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IntroductionCancer combination treatments involving immunotherapies with targeted radiation therapy are at the forefront of treating cancers. However, dosing and scheduling of these therapies pose a challenge. Mathematical models provide a unique way of optimizing these therapies.MethodsUsing a preclinical model of multiple myeloma as an example, we demonstrate the capability of a mathematical model to combine these therapies to achieve maximum response, defined as delay in tumor growth. Data from mice studies with targeted radionuclide therapy (TRT) and chimeric antigen receptor (CAR)-T cell monotherapies and combinations with different intervals between them was used to calibrate mathematical model parameters. The dependence of progression-free survival (PFS), overall survival (OS), and the time to minimum tumor burden on dosing and scheduling was evaluated. Different dosing and scheduling schemes were evaluated to maximize the PFS and optimize timings of TRT and CAR-T cell therapies.ResultsTherapy intervals that were too close or too far apart are shown to be detrimental to the therapeutic efficacy, as TRT too close to CAR-T cell therapy results in radiation related CAR-T cell killing while the therapies being too far apart result in tumor regrowth, negatively impacting tumor control and survival. We show that splitting a dose of TRT or CAR-T cells when administered in combination is advantageous only if the first therapy delivered can produce a significant benefit as a monotherapy.DiscussionMathematical models are crucial tools for optimizing the delivery of cancer combination therapy regimens with application along the lines of achieving cure, maximizing survival or minimizing toxicity.

Aim: We compared the effectiveness of teclistamab versus real-world physicians choice of therapy (RWPC) in triple-class exposed relapsed/refractory multiple myeloma. Materials & methods: MajesTEC-1 eligibility criteria were applied to the RWPC cohort. Baseline covariate imbalances were adjusted using inverse probability of treatment weighting. Overall survival, progression-free survival and time to next treatment were compared. Results: After inverse probability of treatment weighting, baseline characteristics were similar between cohorts (teclistamab, n = 165; RWPC, n = 364 [766 observations]). Teclistamab treated patients had numerically better overall survival (hazard ratio [HR]: 0.82 [95% CI: 0.59-1.14]; p = 0.233) and significantly greater progression-free survival (HR: 0.43 [0.33-0.56]; p

BackgroundVaccines for SARS-CoV-2 have been considerably effective in reducing rates of infection and severe COVID-19. However, many patients, especially those who are immunocompromised due to cancer or other factors, as well as individuals who are unable to receive vaccines or are in resource-poor countries, will continue to be at risk for COVID-19. We describe clinical, therapeutic, and immunologic correlatives in two patients with cancer and severe COVID-19 who were treated with leflunomide after failing to respond to standard-of-care comprising remdesivir and dexamethasone. Both patients had breast cancer and were on therapy for the malignancy.MethodsThe protocol is designed with the primary objective to assess the safety and tolerability of leflunomide in treating severe COVID-19 in patients with cancer. Leflunomide dosing consisted of a loading dose of 100 mg daily for the first three days, followed by daily dosing, at the assigned dose level (Dose Level 1: 40 mg, Dose Level -1, 20 mg; Dose Level 2, 60 mg), for an additional 11 days. At defined intervals, serial monitoring of blood samples for toxicity, pharmacokinetics, and immunologic correlative studies were performed, as well as nasopharyngeal swabs for PCR analysis of SARS-CoV-2.ResultsPreclinically, leflunomide impaired viral RNA replication, and clinically, it led to a rapid improvement in the two patients discussed herein. Both patients completely recovered, with minimal toxicities; all adverse events experienced were considered unrelated to leflunomide. Single-cell mass-cytometry analysis showed that leflunomide increased levels of CD8+ cytotoxic and terminal effector T cells and decreased naïve and memory B cells.ConclusionsWith ongoing COVID-19 transmission and occurrence of breakthrough infections in vaccinated individuals, including patients with cancer, therapeutic agents that target both the virus and host inflammatory response would be helpful despite the availability of currently approved anti-viral agents. Furthermore, from an access to care perspective, especially in resource-limited areas, an inexpensive, readily available, effective drug with existing safety data in humans is relevant in the real-world setting.

