Background High dose chemotherapy followed by autologous stem cell transplantation (ASCT) plays an important role in the treatment of transplant-eligible multiple myeloma (MM) patients and yields deep responses, prolongs progression-free survival (PFS) and overall survival (OS). Daratumumab (Dara), a humanized monoclonal antibody that binds to CD38+ on the surface of myeloma cells and is increasingly used upfront to treat MM. Up to 75% of mobilized CD34+ hematopoietic progenitors also express CD38 and, hence exposure to Dara may potentially impact stem cell mobilization, and, given the extended half-life of Dara, also impair engraftment. The Cassiopeia trial (Moreau, P. 2019) showed the utility of Dara in combination with bortezomib and thalidomide as upfront treatment for MM without a negative impact on stem cell collection yield. Similarly, the Griffin trial (Voorhees, PM, 2020) demonstrated the safety of upfront Dara when combined with bortezomib and lenalidomide also with no impact on stem cell collection or engraftment. However, others(Al Saleh, A. 2019) reported delayed neutrophil engraftment in patients treated with Dara. Given the conflicting findings of these studies and scarcity of data on the direct impact of Dara on erythroid and myeloid progenitors, we investigated the effect of Dara on stem cell collection yield, graft composition and time to engraftment among patients who underwent ASCT. Methods We evaluated all patients with MM who underwent ASCT at our institute between 2017-2020 and excluded patients undergoing 2nd transplant or tandem ASCT. Disease risk stratification was assessed as per International Staging System (ISS) for MM. Treatment response prior to transplant was assessed as per response criteria definitions by International Myeloma Working Group (IMWG). Stem cells were collected according to institutional protocol and prior to cryopreservation, 1x105 peripheral blood cells are plated in duplicate in semi-solid media- MethoCult™ H4434 (Stem Cell Technologies, Vancouver, BC) and cultured in 37°C, 5% CO2 following which CFU-GM (colony forming unit- granulocyte macrophage) and BFU-E (burst forming units- erythroid) colonies are scored on day 14 based on morphological recognition, and reported as 104 colonies per kg of recipient weight. CFU-C (colony forming unit combined) is calculated by combining BFU-E and CFU-GM. Results Patients (N=108) that underwent ASCT between 2017-2020 were identified and demographic data are summarized (Table 1). Sixteen patients received Dara as part of upfront treatment prior to stem cell collection. Median age was 62 years old for the entire group with no significant age difference between patients who received Dara vs. those who did not receive. Similarly, there was no difference in race, ISS stage, pre-transplant response, plerixafor or lenalidomide use between the groups. Pts who received Dara were more likely to have received more than one chemotherapy regimen prior to transplant (62.5% vs. 30%, p-value=0.014). Although, total and day 1 collection of CD34+ stem cells was lower in the Dara treated group (7.18 x 106/kg) compared to Dara untreated (8.78 x 106/kg), the difference was not statistically significant. (p-value=0.151). Stem cell product composition based on measurement of BFU-E, CFU-GM and CFU-C colonies were similar independent of Dara use. Prior exposure to Dara was also not predictive of day 1 stem cell collection failure (defined as < 5x106 CD34+ cells/kg) as determined by multivariate analysis. Median time to absolute neutrophil count (ANC) recovery (defined as ANC >1500) was 12 days in both groups (p-value=0.09). Median time to platelet recovery (defined as platelet count >20k) was 12 days in the Darauntreated group vs. 13 days Dara treated group (p-value=0.06). Discussion In this single institute experience, there was a trend towards lower CD34+ collection as well as lower progenitor scoring with Dara use but was not statistically significant and also there was no difference in time to ANC or platelet recovery. The majority of patients in this study received plerixafor for mobilization, which might abrogate the effect of Dara and lenalidomide on the graft and stem cell collection. Further studies to investigate the impact of Dara on CD38+ mobilized hematopoietic cells is warranted. Disclosures Manjappa: Pfizer: Research Funding. Caimi:Amgen: Other: Advisory Board; Bayer: Other: Advisory Board; Verastem: Other: Advisory Board; Celgene: Speakers Bureau; Kite pharmaceuticals: Other: Advisory Board; ADC therapeutics: Other: Advisory Board, Research Funding. de Lima:BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding. Malek:Clegene: Other: Advisory board , Speakers Bureau; Janssen: Other: Advisory board, Speakers Bureau; Sanofi: Other: Advisory board; Amgen: Honoraria; Medpacto: Research Funding; Cumberland: Research Funding; Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau.
