ALBERT

Description: INTRODUCTION: Lenalidomide and Rituximab (R2) is an effective frontline treatment regimen for patients (pts) with indolent B-cell lymphoma including follicular lymphoma (FL). Recent phase III data from the RELEVANCE trial comparing R2 to traditional chemoimmunotherapy showed that this regimen is generally well-tolerated and has favorable clinical efficacy [61% overall response, 53% CR rate, 77% 3-year progression free survival (PFS) (Morschhauser, et al)]. Proteasome inhibitors such as bortezomib disrupt NF-KB signaling and have shown clinical activity in indolent NHL. Although randomized trials have failed to demonstrate clinical benefit of adding bortezomib to standard chemoimmunotherapy regimen bendamustine + rituximab (BR) for frontline treatment of FL, the addition of proteasome inhibitors to lenalidomide is a mainstay of treatment for plasma cell neoplasms due to synergistic antitumor effect. The oral proteasome inhibitor ixazomib has less potential for dose-limiting neuropathy than bortezomib, making it an attractive option to incorporate into the R2 regimen. We sought to investigate the safety and efficacy of the addition of ixazomib to R2 for FL and indolent B-cell NHL through a phase I clinical trial of this combination for patients with high risk disease. METHODS: Adult (age ≥ 18) pts with untreated FL or other indolent lymphoma, adequate organ function and performance status were enrolled. To be enrolled, FL patients were required to have stage 2, 3 or 4 disease, with high tumor burden by GELF criteria and/or FLIPI score of 3-5. During 3 x 3 dose escalation, ixazomib was given at a dose of 2 mg (n=3), 3 mg (n=3) or 4 mg (n=12) PO on days 1, 8, and 15 with lenalidomide 20 mg PO on days 1-21 every 28 days. Rituximab was administered at standard dosing on days 1,8,15,21 for cycle 1, once every 28 days for cycles 2-6 and then once every 2 months for cycles 7-12. Treatment was continued for 12 cycles and no maintenance therapy was specified per protocol. All pts received low dose aspirin for venous thromboembolism prophylaxis and acyclovir for prevention of VZV reactivation. Response assessments by CT were performed after cycle 3 and 6 and by PET/CT at the end-of-treatment (cycle 12). RESULTS: 20 pts were enrolled and 18 were eligible for treatment [15 FL (14 grade 1-2, 1 grade 3A), 2 splenic marginal zone lymphoma and 1 nodal marginal zone lymphoma].The median age of treated pts was 61 (range 40-83) years old. 55% of patients were female. Stage at diagnosis was II (n =2), III (n = 4) and IV (n = 12). For FL pts, FLIPI scores at enrollment were low (n=2), intermediate (n = 5) and high risk (n=8) and FLIPI-2 scores were low (n=3), intermediate (n = 2) and high risk (n=10). There were no dose limiting toxicities during 3 x 3 dose escalation. Grade (G) 1/2 and G3/4 treatment-related hematologic adverse events (AEs) included neutropenia (6%, 28%), thrombocytopenia (16.7%, 5.6%) and anemia (16.7%, 0%). The most common treatment-related AEs included nausea/vomiting (44% G1, 11% G2), diarrhea, (50% G1, 22% G2, 5% G3), rash (33% G1, 6% G2, 11%G3), peripheral neuropathy (22% G1, 6% G2), myalgia/arthralgia (17% G1, 17% G2), and infection (33% G2, 17% G3). There was one pulmonary embolism and no cases of febrile neutropenia. As of June, 2020, median follow-up among living pts was 21 months. 