BackgroundTeclistamab is a T-cell-redirecting bispecific antibody that targets both CD3 expressed on the surface of T cells and B-cell maturation antigen expressed on the surface of myeloma cells. In the phase 1 dose-defining portion of the study, teclistamab showed promising efficacy in patients with relapsed or refractory multiple myeloma.MethodsIn this phase 1-2 study, we enrolled patients who had relapsed or refractory myeloma after at least three therapy lines, including triple-class exposure to an immunomodulatory drug, a proteasome inhibitor, and an anti-CD38 antibody. Patients received a weekly subcutaneous injection of teclistamab (at a dose of 1.5 mg per kilogram of body weight) after receiving step-up doses of 0.06 mg and 0.3 mg per kilogram. The primary end point was the overall response (partial response or better).ResultsAmong 165 patients who received teclistamab, 77.6% had triple-class refractory disease (median, five previous therapy lines). With a median follow-up of 14.1 months, the overall response rate was 63.0%, with 65 patients (39.4%) having a complete response or better. A total of 44 patients (26.7%) were found to have no minimal residual disease (MRD); the MRD-negativity rate among the patients with a complete response or better was 46%. The median duration of response was 18.4 months (95% confidence interval [CI], 14.9 to not estimable). The median duration of progression-free survival was 11.3 months (95% CI, 8.8 to 17.1). Common adverse events included cytokine release syndrome (in 72.1% of the patients; grade 3, 0.6%; no grade 4), neutropenia (in 70.9%; grade 3 or 4, 64.2%), anemia (in 52.1%; grade 3 or 4, 37.0%), and thrombocytopenia (in 40.0%; grade 3 or 4, 21.2%). Infections were frequent (in 76.4%; grade 3 or 4, 44.8%). Neurotoxic events occurred in 24 patients (14.5%), including immune effector cell-associated neurotoxicity syndrome in 5 patients (3.0%; all grade 1 or 2).ConclusionsTeclistamab resulted in a high rate of deep and durable response in patients with triple-class-exposed relapsed or refractory multiple myeloma. Cytopenias and infections were common; toxic effects that were consistent with T-cell redirection were mostly grade 1 or 2. (Funded by Janssen Research and Development; MajesTEC-1 ClinicalTrials.gov numbers, NCT03145181 and NCT04557098.).

Measuring response among patients with multiple myeloma is essential for the care of patients. Deeper responses are associated with better progression free survival (PFS) and overall survival (OS). To test the hypothesis that Mass-Fix, a mass spectrometry-based means to detect monoclonal proteins, is superior to existing methodologies to predict for survival outcomes, samples from the STAMINA trial (NCT01109004), a trial comparing three transplant approaches, were employed. Samples from 575 patients from as many as three time points (post-induction [post-I; pre-maintenance [pre-M]; 1 year post enrollment [1YR]) were tested when available. Four response parameters were assessed: Mass-Fix, serum immunofixation, complete response, and measurable residual disease (MRD) by next generation flow cytometry. Of the four response measures, only MRD and Mass-Fix predicted for PFS and OS at multiple testing points on multivariate analyses. Although MRD drove Mass-Fix from the model for PFS at post-I and pre-M, 1YR Mass-Fix was independent of 1YR MRD. For OS, the only prognostic pre-I measure was Mass-Fix, and the only 1YR measures that were prognostic on multivariate analysis were 1YR MRD and 1YR Mass-Fix. SIFE and CR were not. Mass-Fix is a powerful means to track response.

Targeted radionuclide therapy (TRT) has recently seen a surge in popularity with the use of radionuclides conjugated to small molecules and antibodies. Similarly, immunotherapy also has shown promising results, an example being chimeric antigen receptor T cell (CAR-T) therapy in hematologic malignancies. Moreover, TRT and CAR-T therapies possess unique features that require special consideration when determining how to dose as well as the timing and sequence of combination treatments including the distribution of the TRT dose in the body, the decay rate of the radionuclide, and the proliferation and persistence of the CAR-T cells. These characteristics complicate the additive or synergistic effects of combination therapies and warrant a mathematical treatment that includes these dynamics in relation to the proliferation and clearance rates of the target tumor cells. Here, we combine two previously published mathematical models to explore the effects of dose, timing, and sequencing of TRT and CAR-T cell-based therapies in a multiple myeloma setting. We find that, for a fixed TRT and CAR-T cell dose, the tumor proliferation rate is the most important parameter in determining the best timing of TRT and CAR-T therapies.