Introduction: Immunomodulatory drugs (IMiDs) are being frequently used as an integral part of induction regimen as well as maintenance after Bone Marrow Stem cell Transplant (BMSCT) therapy as backbone of therapy for patients with plasma cell neoplasm (PCN) including Multiple Myeloma (MM). Therapy is often complicated by dermatologic adverse effects which may herald a favorable prognosis suggesting a more robust immune stimulation by this class of drugs. The incidence of IMiD-associated rash is up to 27% in some reports and can range from mild to moderate to severe and life threatening skin toxicity including Steven-Johnsons syndrome and toxic epidermal necrolysis. IMiD-associated skin eruptions are thought to result from differential T cell immune modulation. The optimal management strategy for IMiD induced rash is unknown. The European Myeloma Network recommends topical corticosteroids and antihistamines for localized skin reactions. For severe reactions, a desensitization protocol with prolonged 6-week steroid taper is recommended based on a case series of five patients that developed delayed cutaneous adverse effects to IMiD [Lee MJ et al]. Dexamethasone used concomitantly with IMiD as part of the treatment regimen does not decrease the occurrence of skin rash as shown by Sviggum et al. The likely explanation is that concurrent dexamethasone is not effectively able to exert immunosuppressive activity to mitigate the occurrence of cutaneous reactions. Hence, a prolonged, daily steroid protocol is required for effective desensitization. Therefore, we designed a standardized 3-week steroid rash prophylaxis protocol with a low dose daily corticosteroid tapering regimen that allows desensitization and reinstitution of the same IMiD. We assessed the impact of this desensitization regimen on clinical outcomes, by comparing patients with versus without dermatologic manifestations. Methods: Dermatologic adverse effects associated with IMiDs in our study were managed by a single oncologist using a standardized approach. A total of 87 patients were evaluated, 24 patients in the rash group vs 63 controls. A cohort of age- and gender-matched without rash (n = 63) was randomly selected from the institutional database. The effects of rash on overall and progression free survival (OS and PFS) were further estimated using Cox regression controlling for the effects of age and gender. Results: Median time to development of rash after IMiD initiation was 28 days (range 2-232 days). The incidence of rash was 27.6% (95% CI: 19.3%-37.8%). All patients were managed by temporary treatment interruption and upon clearance of rash, re-institution of the same IMiD concomitantly with a standardized 3-week steroid rash prophylaxis protocol (prednisone at 10 mg daily for 10 days, followed by 5 mg daily for 10 days, followed by 5 mg on alternate days for 10 days). As a result, all patients were able to restart the same IMiD with none re-experiencing any dermatologic adverse effect afterward. Comparing to controls without rash, there was no significant difference in PFS (p=0.769) or OS (p=0.24) in the multivariable regression model. Conclusions: Proposed 3-week corticosteroid regimen showed 100% success rate in re-instituting IMiDs without recurrence of skin rashes in our cohort. The results of our study indicate that the 30-day prednisone course is practical, well tolerated, effectively desensitizes and allows re-institution of IMiD enabling patients to enjoy comparable outcomes to those without skin rash. Whether development of rash correlates with improved outcomes is unknown. Here, outcomes were similar in both cohorts. Disclosures Caimi: Celgene Corp: Other: Incyte Corporation - Ownership - Pharmacyclics, Inc. - Ownership - Celgene Corp. - Other, Speakers Bureau; ADC Therapeutics: Research Funding; Genentech: Research Funding. de Lima:BMS: Other: Personal Fees, advisory board; Celgene: Research Funding; Pfizer: Other: Personal fees, advisory board, Research Funding; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board. Malek:Bluespark: Research Funding; Takeda: Other: Advisory board , Speakers Bureau; Medpacto: Research Funding; Cumberland: Research Funding; Amgen: Honoraria; Clegene: Other: Advisory board , Speakers Bureau; Sanofi: Other: Advisory board; Janssen: Other: Advisory board, Speakers Bureau.