4 pts discontinued treatment due to disease progression; 2 with transformation to aggressive lymphoma. Of the transformed cases, one subject died on study due to progression disease and one developed CNS disease on study treatment but proceeded to autologous stem cell transplant. The best overall response rate was 61.2% [55.6% CR, 5.6% PR): 22.2% had stable disease and 16.7% had disease progression. 18-month Kaplan-Meier estimates of PFS and overall survival were 71% and 94%, respectively (Figure). CONCLUSION: R2 can safely be combined with at the target dose of 4 mg of ixazomib for treatment-naïve indolent NHL patients. Non-hematologic AEs were generally consistent with known toxicity of each component of therapy. CR rate and PFS were was similar to the outcomes reported in the RELEVANCE trial despite enrolling high risk patient. R2 may serve as backbone for future studies of novel treatment combinations for high risk FL after thorough evaluation for occult transformation to aggressive lymphoma. Disclosures Hill: Abbvie: Consultancy, Honoraria, Research Funding; Genentech: Consultancy, Honoraria, Research Funding; Novartis: Consultancy, Honoraria; BMS: Consultancy, Honoraria, Research Funding; Celgene: Consultancy, Honoraria, Research Funding; Takeda: Research Funding; Karyopharm: Consultancy, Honoraria, Research Funding; AstraZenica: Consultancy, Honoraria, Research Funding; Kite, a Gilead Company: Consultancy, Honoraria, Research Funding; Beigene: Consultancy, Honoraria, Research Funding; Pharmacyclics: Consultancy, Honoraria, Research Funding. Jagadeesh:MEI Pharma: Research Funding; Regeneron: Research Funding; Seattle Genetics: Membership on an entity's Board of Directors or advisory committees, Research Funding; Debiopharm Group: Research Funding; Verastem: Membership on an entity's Board of Directors or advisory committees. Caimi:Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. Smith:Takeda: Research Funding; Celgene: Research Funding. OffLabel Disclosure: Ixazomib is off-label for treatment of NHL

Description: Background: Gilteritinib, an oral FMS-like tyrosine kinase 3 (FLT3) inhibitor, demonstrated antileukemic responses in patients with FLT3-mutated (FLT3mut+) relapsed/refractory acute myeloid leukemia (AML). We report final results from a phase 1 study of once-daily oral gilteritinib plus intravenous (IV) chemotherapy in patients with newly diagnosed AML. Methods: This 4-part, open-label, phase 1 study (NCT02236013) assessed the safety/tolerability and antileukemic effects of gilteritinib plus 7+3 induction and high-dose cytarabine consolidation chemotherapy, and as single-agent maintenance therapy in adults with newly diagnosed AML. In part 1, successive cohorts of 3-6 patients received 40-200 mg/d gilteritinib (Days 4-17) and ≤2 cycles of induction (cytarabine 100 mg/m2/d IV, Days 1-7; idarubicin 12 mg/m2/d IV, Days 1-3). In part 2, patients (n=33, of which at least 15 were FLT3mut+) received the recommended 120 mg/d gilteritinib expansion dose and ≤2 cycles of the part 1 induction schedule. In part 3, patients were stratified into 2 cohorts: one receiving treatment from part 2 (n=7) and the other receiving treatment that replaced idarubicin with daunorubicin (90 mg/m2/d IV, Days 1-3; n=7). In part 4, patients (n=12) received the same induction as the part 3/daunorubicin cohort (with a reduction in cycle 2 to daunorubicin 45 mg/m2/d). During consolidation, patients received ≤3 cycles of cytarabine (1.5 g/m2 every 12 hours; Days 1, 3, and 5) and gilteritinib (Days 1-14 for parts 1-3; Days 1-56 for part 4) at the induction dose. Gilteritinib was given once daily in 28-day cycles for up to 26 cycles as maintenance