Hassoun, Hani

Abstract Studies have reported conflicting findings regarding the contribution of germline variants or somatic genomic drivers to racial disparities in multiple myeloma. To comprehensively investigate somatic drivers in relation to inherited genetics in multiple myeloma, we combined newly sequenced whole-genome sequencing data with publicly available datasets (total n = 1,286). Overall, we did not identify germline or somatic genomic differences that explain the different risk of developing multiple myeloma between patients with genetic similarity to African (AFR) or European (EUR) reference populations. A difference in the detectability and timing of APOBEC-associated and germinal center mutational activity was observed. Integrating epidemiologic data and mutational signature-based temporal estimates, we challenge the assumption that individuals in the AFR group develop multiple myeloma at a younger age. Finally, we demonstrate that, with equal access to efficacious therapies, patients in the AFR and EUR groups have equivalent clinical outcomes. Significance: Multiple myeloma is reported to occur at higher rates in individuals who self-identify as non-Hispanic Black. In this large dataset, genomic drivers occur at the same rate among ancestry groups, except for APOBEC mutagenesis. With equivalent therapy, clinical outcomes did not differ for patients grouped by genetic ancestry similarity.

Abstract Consumption of a Western diet and high body mass index (BMI) are risk factors for progression from premalignant phenotypes to multiple myeloma, a hematologic cancer. In the NUTRIVENTION trial (NCT04920084), we administered a high-fiber, plant-based diet (HFPBD; meals for 12 weeks, coaching for 24 weeks) to 23 participants with myeloma precursor states and elevated BMI. The intervention was feasible and improved quality of life and modifiable risk factors: metabolic (BMI, insulin resistance), microbiome (diversity, composition), and immune (inflammation, monocyte subsets). Disease progression trajectory improved (n = 2) or was stable. Findings were translated to Vk*MYC mice modeling the myeloma precursor state, in which a high-fiber diet (HFD) delayed disease progression through improved metabolism and microbiome composition, leading to increased short-chain fatty acid production that reinvigorated antitumor immunity and inhibited tumor growth. These effects from fiber consumption were independent of calorie restriction and weight loss. A HFD is a low-risk intervention that may delay progression to myeloma. Significance: A HFPBD in participants with precursor plasma cell disorders and an elevated BMI improved metabolic, microbiome, and immune biomarkers of disease. In a subset, it may delay progression to myeloma. In mouse models, a HFD delayed progression to myeloma independent of calorie restriction. See related commentary by Fairfield and Reagan, p. 623

Introduction Poor diet quality, elevated body mass index (BMI), insulin resistance, microbiome dysbiosis, inflammation as well as immune dysfunction have all been implicated in progression from monoclonal gammopathy of undetermined significance (MGUS) and smoldering multiple myeloma (SMM) to multiple myeloma (MM). Plant-based diets have been associated with reduced risk of MGUS and MM in epidemiological studies. Whether a dietary intervention can impact these modifiable risk factors and delay disease progression has not been investigated. Methods We conducted a pilot, single-arm trial providing controlled high fiber plant based dietary (HFPBD) intervention for 12 weeks and health coaching for 24 weeks in 20 patients with MGUS/SMM with BMI≥25 (NCT04920084). The primary endpoint was feasibility (adherence and BMI reduction). Secondary and exploratory endpoints included quality of life, metabolic markers (insulin, adiponectin, leptin, LDL cholesterol), microbiome (diversity and composition by 16S and shotgun sequencing) and immune profiling in peripheral blood (flow cytometry and Olink inflammation panel) and bone marrow (scRNAseq and ATACseq). We also conducted an in vivo study in transgenic Vk*MYC mice fed a high fiber or control diet at the phase of mouse(m)SMM. The mice were monitored for the progression to active mMM. Differences in microbiome and immune response profiles between high fiber- and control-treated mice were assessed via microbiome 16S sequencing and flow cytometry. Results The HFPBD intervention was safe, feasible, improved quality of life and addressed modifiable risk factors - metabolic profile (improved BMI, insulin resistance, adiponectin leptin ratio), microbiome profile (increased alpha-diversity and butyrate producers) and immune (decreased inflammation and increased anti-inflammatory classical monocyte) subsets. A reduction in long-term progression trajectory was observed in 2 patients. Consistently, the high fiber diet delayed progression from mSMM to mMM in Vk*MYC mice increasing median progression-free survival from 12 weeks in the control arm to 30 weeks in the high fiber diet intervention arm. Additionally, in the intervention arm 40% of mice did not progress to mMM during the study period whereas all mice in the control arm progressed. Both human and mouse data showed that HFPBD modulated gut microbiota composition favoring the expansion of butyrate-producing bacteria. Additionally, short-chain fatty acids were increased in the feces of mice fed a high fiber diet. Integrated analysis from human bone marrow and peripheral blood analysis indicated that the dietary intervention reduced inflammatory biomarkers and skewed the immune response towards T helper and CD14+ monocytes. Consistently, the bone marrow of Vk*MYC mice fed high fiber diet was more infiltrated by IFNg-producing T lymphocytes while displaying less exhausted T cells and immunosuppressive myeloid cells. Conclusion This is the first interventional clinical trial and in vivo study to show that a HFPBD intervention may delay progression from MGUS/SMM to MM. To our knowledge there has been no similar dietary interventional study in hematological cancers or solid tumors. Together our in vivo and clinical data support the beneficial anti-inflammatory role of a HFPBD providing a link between diet, microbiota, and immune modulation to delay disease progression in MGUS/SMM.

