphorylating CEP170. Interestingly, CHEK1 promoted osteoclast differentiation by upregulating NFATc1 expression. Intriguingly, we discovered that MM cells expressed circCHEK1_246aa, a circular CHEK1 RNA, which encoded and was translated to the CHEK1 kinase catalytic center. Transfection of circCHEK1_246aa increased MM CIN and osteoclast differentiation similarly to CHEK1 overexpression, suggesting that MM cells could secrete circCHEK1_246aa in the BM niche to increase the invasive potential of MM cells and promote osteoclast differentiation. CONCLUSIONS: Our findings suggest that targeting the enzymatic catalytic center encoded by CHEK1 mRNA and circCHEK1_246aa is a promising therapeutic modality to target both MM cells and BM niche.

Efficient Bloch mode calculation of periodic systems with arbitrary geometry and open boundary conditions in the complex wavevector domain.

We show how existing iterative methods can be used to efficiently and accurately calculate Bloch periodic solutions of Maxwell's equations in arbitrary geometries. This is carried out in the complex-wavevector domain using a commercial frequency-domain finite-element solver that is available to the general user. The method is capable of dealing with leaky Bloch mode solutions, and is extremely efficient even for 3D geometries with non-trivial material distributions. We perform independent finite-difference time-domain simulations of Maxwell's equations to confirm our results. This comparison demonstrates that the iterative mode finder is more accurate, since it provides the true solutions in the complex-wavevector domain and removes the need for additional signal processing and fitting. Due to its efficiency, generality and reliability, this technique is well suited for complex and novel design tasks in integrated photonics, and also for a wider range of photonics problems.

Fiber Fabry-Perot astrophotonic correlation spectroscopy for remote gas identification and radial velocity measurements.

We present a novel, to the best of our knowledge, remote gas detection and identification technique based on correlation spectroscopy with a piezoelectric tunable fiber-optic Fabry-Perot filter. We show that the spectral correlation amplitude between the filter transmission window and gas absorption features is related to the gas absorption optical depth, and that different gases can be distinguished from one another using their correlation signal phase. Using a previously captured telluric-corrected high-resolution near-infrared spectrum of Venus, we show that the radial velocity of Venus can be extracted from the phase of higher order harmonic lock-in signals. This correlation spectroscopy technique has applications in the detection and radial velocity determination of weak spectral features in astronomy and remote sensing. We experimentally demonstrate a remote CO2 detection system using a lock-in amplifier, fiber-optic Fabry-Perot filter, and single channel avalanche photodiode.

Association of adverse events and associated cost with efficacy for approved relapsed and/or refractory multiple myeloma regimens: A Bayesian network meta-analysis of phase 3 randomized controlled trials.

BACKGROUND: Several new treatment options have been approved for relapsed and/or refractory multiple myeloma (RRMM). In this systematic review, associations of the efficacy of each approved regimen with adverse events (AEs) and the total cost per cycle were compared with a Bayesian network meta-analysis (NMA) of phase 3 randomized controlled trials (RCTs). METHODS: Scopus, Cochrane, PubMed Publisher, and Web of Science were searched from January 1999 to July 2018 for phase 3 RCTs of regimens (approved by the US Food and Drug Administration) used in RRMM. The relative ranking of agents was assessed with surface under the cumulative ranking (SUCRA) probabilities. The primary efficacy, safety, and cost outcomes were progression-free survival with the regimen, grade 3 to 4 AEs, and the total cost per cycle (regimen cost plus average cost of managing AEs). RESULTS: Fifteen studies including 7718 patients and evaluating 14 different regimens were identified. Daratumumab, lenalidomide, and dexamethasone were ranked highest for reducing progression (hazard ratio, 0.13; 95% credible interval, 0.09-0.19; SUCRA, 1) but carried the highest probability of total cost per cycle ($41,420; 95% Credible Interval [CrCl], $58,665-$78,041; SUCRA, 0.02). Panobinostat, bortezomib, and dexamethasone were the least effective and least safe (SUCRA, 0.24), whereas bortezomib, thalidomide, and dexamethasone emerged as least effective with the highest total cost per cycle (SUCRA, 0.33). Carfilzomib and dexamethasone emerged as the winner when this regimen was considered in terms of efficacy and safety (SUCRA, 0.61) and efficacy and total cost per cycle (SUCRA, 0.60). CONCLUSIONS: The results of this NMA can provide additional guidance for the decision-making process when one is choosing the most appropriate regimen for RRMM.