therapy (maintenance phase is still ongoing). Patients achieving composite complete remission (CRc) or partial remission could undergo hematopoietic stem cell transplant (HSCT) and resume maintenance gilteritinib treatment post-HSCT. Results: As of 23 June 2020, 80 patients were allocated to treatment (safety analysis set, n=79); median age was 59.0 y (range, 23-77) and most were male (62.0%). Median follow-up for overall survival (OS) was 35.8 mo. Dose-limiting toxicities are provided in Table 1. The maximum tolerated dose was 120 mg/d. Serious treatment-related adverse events (AEs) and AEs leading to discontinuation of gilteritinib occurred in 12.7% (n=10) and 5.1% (n=4) of patients, respectively. One (1.3%) death occurred across all treatment phases. Grade ≥3 nonhematologic AEs (≥10% of patients) were increased alanine aminotransferase (13.9%), pneumonia (13.9%), sepsis (11.4%), and bacteremia (11.4%). At the end-of-induction time point, there were 44 (55.7%) total FLT3mut+ patients across all dose groups and 38 (48.1%) patients who received gilteritinib 120 mg/d. Investigator-reported CRc was achieved by 81.8% of patients across all dose groups (n=36) and 81.6% among patients who received gilteritinib 120 mg/d (n=31; Table 2). Anthracycline choice had no clear impact on CRc rate, although the number of patients in these cohorts was low. In FLT3mut+ patients who achieved CRc in any dose group, median (95% CI) duration of CRc and disease-free survival were 14.1 (4.0-29.9) and 15.3 (9.8-not reached) mo, respectively. Median OS for FLT3mut+ patients has not been reached. The survival probability (95% CI) in all FLT3mut+ patients at weeks 8, 12, 26, 52, and 104 were 97.7% (84.6%-99.7%), 95.3% (82.5%-98.8%), 92.9% (79.6%-97.7%), 83.1% (67.7%-91.5%), and 71.8% (54.6%-83.4%), respectively. In patients with FLT3 internal tandem duplication (ITD)-positive AML achieving CRc, mutational clearance (summed FLT3 ITD signal ratio of ≤10-4 after induction or consolidation) was achieved by 70% (n/N=16/23) of patients receiving a gilteritinib dose of ≥120 mg. HSCT occurred in 30.4% of the total population (n/N=24/79). Analysis of plasma inhibitory activity and pharmacokinetics of gilteritinib will be available at presentation. Conclusions: Gilteritinib plus induction and consolidation chemotherapy is well tolerated in patients with newly diagnosed AML. Favorable antileukemic responses were observed in FLT3mut+ patients regardless of anthracycline type or gilteritinib administration schedule, with a mutational clearance rate of 70.0%. Based on these results, randomized clinical trials of induction and consolidation chemotherapy plus gilteritinib vs midostaurin in FLT3mut+ AML patients have been initiated. Disclosures Pratz: AbbVie: Other: Scientific Advisory Board, Research Funding; Astellas: Other: Scientific Advisory Board, Research Funding; Boston BioMedical: Consultancy; Celgene: Other: Scientific Advisory Board; Agios: Other: Scientific Advisory Board, Research Funding; Jazz Pharmaceutical: Consultancy; Millennium: Research Funding; Daiichi Sankyo: Research Funding. Cherry:Pfizer: Other: Advisory Board; BMS: Other: Advisory Board; Kite: Other: Advisory Board. Altman:PeerView: Consultancy; ASH: Consultancy; Syros: Consultancy; Janssen: Consultancy; Genentech: Research Funding; Amphivena: Research Funding; Amgen: Research Funding; Aprea: Research Funding; ImmunoGen: Research Funding; Celgene: Research Funding; Boehringer Ingelheim: Research Funding; PrIME Oncology: Consultancy; Immune