Abstract BACKGROUND: Pomalidomide-dexamethasone (Pom-Dex) represents an important therapeutic advance for the treatment of patients with relapsed/refractory multiple myeloma (MM). Nonetheless, patients with lenalidomide (Len) and bortezomib (double) refractory disease have a median progression-free survival of only 3.7 months with the combination, thus highlighting the need for further progress. Ixazomib, a novel, oral proteasome inhibitor, has pharmacodynamic properties that may allow for improved proteasome inhibition at the tumoral level and has synergistic activity in combination with IMiDs in preclinical MM models. Clinical studies have demonstrated activity as a single agent in relapsed/refractory MM and in combination with Len-Dex in newly diagnosed patients. We therefore evaluated the safety and preliminary efficacy of the combination of Pom, ixazomib and Dex in patients with Len and proteasome inhibitor (PI) refractory MM in the phase I portion of Alliance study A061202. METHODS: Key eligibility criteria included: relapsed or relapsed/refractory disease; ≥2 prior lines of therapy; double refractory disease (progression on or ≤60 days from the last dose of a Len- and PI-based therapy); ECOG performance status (PS) ≤2; absolute neutrophil count ≥1.0 x 109/L, platelets ≥50 x 109/L, creatinine clearance ≥50 mL/min; and ≤grade 2 peripheral neuropathy. Patients were treated with escalating doses of Pom and ixazomib utilizing a standard 3 + 3 dose escalation design in combination with standard dose Dex (Table 1). Patients received 2 - 4 mg of Pom on days 1 - 21; ixazomib 3 - 4 mg on days 1, 8 and 15; and Dex 40 mg (20 mg for those >75 years of age) on days 1, 8, 15 and 22 of a 28-day cycle. Patients were treated until disease progression or the development of unacceptable toxicity. RESULTS: Out of 17 evaluable patients, the median age was 64 (range 47 - 77) and the median time from diagnosis 5.5 years (range 3.3 - 8.3). Sixty-five percent, 24% and 12% had ISS stage 1, 2 and 3 disease at the start of treatment, respectively, and 65% had high-risk cytogenetics (gain of 1q, del[17p] and/or high-risk IgH translocation). All patients had an ECOG PS of 0 or 1 (59% and 41%, respectively). Of 14 patients with complete prior treatment data available, 100% had received prior Len, bortezomib and Dex, 71% alkylating agents (cyclophosphamide or low dose melphalan), 71% autologous stem cell transplant and 29% carfilzomib. Eighty-two percent were refractory to sequential Len- and bortezomib regimens, whereas 6% were refractory to a prior Len/proteasome inhibitor combination (12% not reported). Two dose limiting toxicities have occurred to date, 1 each at dose levels 3 and 4 (Table 1). Grade 3 and 4 neutropenia, thrombocytopenia and lymphopenia attributable to protocol therapy have been seen in 29%/6%, 12%/6% and 29%/0% of patients, respectively. Twelve percent of patients have experienced grade 3 infection, regardless of attribution, but none have experienced ≥grade 4 infection. The incidence of therapy-related peripheral neuropathy was 24%, none of which was ≥grade 3 in severity. Other common, therapy-related adverse events have included fatigue (53%), nausea (24%), constipation (18%), diarrhea (29%), rash (18%), tremor (24%), anxiety (18%), insomnia (29%) and edema (24%), all of which were ≤grade 2 in severity. Fifty-three percent of patients had at least 1 of the 3 medications dose reduced, and 35% experienced dose delays. To date, 1 patient has discontinued therapy due to adverse events and 1 due to refusal of further therapy. Of 13 patients receiving >1 cycle of therapy, the best overall response rate was 62% (7 partial responses, 1 very good partial response). CONCLUSIONS: The Pom, ixazomib and Dex combination has demonstrated an acceptable toxicity profile thus far with encouraging preliminary efficacy. Updated results of the phase I portion of the study will be presented at the meeting, including the maximum tolerated dose that will be used in the randomized, phase II portion of the study, in which the 3-drug combination will be compared with Pom-Dex in double refractory MM patients. ClinicalTrials.gov Identifier: NCT02004275. Supported by U10CA180821, U10CA180882. Table 1. Dose Level Pomalidomide Dose (mg) Ixazomib Dose (mg) DLT Evaluable DLTs 1 2 3 3 None 2 3 3 3 None 3 4 3 6 1 febrile neutropenia 4‡ 4 4 4 1 grade 4 thrombocytopenia lasting 8 days ‡enrollment into dose level 4 is complete. Disclosures Voorhees: Janssen, Celgene, GlaxoSmithKline, Onyx Pharmaceuticals and Oncopeptides: Consultancy, Research Funding; Array BioPharma, Celgene, GlaxoSmithKline, and Oncopeptides: Consultancy; Millennium/Takeda and Novartis: Honoraria, Membership on an entity's Board of Directors or advisory committees. Off Label Use: We will discuss the use of Ixazomib, an agent that is not FDA approved, in combination with pomalidomide and dexamethasone for the treatment of multiple myeloma.. Richardson:Jazz Pharmaceuticals: Membership on an entity's Board of Directors or advisory committees, Research Funding; Gentium S.p.A.: Membership on an entity's Board of Directors or advisory committees, Research Funding; Millennium Takeda: Membership on an entity's Board of Directors or advisory committees; Novartis: Membership on an entity's Board of Directors or advisory committees; Celgene Corporation: Membership on an entity's Board of Directors or advisory committees.