Spectrum-free integrated photonic remote molecular identification and sensing.

Absorption spectroscopy is widely used in sensing and astronomy to understand remote molecular compositions. However, dispersive techniques require multichannel detection, reducing detection sensitivity while increasing instrument cost when compared to spectrophotometric methods. We present a novel non-dispersive infrared molecular detection and identification scheme that performs spectral correlation optically using a specially tailored integrated silicon ring resonator. We show experimentally that the correlation amplitude is proportional to the number of overlapping ring resonances and gas lines, and that molecular specificity can be achieved from the phase of the correlation signal. This strategy can enable on-chip detection of extremely faint remote spectral signatures.

Photonic temperature and wavelength metrology by spectral pattern recognition.

Spectral pattern recognition is used to measure temperature and generate calibrated wavelength/frequency combs using a single silicon waveguide ring resonator. The ring generates two incommensurate interleaving TE and TM spectral combs that shift independently with temperature to create a spectral pattern that is unique at every temperature. Following an initial calibration, the ring temperature can be determined by recognizing the spectral resonance pattern, and as a consequence, the wavelength of every resonance is also known. Two methods of pattern-based temperature retrieval are presented. In the first method, the ring is locked to a previously determined temperature set-point defined by the coincidence of only two specific TE and TM cavity modes. Based on a prior calibration at the set-point, the ring temperature and hence all resonance wavelengths are then known and the resulting comb can be used as a wavelength calibration reference. In this configuration, all reference comb wavelengths have been reproduced within a 5 pm accuracy across an 80 nm range by using an on-chip micro-heater to tune the ring. For more general photonic thermometry, a spectral correlation algorithm is developed to recognize a resonance pattern across a 30 nm wide spectral window and thereby determine ring temperature continuously to 50 mK accuracy. The correlation method is extended to simultaneously determine temperature and to identify and correct for wavelength calibration errors in the interrogating light source. The temperature and comb wavelength accuracy is limited primarily by the linewidth of the ring resonances, with accuracy and resolution scaling with the ring quality factor.

Perfectly vertical surface grating couplers using subwavelength engineering for increased feature sizes.

We present perfectly vertical grating couplers for the 220 nm silicon-on-insulator platform incorporating subwavelength metamaterials to increase the minimum feature sizes and achieve broadband low back-reflection. Our study reveals that devices with high coupling efficiencies are distributed over a wide region of the design space with varied back-reflections, while still maintaining minimum feature sizes larger than 100 nm and even 130 nm. Using 3D-finite-difference time-domain simulations, we demonstrate devices with broadband low back-reflection of less than -20dB over more than 100 nm bandwidth centered around the C-band. Coupling efficiencies of 72% and 67% are achieved for minimum feature sizes of 106 nm and 130 nm, respectively. These gratings are also more fabrication tolerant compared to similar designs not using metamaterials.

Highly efficient optical antenna with small beam divergence in silicon waveguides.

Optical antennas are key components in optical phased arrays for light detection and ranging technology requiring long sensing range and high scanning resolution. To achieve a narrow beam width in the far-field region, antenna lengths of several millimeters or more are required. To date, such long antennas have been impossible to achieve in silicon waveguides because currently demonstrated technologies do not allow accurate control of grating strength. Here, we report on a new type of surface-emitting silicon waveguide with a dramatically increased antenna length of L=3.65mm. This is achieved by using a subwavelength metamaterial waveguide core evanescently coupled with radiative segments laterally separated from the core. This results in a far-field diffracted beam width of 0.025°, which is a record small beam divergence for a silicon photonics surface-emitting device. We also demonstrate that by using a design with L-shaped surface-emitting segments, the radiation efficiency of the antenna can be substantially increased compared to a conventional design, with an efficiency of 72% at the wavelength of 1550 nm.

Trends in the use of therapeutic plasma exchange in multiple myeloma.