Pharmaceuticals: Consultancy; Novartis: Consultancy; Glycomimetics: Other: Data safety and monitoring committee; Daiichi Sankyo: Other: Advisory Board - no payment but was reimbursed for travel; Kura Oncology: Other: Scientific Advisory Board - no payment accepted, Research Funding; Kartos: Research Funding; AbbVie: Other: advisory board, Research Funding; Fujifilm: Research Funding; BioSight: Other: No payment but was reimbursed for travel , Research Funding; Bristol-Myers Squibb: Consultancy; Astellas: Other: Advisory Board, Speaker (no payment), Steering Committee (no payment), Research Funding; Cancer Expert Now: Consultancy; Agios: Other: advisory board, Research Funding; Theradex: Other: Advisory Board; France Foundation: Consultancy. Cruz:Takeda: Speakers Bureau. Jurcic:Celgene: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; BMS: Consultancy, Research Funding; Daiichi-Sankyo: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding; Novartis: Consultancy, Membership on an entity's Board of Directors or advisory committees; Arog Pharmaceuticals: Research Funding; Astellas: Research Funding; Forma Therapeutics: Research Funding; Genentech: Research Funding; Kura Oncology: Research Funding; PTC Therapeutics: Research Funding; Syros Pharmaceuticals: Research Funding; AbbVie: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding. Levis:Menarini: Honoraria; Amgen: Honoraria; FujiFilm: Honoraria, Research Funding; Daiichi-Sankyo: Honoraria; Astellas: Honoraria, Research Funding. Lin:Pfizer: Research Funding; Bio-Path Holdings: Research Funding; Abbvie: Research Funding; Seattle Genetics: Research Funding; Tolero Pharmaceuticals: Research Funding; Ono Pharmaceutical: Research Funding; Prescient Therapeutics: Research Funding; Incyte: Research Funding; Genetech-Roche: Research Funding; Gilead Sciences: Research Funding; Aptevo: Research Funding; Celyad: Research Funding; Celgene: Research Funding; Astellas Pharma: Research Funding; Mateon Therapeutics: Research Funding; Jazz: Research Funding; Trovagene: Research Funding. Perl:Bayer HealthCare Pharmaceuticals: Research Funding; Syndax: Consultancy, Honoraria; Jazz: Honoraria, Other; Arog Pharmaceuticals Inc: Other: uncompensated consulting, travel costs for meetings; Biomed Valley Discoveries: Research Funding; Agios: Consultancy, Honoraria, Other; FUJIFILM Pharmaceuticals USA, Inc: Research Funding; AbbVie Inc: Consultancy, Honoraria, Other, Research Funding; Loxo Oncology Inc, a wholly owned subsidiary of Eli Lilly & Company: Consultancy, Honoraria, Other; Takeda: Honoraria, Other: Travel costs for meeting; Astellas: Consultancy, Honoraria, Other: writing/editorial support, travel costs for meeting presentations related to study, Research Funding; Leukemia & Lymphoma Society, Beat AML: Consultancy; New Link Genetics: Honoraria, Other; Daiichi Sankyo: Consultancy, Honoraria, Other: Writing/editorial support, travel costs for meetings, Research Funding; FORMA Therapeutics: Consultancy, Honoraria, Other; Actinium Pharmaceuticals Inc: Consultancy, Honoraria, Research Funding; Novartis: Honoraria, Other, Research Funding. Podoltsev:Arog Pharmaceuticals: Research Funding; Astex Pharmaceuticals: Research Funding; Jazz Pharmaceuticals: Research Funding; Sunesis Pharmaceuticals: Research Funding; Boehringer Ingelheim: Research Funding; Daiichi Sankyo: Research Funding; Astellas Pharma: Research Funding; CTI biopharma: Consultancy, Honoraria, Research Funding; Bristol-Myers Squib: Consultancy, Honoraria; Genentech: Research Funding; Novartis: Consultancy, Honoraria; Celgene: Consultancy, Honoraria, Research Funding; Samus Therapeutics: Research Funding; Agios Pharmaceuticals: Consultancy, Honoraria; Pfizer: Consultancy, Honoraria, Research Funding; Incyte: Consultancy, Honoraria; Blueprint Medicines: Consultancy, Honoraria; Alexion: Consultancy, Honoraria; Kartos Therapeutics: Research Funding; AI Therapeutics: Research Funding. Schiller:Abbvie: Research Funding; Actinium: Research Funding; Ariad: Research Funding; Amgen: Consultancy, Current equity holder in publicly-traded company, Research Funding, Speakers Bureau; AstraZeneca: Consultancy; Incyte: Consultancy, Research Funding, Speakers Bureau; Novartis: Consultancy, Research Funding; Ono Pharma: Consultancy; Kite Pharma: Research Funding; Stemline: Speakers Bureau; Gilead: Speakers Bureau; Celgene: Research Funding, Speakers Bureau; Sanofi: Speakers Bureau; Agios: Consultancy, Research Funding, Speakers Bureau; DeltaFly: Research Funding; Deciphera: Research Funding; Daiichi Sankyo: Research Funding; Cyclacel: Research Funding; Constellation: Research Funding; Celator: Research Funding; Astellas Pharma: Honoraria, Research Funding; Bristol-Myers Squibb: Current equity holder in publicly-traded company, Research Funding; Forma: Research Funding; FujiFilm: Research Funding; Gamida: Research Funding; Genentech-Roche: Research Funding; Geron: Research Funding; Jazz Pharmaceuticals: Research Funding; Karyopharm: Research Funding; Mateon: Research Funding; MedImmune: Research Funding; Onconova: Research Funding; Pfizer: Current equity holder in publicly-traded company, Research Funding; Regimmune: Research Funding; Samus: Research Funding; Sangamo: Research Funding; Tolero: Research Funding; Trovagene: Research Funding; Kaiser Permanente: Consultancy; Johnson & Johnson: Current equity holder in publicly-traded company. Hill:Targeted Molecular Diagnostics: Patents & Royalties: US7862995; Astellas: Current Employment; Ligacept, LLC: Current equity holder in publicly-traded company, Patents & Royalties: US9051388, US9683222. James:Astellas: Current Employment. Lu:Astellas: Current Employment. Tiu:Astellas Pharma Global Development: Current Employment; Eli Lilly & Company: Current equity holder in publicly-traded company, Ended employment in the past 24 months. OffLabel Disclosure: New Indication

Description: Background Reduced-intensity conditioning (RIC) regimens provide insufficient disease control in patients with high-risk hematological malignancies who are ineligible for myeloablative hematopoietic cell transplantation (HCT) due to advanced age or comorbidities. RIC fludarabine/busulfan (Flu/Bu) is generally well tolerated, but is associated with high relapse rates. We hypothesized that intensification of RIC Flu/Bu with targeted marrow irradiation (TMI) would be feasible and improve outcomes in such patients. Methods This dose escalation phase I clinical trial incorporated 3+3 design with expansion. The primary endpoint was to estimate safety and feasibility of TMI combined with Flu/Bu. Secondary endpoints included transplant-related mortality (TRM), disease free survival (DFS) and overall survival (OS). Eligible patients were ≥ 18 years diagnosed with high-risk hematological malignancies who were not candidates for myeloablative HCT. The conditioning regimen consisted of TMI (dose levels: 3 Gy, 4.5 Gy and 6 Gy) delivered at 1.5 Gy/fraction in twice daily fractions on days -10 through -7, fludarabine (30 mg/m2) on days -6 through -2 