18F-Fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) is one of the most widely used imaging techniques to detect multiple myeloma (MM). Intracellular FDG uptake depicts in vivo metabolic activity, which can be seen in both malignant and nonmalignant cells, resulting in limited sensitivity and specificity. Our group showed preclinically that tracing MM dissemination using a CD38-directed human antibody, daratumumab, that is radioconjugated with 64Cu via the chelator DOTA (64Cu-daratumumab), led to improved sensitivity and specificity over that of FDG. Here, we report the results of a phase 1 trial designed to (1) assess the safety and feasibility of 64Cu-daratumumab PET/CT and (2) preliminarily evaluate and characterize the ability of 64Cu-daratumumab to accurately detect or exclude MM lesions. A total of 12 daratumumab-naive patients were imaged. Prior to the injection of 15 mCi/5 mg of 64Cu-daratumumab, patients were treated with 0 (n = 3), 10 (n = 3), 45 (n = 3), or 95 mg (n = 3) of unlabeled daratumumab to assess its effect on image quality. No significant adverse events were observed from either unlabeled daratumumab or 64Cu-daratumumab. Of the dose levels tested, 45 mg unlabeled daratumumab was the most optimal in terms of removing background signal without saturating target sites. 64Cu-daratumumab PET/CT provided safe whole-body imaging of MM. A trial comparing the sensitivity and specificity of 64Cu-daratumumab PET/CT with that of FDG PET/CT is planned. This trial was registered at www.clinicaltrials.gov as #NCT03311828.

Outcomes in multiple myeloma (MM) have improved dramatically in the last two decades with the advent of novel therapies including immunomodulatory agents (IMiDs), proteasome inhibitors and monoclonal antibodies. In recent years, immunotherapy for the treatment of MM has advanced rapidly, with the approval of new targeted agents and monoclonal antibodies directed against myeloma cell-surface antigens, as well as maturing data from late stage trials of chimeric antigen receptor CAR T cells. Therapies that engage the immune system to treat myeloma offer significant clinical benefits with durable responses and manageable toxicity profiles, however, the appropriate use of these immunotherapy agents can present unique challenges for practicing physicians. Therefore, the Society for Immunotherapy of Cancer convened an expert panel, which met to consider the current role of approved and emerging immunotherapy agents in MM and provide guidance to the oncology community by developing consensus recommendations. As immunotherapy evolves as a therapeutic option for the treatment of MM, these guidelines will be updated.

PurposeSingle-cycle melphalan 200 mg/m2 and autologous hematopoietic cell transplantation (AHCT) followed by lenalidomide (len) maintenance have improved progression-free survival (PFS) and overall survival (OS) for transplantation-eligible patients with multiple myeloma (MM). We designed a prospective, randomized, phase III study to test additional interventions to improve PFS by comparing AHCT, tandem AHCT (AHCT/AHCT), and AHCT and four subsequent cycles of len, bortezomib, and dexamethasone (RVD; AHCT + RVD), all followed by len until disease progression.Patients and methodsPatients with symptomatic MM within 12 months from starting therapy and without progression who were age 70 years or younger were randomly assigned to AHCT/AHCT + len (n = 247), AHCT + RVD + len (n = 254), or AHCT + len (n = 257). The primary end point was 38-month PFS.ResultsThe study population had a median age of 56 years (range, 20 to 70 years); 24% of patients had high-risk MM, 73% had a triple-drug regimen as initial therapy, and 18% were in complete response at enrollment. The 38-month PFS rate was 58.5% (95% CI, 51.7% to 64.6%) for AHCT/AHCT + len, 57.8% (95% CI, 51.4% to 63.7%) for AHCT + RVD + len, and 53.9% (95% CI, 47.4% to 60%) for AHCT + len. For AHCT/AHCT + len, AHCT + RVD + len, and AHCT + len, the OS rates were 81.8% (95% CI, 76.2% to 86.2%), 85.4% (95% CI, 80.4% to 89.3%), and 83.7% (95% CI, 78.4% to 87.8%), respectively, and the complete response rates at 1 year were 50.5% (n = 192), 58.4% (n = 209), and 47.1% (n = 208), respectively. Toxicity profiles and development of second primary malignancies were similar across treatment arms.ConclusionSecond AHCT or RVD consolidation as post-AHCT interventions for the up-front treatment of transplantation-eligible patients with MM did not improve PFS or OS. Single AHCT and len should remain as the standard approach for this population.