INTRODUCTION: Therapeutic plasma exchange (TPE) is traditionally performed for hyperviscosity, neuropathy and to mitigate renal injury in the setting of high clonal free light chain burden in patients with multiple myeloma (MM) with unknown clinical benefit. MATERIALS AND METHODS: Retrospective study of adults ≥18 years with MM who received TPE in the in-patient setting in the United States from 1993 to 2015. We examined the temporal trends of TPE utilization in MM hospitalizations, hospital charges, in-hospital mortality, and length of hospitalization and the predictors of in-hospital mortality and length of hospitalizations. RESULTS: The number of MM-hospitalizations for TPE in adults increased significantly from 1993 to 2015 (1% in 1993-1999 to 2.1% in 2008-2015 of all MM discharges, P for trend <.0001). About 70% of TPE recipients had acute kidney injury (AKI). The median hospital charges increased 5-fold during the time period ($ 24 407 to $ 113 496; P for trend <.0001). In-hospital mortality decreased (17.5% (SE 2.66) in 1993-1997 to 8.7% (1.39) in 2007 to 2013) P for trend <.005) while the length of stay remained unchanged (11.2 days vs 11.9 days, P for trend 0.17). On adjusted analysis, significant predictors of in-hospital mortality among MM TPE recipients include, Charlson Comorbidity Index (CCI) (3 vs 2 adjusted odds ratio, aOR 2.16, 95% CI 1.26-3.71; P = .005), year (continuous) (aOR 0.93, 95% CI 0.90-0.96; P < .001) and race (other vs white; aOR 0.44, 95% CI 0.25-0.78; P = 0.004). CONCLUSIONS: There has been a substantial increase in the use and associated cost of TPE in hospitalized MM patients.

Chronic intermittent hypoxia enhances disease progression in myeloma-resistant mice.

Obesity is the only known modifiable risk factor for multiple myeloma (MM), an incurable cancer of bone marrow plasma cells. The mechanism linking the two is unknown. Obesity is associated with an increased risk of sleep apnea, which results in chronic intermittent hypoxia (CIH), and drives solid tumor aggressiveness. Given the link between CIH and solid tumor progression, we tested the hypothesis that CIH drives the proliferation of MM cells in culture and their engraftment and progression in vivo. Malignant mouse 5TGM1 cells were cultured in CIH, static hypoxia, or normoxia as a control in custom, gas-permeable plates. Typically MM-resistant C57BL/6J mice were exposed to 10 h/day CIH (AHI = 12/h), static hypoxia, or normoxia for 7 days, followed by injection with 5TGM1 cells and an additional 28 days of exposure. CIH and static hypoxia slowed the growth of 5TGM1 cells in culture. CIH-exposed mice developed significantly more MM than controls (67 vs. 12%, P = 0.005), evidenced by hindlimb paralysis, gammopathy, bone lesions, and bone tumor formation. Static hypoxia was not a significant driver of MM progression and did not reduce survival (P = 0.117). Interestingly, 5TGM1 cells preferentially engrafted in the bone marrow and promoted terminal disease in CIH mice, despite a lower tumor burden, compared with the positive controls. These first experiments in the context of hematological cancer demonstrate that CIH promotes MM through mechanisms distinct from solid tumors and that sleep apnea may be a targetable risk factor in patients with or at risk for blood cancer.

Empirical model for the temperature dependence of silicon refractive index from O to C band based on waveguide measurements.

An accurate model for the silicon refractive index including its temperature and wavelength dependence is critically important for many disciplines of science and technology. Currently, such a model for temperatures above 22°C in the optical communication bands is not available. The temperature dependence in the spectral response of integrated echelle grating filters made in silicon-on-insulator is solely determined by the optical properties of the slab waveguide, making it largely immune to dimensional uncertainties. This feature renders the echelle filters a reliable tool to evaluate the thermo-optic properties of silicon. Here we investigate the temperature dependence of silicon echelle filters for the wavelength range of both O and C bands, measured between 22°C to 80°C. We show that if a constant thermo-optic coefficient of silicon is assumed for each band, as is common in the literature, the predictions show an underestimate of up to 10% in the temperature-induced channel wavelength shift. We propose and assess a model of silicon refractive index that encompasses both the wavelength and temperature dependence of its thermo-optic coefficients. We start from literature data for bulk silicon and further refine the model using the echelle filter measurement results. This model is validated through accurate predictions of device channel wavelengths and their temperature dependence, including the quadratic term, over a wide wavelength and temperature range. This work also demonstrates a new high-precision method for characterizing the optical properties of a variety of materials.

Bragg filter bandwidth engineering in subwavelength grating metamaterial waveguides.