and busulfan (AUC 4800 µM*minute) on days -5 and -4. Radiation was targeted to bone marrow and spleen using intensity modulated radiation therapy (IMRT) technique while minimizing injury to organs at risk. GVHD prophylaxis included tacrolimus and methotrexate for matched sibling and unrelated donors (UD), and tacrolimus, mycophenolate mofetil and post-cyclophosphamide for haploidentical donors. Antithymocyte globulin (ATG) was added for recipients of UD transplants. Dose limiting toxicity (DLT) was defined as engraftment failure, grade ≥ 4 mucositis and grade ≥ 3 other non-hematological adverse events (AEs) from day -10 to day +32. Results A total of 26 patients (median age 64 years [range, 25-76]; 61% females) were enrolled in two transplant centers (Table 1). Diagnoses included AML (n=15), MDS (n=5), T-PLL (n=2), CLL (n=1), DLBCL (n=1), multiple myeloma (n=1) and myeloproliferative disorder (n=1). Sixteen (61%) patients had intermediate/high HCT-comorbidity index and high/very high disease risk index (DRI). At the time of HCT, 19 (73%) patients had active or residual disease. Donors were UD (n=18), matched sibling (n=5) and haploidentical (n=3). All patients engrafted neutrophils (median, 16 days [range, 10-29]). Most frequent AEs were mucositis (65%), gastrointestinal toxicity (62%), hepatotoxicity (hyperbilirubinemia and/or increased transaminase levels) (65%) and fatigue (69%). Twenty-four grade ≥ 3 AEs occurred in 13 patients; 2 patients experienced reversible DLT (mucositis and hepatotoxicity) at 6 Gy TMI dose level. Additional escalation was halted and 6 Gy cohort was expanded. Only 1 patient experienced reversible hepatotoxicity in the expansion cohort. Grade II-IV and III-IV acute GVHD rates at day +100 were 57% (95% CI, 39%-84%) and 22% (95% CI, 9%-53%), respectively. The 1-year cumulative incidence of chronic GVHD was 42% (95% CI, 24%-74%). The 1-year cumulative incidence of TRM and relapse was 8% (95% CI, 2%-32%) and 26% (95% CI, 13%-52%), respectively (Figure 1A). The overall TRM for 3 Gy, 4.5 Gy and 6 Gy cohorts was 25%, 12.5% and 12%, respectively. With a median follow up of 12.7 months (range, 1.1-36.8), 1-year DFS was 55% (95% CI, 34%-76%) and OS was 65% (95% CI, 46%-85%) (Figure 1B). One-year DFS was equivalent for patients transplanted in CR or with active disease (54% [95% CI, 14%-93%] vs 55% [95% CI, 29%-80%]; p=0.83) (Figure 1C). While no difference in DFS was observed between the 4.5 Gy and 6 Gy cohorts, the 3 Gy cohort was associated with inferior DFS (p=0.004) (Figure 1D). One-year DFS and OS for 6 Gy cohort was 58% (95% CI, 30%-87%) and 82% (95% CI, 59%-100%), respectively. Conclusion Intensification of RIC Flu/Bu with TMI is feasible, with low incidence of TRM in medically frail patients. Reversible mucositis and hepatotoxicity prevented dose escalation beyond 6 Gy. DFS and OS at 6 Gy are promising and deserve further investigation. Disclosures Malek: Janssen: Other: Advisory board, Speakers Bureau; Medpacto: Research Funding; Sanofi: Other: Advisory board; Clegene: Other: Advisory board , Speakers Bureau; Amgen: Honoraria; Takeda: Other: Advisory board , Speakers Bureau; Bluespark: Research Funding; Cumberland: Research Funding. de Lima:Pfizer: Other: Personal fees, advisory board, Research Funding; Celgene: Research Funding; Kadmon: Other: Personal Fees, Advisory board; Incyte: Other: Personal Fees, advisory board; BMS: Other: Personal Fees, advisory board. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding; Celgene: Speakers Bureau.