Monoclonal antibodies targeting CD38 are emerging as a mainstay of therapy for Multiple Myeloma (MM) in the relapse setting as well as upfront. These antibodies not only target CD38 on myeloma cells inducing anti-tumor pleiotropic effects, they also influence normal CD38-expressing cells, including normal plasma cells, natural killer cells and immunosuppressive regulatory cells (van de Donk et al , 2018). These cells play a key role in innate as well as humoral immunity and provide protection against a variety of infectious insults; hence, their depletion in MM patients (pts) can be expected to have deleterious immunological effects due to the dismantling of an effective immune responses in a population already strained by dysfunctional immunity. While it has been previously shown that NK cells decline with exposure to daratumumab (DARA) (Casneuf et al , 2017), its clinical impact on the incidence of infection has yet to be elucidated because clinical trials have shown conflicting results, while POLLUX and CASTOR trials showed generally similar rates of grade 3 or 4 infections (28·3% vs. 22·8% and 21·4% vs. 19·0%, respectively, the ALCYONE trial, reported that grade 3-4 infections were higher in the DARA arm (23·1% vs. 14·7%). Here, we aim to explore the impact of different risk factors on infection during DARA therapy. Methods: We retrospectively reviewed patient records who received DARA-containing regimens for MM between Jan 2016 and Jan 2020. The history of infection, prior therapies, rate of infection during therapy with DARA, hospitalizations, baseline and nadir absolute counts of lymphocyte, monocyte and neutrophil population were extracted. Pts who had less than 1 month of DARA were excluded. Survival was measured from time of DARA start. Survival distribution was estimated using Kaplan-Meier methods and differences of OS, PFS between groups was examined by Wilcoxon test. The effect of treatment on OS and PFS was estimated using a Cox model after controlling for the effects of different variables. Results: Of 123 pts reviewed, median line of therapy was 3 (range: 0-9). Median time from diagnosis was 52 months (range: 0- 232 months). 43 pts (35%) were Black and 77 (63%) Caucasian. Median age was 70 (range 34-94 y/o). 86 (70%) were IgG, 24 were IgA (20%) and 10 light chain myeloma (10%). 24 (20%) had stage I, 37 (30%) had stage II and 61 (50%) had ISS stage III. 66 (53%) pts had transplant as prior therapy and the rest did not undergo transplant. 29 (24%) pts had DARA as a single agent, 66 (53%) in combination with IMiDs and 28 (23%) pts in combination with PI. Median duration of therapy was 133 days (range 30-1245 days). Median ANC 1243 /ml (range: 420-1120). Median ALC 710 /mL (170-8020). Median AMC was 455 /mL (0-2300). 31 pts had history of prior infections and the rest did not. 39 pts had infection during DARA. Overall, there were 125 hospital admission encounters for whole cohort occurred in 36% of cases, more than half of them (55%) were attributable to an infectious process. Bacterial pathogens accounted for the majority of infection. Pts with infection during DARA therapy had statistically significant nadir ALC (median 560 /ml) compared to pts without any infection. The univariate analysis showed age, history of infection, nadir ALC less than 600/ml and number of prior line of therapy as significant factors associated with infection rate during DARA therapy. Multivariate analysis after controlling for these factors shows only Low nadir ALC less than 600 /ml, hazard ratio (HR): 2.15, 95% confidence interval (CI): 1.19-3.76, and history of infection, HR: 1.87, 95% CI: 1.11-2.92, stands out as statistically significant factor. The whole cohort were divided based on ALC<600 during the therapy or history of previous infection; the group with none of these two risk factors was assigned as low risk, the group with either of those as intermediate risk and the pts with both risk factor were characterized as high-risk group (Figure-1). Conclusion: Here we showed that infections is frequent among MM pts treated with DARA-containing regimen and assessed risk factors associated infection during DARA therapy. Dropping ALC and history of prior infection are significant factors associated with higher risk of infection during DARA therapy. These finding suggests vigilance for, and identification of risk factor are warranted for treating MM patient with DARA. The risk model is warranted to be examined in a prospective study. Disclosures de Lima: Pfizer: Other: Personal fees, advisory board, Research Funding; BMS: Other: Personal Fees, advisory board; Incyte: Other: Personal Fees, advisory board; Kadmon: Other: Personal Fees, Advisory board; Celgene: Research Funding. Malek:Cumberland: Research Funding; Takeda: Other: Advisory board , Speakers Bureau; Bluespark: Research Funding; Sanofi: Other: Advisory board; Clegene: Other: Advisory board , Speakers Bureau; Amgen: Honoraria; Medpacto: Research Funding; Janssen: Other: Advisory board, Speakers Bureau.