Bragg gratings are fundamental building blocks for integrated photonic circuits. In the high-index contrast silicon-on-insulator material platform, it is challenging to accurately control the grating strength and achieve narrow spectral bandwidths. Here we demonstrate a novel Bragg grating geometry utilizing a silicon subwavelength grating (SWG) waveguide with evanescently coupled periodic Bragg loading segments placed outside the SWG core. We report experimental 3 dB filter bandwidths in a range from 8 nm to 150 pm by adjusting the distance of the Bragg loading segments from the core and the relative phase shift of the segments on the two sides of the waveguide, with a structure that has a minimum feature size of 100 nm.

Correction to: Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma.

As a result of an author oversight in the original article [1], the legend of Figure 5A and C is inaccurate and one panel in Figure 5C (FOXM1N H929 cells shown in the top row, left) is wrong.

Athermal echelle grating filter in silicon-on-insulator using a temperature-synchronized input.

Athermal design of integrated photonic devices can reduce the need for active temperature stabilization and consequently the energy required to operate photonic integrated circuits. For silicon photonic filters such as AWGs which employ wire or ridge waveguides, temperature insensitivity can be achieved using cladding materials with negative thermo-optic coefficients. On the other hand, in echelle grating filters the inteference takes place in the slab free-propagation region, and therefore the modal overlap with the cladding is small, rendering this method ineffective. In this work we present an approach to design an athermal echelle grating filter exploiting a temperature-synchronized Mach-Zehnder interferometer as input. This reduces the spectral shift over a temperature range of 20 K to less than ±45 pm compared to the 1.6 nm shift for the same echelle grating with a conventional waveguide input. Furthermore, the proposed design relies exclusively on a standard fabrication process for silicon-on-insulator photonic devices and exhibits a good tolerance to fabrication uncertainties.

Upregulation of FOXM1 leads to diminished drug sensitivity in myeloma.

BACKGROUND: Following up on previous work demonstrating the involvement of the transcription factor forkhead box M1 (FOXM1) in the biology and outcome of a high-risk subset of newly diagnosed multiple myeloma (nMM), this study evaluated whether FOXM1 gene expression may be further upregulated upon tumor recurrence in patients with relapsed multiple myeloma (rMM). Also assessed was the hypothesis that increased levels of FOXM1 diminish the sensitivity of myeloma cells to commonly used myeloma drugs, such as the proteasome inhibitor bortezomib (Bz) and the DNA intercalator doxorubicin (Dox). METHODS: FOXM1 message was evaluated in 88 paired myeloma samples from patients with nMM and rMM, using gene expression microarrays as measurement tool. Sources of differential gene expression were identified and outlier analyses were performed using statistical methods. Two independent human myeloma cell lines (HMCLs) containing normal levels of FOXM1 (FOXM1N) or elevated levels of lentivirus-encoded FOXM1 (FOXM1Hi) were employed to determine FOXM1-dependent changes in cell proliferation, survival, efflux-pump activity, and drug sensitivity. Levels of retinoblastoma (Rb) protein were determined with the assistance of Western blotting. RESULTS: Upregulation of FOXM1 occurred in 61 of 88 (69%) patients with rMM, including 4 patients that exhibited > 20-fold elevated expression peaks. Increased FOXM1 levels in FOXM1Hi myeloma cells caused partial resistance to Bz (1.9-5.6 fold) and Dox (1.5-2.9 fold) in vitro, using FOXM1N myeloma as control. Reduced sensitivity of FOXM1Hi cells to Bz was confirmed in vivo using myeloma-in-mouse xenografts. FOXM1-dependent regulation of total and phosphorylated Rb agreed with a working model of myeloma suggesting that FOXM1 governs both chromosomal instability (CIN) and E2F-dependent proliferation, using a mechanism that involves interaction with NIMA related kinase 2 (NEK2) and cyclin dependent kinase 6 (CDK6), respectively. CONCLUSIONS: These findings enhanced our understanding of the emerging FOXM1 genetic network in myeloma and provided preclinical support for the therapeutic targeting of the FOXM1-NEK2 and CDK4/6-Rb-E2F pathways using small-drug CDK and NEK2 inhibitors. Clinical research is warranted to assess whether this approach may overcome drug resistance in FOXM1Hi myeloma and, thereby, improve the outcome of patients in which the transcription factor is expressed at high levels.