Description: Background: The introduction of novel targeted agents that inhibit specific cellular pathways has improved the prognosis of chronic lymphocytic leukemia (CLL) patients. CLL patients have a higher risk of secondary malignancies, but this risk has not yet been defined for patients treated with targeted agents, including inhibitors of BTK, PI3K or BCL2. Methods: We conducted a retrospective cohort study of CLL patients managed at a large tertiary care center between 1994 and 2018. Patients were classified according to whether they were treated with cytotoxic chemotherapy alone, chemoimmunotherapy or if they received a targeted agent (BTK inhibitor, PI3K inhibitor, BCL2 inhibitor) during the course of their disease. Time to first secondary malignancy corresponds to time elapsed between CLL diagnosis and the earliest secondary malignancy. Cumulative incidence of secondary malignancy was estimated considering competing risk of death. Multivariable analysis of cumulative risk of secondary malignancies was performed using Gray's method. Survival analysis was done with the Kaplan Meier method, comparisons were done using log - rank. Results: 265 CLL patients received care at our institution, median age (range) at diagnosis was 62 years (28-94), 168 (63.4%) were male, 199 (82.9%) were white, and 107 (41.5%) had Rai stage 3 or 4 at diagnosis. Median follow up was 10.5 years. Treatment was prescribed for 185 (70.1%) patients, 33 (17.7%) patients received only chemotherapy, 110 (59.1%) received chemoimmunotherapy, and 43 (23.1%) received targeted agents in the course of their disease. Median time to treatment was 11 months (IQR 1 - 177). Patients who did not receive therapy had a shorter median follow up (8.5 years) compared with treated patients (11.8 years) (p =

Description: Multiple Myeloma (MM) is a cancer of terminally-differentiated plasma cells residing in the bone marrow. Myeloma cells frequently secrete monoclonal proteins that can be used to assess tumor volume and patient response to therapy. Monoclonal proteins are measured by gel electrophoresis and subsequent immunofixation of the observed M-spike for protein typing. However, this a time-consuming process that may take up to 3-5 days that delays physician-patient decision-making, determining response to treatment and can be a significant psychological stressor for patients. Hence, there is an unmet need to develop a more rapid, point-of-care method to determine M-spike levels. Gamma gap is the difference between total serum protein and albumin and includes a variety metabolic proteins, i.e., transferrin, as well as immunologic proteins, e.g., non-involved immunoglobulins, in addition to the M-spike. Since estimation of the non-M-spike portion of the gamma gap cannot be achieved on routine patient care, the gamma gap cannot serve as an accurate surrogate for M-spike protein levels. Here, we hypothesized that an artificial intelligence (AI) algorithm utilizing readily available clinical and laboratory data along with previous and same-day lab variables can accurately predict M-spike levels without the need for serum electrophoresis. Methods: A total of 171 MM patients with 1,472 observations were included in the study, where the upper limit of the observed M-spike was 3.5 gr/dL. Correlation of the observed M-spike with gamma gap was assessed by two correlation methods using the Pearson and Spearman tests. Forty three clinical and lab variables (including total serum protein and albumin) as predictors of M-spike were fed into the machine learning model. Two lagged variables as the last two preceding M-spike values by the same subject were included. When needed, imputation for missing values was applied through interpolation from subject-level linear trend analysis. The random forest model was used, where regression forests are an ensemble of different regression trees and are used for nonlinear multiple regression. The default number of trees was set to be n = 500, and the number of variables considered at each split after random selection was 13. The goal of using a large number of trees was to train enough that each feature had a chance to appear in several models. The data was randomly split into a training set (80%) and a test set (20%), and a regression tree was built with the training set and then validated using the test set. Bootstrapping was used to generate a collection of data sets (n=500), leading to a random forest of regression trees. Results and estimates were combined across trees. Importance was measured by leaving a covariate out of models, and comparing performance with its inclusion. All analyses were performed using R v3.6.2 and its libraries. Results: Median age of the study cohort was 73 years old, range: 42-96), and 44% were male. The median M-spike value was (0.7 gr/dL, range: 0.1-3.5). Fig. 1 shows the number of observations and magnitude distribution for M-spike levels among the patients included in our study. The correlation of the calculated gamma gap and observed M-spike levels was assessed by two methods (Fig.2). The Pearson coefficient was 0.43 for M-spike levels 1 gr/dL, respectively (Fig.2a). The Spearman coefficient was 0.41 for M-spike levels 1 suggesting a low overall correlation overall, especially for M-spike levels