BACKGROUND: Daratumumab is a human CD38-directed monoclonal antibody indicated for the treatment of relapsed and refractory multiple myeloma (MM). METHODS: A multicenter, open-label treatment protocol provided early access to daratumumab for patients who had progressive MM after they received ≥3 prior lines of therapy that included a proteasome inhibitor and an immunomodulatory agent or if they were refractory to both a proteasome inhibitor and an immunomodulatory agent. Patients received daratumumab 16 mg/kg weekly for 8 weeks, every other week for 16 weeks, and monthly until they developed disease progression, unacceptable toxicity, or 60 days after the drug gained US approval. Treatment-emergent grade ≥3 adverse events (AEs), serious AEs, and AEs of special interest were collected. RESULTS: Three hundred forty-eight patients were enrolled at 39 US sites between June and December 2015. Patients received study therapy for a median of 1.9 months (range, 0.03-6.0 months). Fifty-two percent of patients transitioned to commercially-available daratumumab and 37% discontinued because of progressive disease. Grade ≥3 AEs occurred in 50% of patients, including thrombocytopenia (15%) and anemia (14%). Serious AEs occurred in 35% of patients (12% were drug-related), including infections (11%). Infusion reactions occurred in 56%, 2%, and 2% of patients during the first, second, and all subsequent infusions, respectively; respiratory symptoms (cough, dyspnea, throat irritation, nasal congestion) were common. The infusion reaction rate for the first infusion was 38% in 50 patients at 2 sites who received montelukast as premedication for their first infusion and 59% in patients who did not receive montelukast. CONCLUSIONS: The current findings are consistent with previously reported trials and confirm the safety profile of daratumumab in heavily pretreated US patients who have relapsed or refractory MM. Cancer 2018;124:000-000.

The American Society for Blood and Marrow Transplantation (ASBMT) Clinical Case Forum (CCF) was launched in 2014 as an online secure tool to enhance interaction and communication among hematopoietic cell transplantation (HCT) professionals worldwide through the discussion of challenging clinical care issues. After 14 months, we reviewed clinical and demographical data of cases posted in the CCF from January 29, 2014 to March 18, 2015. A total of 137 cases were posted during the study period. Ninety-two cases (67%) were allogeneic HCT, 29 (21%) were autologous HCT, and in 16 (12%), the type of transplantation (autologous versus allogeneic) was still under consideration. The diseases most frequently discussed included non-Hodgkin lymphoma (NHL; n = 30, 22%), acute myeloid leukemia (n = 23, 17%), and multiple myeloma (MM; n = 20, 15%). When compared with the US transplantation activity reported by the US Department of Health and Human Services, NHL and acute lymphoblastic leukemia cases were over-represented in the CCF, whereas MM was under-represented (P < .001). A total of 259 topics were addressed in the CCF with a median of 2 topics/case (range, 1 to 6). Particularly common topics included whether transplantation was indicated (n = 57, 41%), conditioning regimen choice (n = 44, 32%), and post-HCT complications after day 100 (n = 43, 31%). The ASBMT CCF is a successful tool for collaborative discussion of complex cases in the HCT community worldwide and may allow identification of areas of controversy or unmet need from clinical, educational and research perspectives.

We describe baseline incidence and risk factors for new cancers in 4161 persons receiving autotransplants for multiple myeloma in the United States from 1990 to 2010. Observed incidence of invasive new cancers was compared with expected incidence relative to the US population. The cohort represented 13,387 person-years at-risk. In total, 163 new cancers were observed, for a crude incidence rate of 1.2 new cancers per 100 person-years and cumulative incidences of 2.6% (95% confidence interval [CI], 2.09 to 3.17), 4.2% (95% CI, 3.49 to 5.00), and 6.1% (95% CI, 5.08 to 7.24) at 3, 5, and 7 years, respectively. The incidence of new cancers in the autotransplantation cohort was similar to age-, race-, and gender-adjusted comparison subjects with an observed/expected (O/E) ratio of 1.00 (99% CI, .81 to 1.22). However, acute myeloid leukemia and melanoma were observed at higher than expected rates with O/E ratios of 5.19 (99% CI, 1.67 to 12.04; P = .0004), and 3.58 (99% CI, 1.82 to 6.29; P < .0001), respectively. Obesity, older age, and male gender were associated with increased risks of new cancers in multivariate analyses. This large data set provides a baseline for comparison and defines the histologic type specific risk for new cancers in patients with MM receiving postautotransplantation therapies, such as maintenance.