Multiple Myeloma (MM) remains a cancer of terminally-differentiated plasma cells that reside predominantly within the bone marrow. Malignant plasma cells are nurtured by a permissive microenvironment that favors tumor progression, drug resistance and disease relapse. Recurrent somatic mutations in hematopoietic stem cells, the source of major components in bone marrow niche, lead to age-associated clonal hematopoiesis of indetermined potential (CHIP) and has been associated with inferior survivals among individuals without malignant hematologic disorders. It is possible that these mutations in non-MM cells would affect remission time after transplant. We performed whole exome sequencing to identify CHIP-associated mutations within the autograft utilized to rescue hematopoiesis after high dose melphalan and autologous hematopoietic cell transplant (HCT). We then correlated the presence of CHIP with the outcome of MM patients (pts) following autologous HCT. Methods. MM pts (N=101) that underwent HCT between 2006 and 2017 were studied. DNA was extracted from 1 ml of cryopreserved mobilized hematopoietic cell product. Targeted sequencing was then performed using Tempus xE whole exome platform (Tempus, Chicago, IL) with variable allele frequency (VAF) ≥0.1. Progression-free survival (PFS) and overall survival (OS) were defined as the time from transplantation until event of interest, with censoring at time of last follow up. Cox regression was used for time-to-event outcomes; hazard ratios (HR) and 95% confidence intervals (CI) were reported. P-values were two-sided and those <0.05 were considered statistically significant. Results. The median age was 60.1 years at the time of HCT. 58 pts were male and 43 female; 29 pts were African-American, 1 Asian/Indian and 71 were Caucasian. Seventy five (75%) and 42 (43%) pts had prior exposure to lenalidomide or cyclophosphamide, respectively. Thirty two pts (32%) underwent hematopoietic cell mobilization with GCS-F and plerixafor, 38 pts (38%) with cyclophosphamide and 31 pts (31%) with GCS-F alone. Forty seven pts (47%) had at least one CHIP-associated mutation. The median number of CD34+ yield in the first day was 6.7 x 10e6/kg for pts with CHIP mutations and 5.64 x 10e6/kg for pts without any CHIP mutation (p = 0.4). The presence or absence of CHIP mutations did not impact the yield of CD34+ stem cells collected (Fig. 1). The majority of mutations were either missense variants or mRNA splicing variations (Fig. 2), most commonly SF3B1, ASXL1, TET2 and ASXL2. CHIP mutations were associated with increased age (p= 0.021), but there was no association with prior history of previous cancer, smoking, cytogenetically-defined high risk disease, pre-HCT hemoglobin level or red blood cell mean corpuscular volume. There was also no significant difference between the transplant course between the two groups in terms of neutrophil and platelet engraftment or length of hospital stay. Median follow up was 32 months. During follow up 3 pts develop MDS/AML (2 pts in the CHIP group and one in no CHIP group). Coronary artery disease was the cause of death in one patient in CHIP cohort versus none in the CHIP negative cohort. Myeloma progression was the major cause of death in CHIP and No CHIP cohorts (66% vs. 60%, p=0.48). Median PFS was 19 months in CHIP cohort vs. 39 months in No CHIP group (HR: 0.62, 95% CI: 0.51-0.92, p= 0.001). Median OS has not been reached in the No CHIP group while it was 56 months in CHIP group (HR: 0.78, 95% CI: 0.62-1.04, P=0.09). In multivariate analysis, presence of CHIP remained a significant predictor of worse PFS after adjusting for age, maintenance therapy, high risk disease, performance status, triplet vs. doublet pre-SCT therapy, melphalan dose and MM genetic risk. (Table 2). Conclusion: Here we showed high frequency of large clonal hematopoiesis clones (i.e., VAF ≥0.1) in autograft of MM pts. The presence of this mutations does not impact stem cell yield or transplant course, however it impacts PFS independent of age and other unfavorable factors. Our data highlights high frequency of SF3B1; the role of this mutant in modulating apoptotic factors in myeloma microenvironment should be investigated. Disclosures Malek: Celgene: Consultancy; Amgen: Speakers Bureau; Adaptive: Consultancy; Janssen: Speakers Bureau; Medpacto: Research Funding; Sanofi: Consultancy; Takeda: Consultancy. Caimi:ADC Therapeutics: Research Funding; Celgene: Speakers Bureau; Fate Therapeutics: Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Kite Pharmaceuticals: Consultancy, Membership on an entity's Board of Directors or advisory committees, Speakers Bureau; Genentech: Consultancy, Membership on an entity's Board of Directors or advisory committees, Research Funding, Speakers Bureau. Caldwell:Tempus Inc.: Employment.
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