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Abstract Pts with HM and particularly those under therapy or with secondary immune deficiency have been reported to have a low or delayed specific immune response. In addition, pts receiving rituximab for either HM or auto-immune disease presented a low specific antibody response. Daratumumab, an anti-CD38 moAb was demonstrated to lower normal plasma cells and to reduce polyclonal IgA, M and E in pts with multiple myeloma (MM). It is fundamental to evaluate the early post-vaccination tolerance and the level of seroconversion for such pts. Patients' population. 194 pts having HM and followed at the Institute (IC), received at least 2 doses of BNTCV (BioNTech Pfizer, Paris, France) by IM route with 3 weeks between the 2 doses. Currently, analysis was performed on 147 pts, including 63 pts with non-Hodgkin lymphoma (NHL), 18 with B-chronic lymphocytic leukemia (CLL), 34 with MM, 14 with monoclonal gammopathy of undetermined significance (MGUS) and 18 with myeloproliferative disorder (MPD). Mean age was 69 years-old (range 27-92). Follow-up of early tolerance in pts using a telemedicine application. 43 pts vaccinated at the IC received Thess®, a telemedicine system connecting the patient to the IC, developed by La Valeriane Inc. (Montpellier, France, www.thess-corp.fr) 24/24h, 7days. Local pain (<1 day) was common and transient, particularly reported after the 2nd dose. Only 4/43 patients reported significant adverse events through telemedicine and followed by a medical call, including mainly severe asthenia for 2 days or more, fever (>38°C) for at least 2 days, headache, or general pain. The satisfaction survey of monitoring system was good. In addition, adherence to vaccination was excellent with only one refusal out of the 194 pts. AcAS follow-up IgG AcAS and IgG+M AcAS were analyzed in the serum 3 to 4 weeks after the 1st dose and 4-8 weeks after the 2 nd dose and every 2 months, respectively by SARS-CoV-2 IgG II Quant ® Assay with a threshold of positivity at 50 AU/mL (Abbott, Rungis, France) and Elecsys ® Anti-SARS-CoV-2 S (Roche Diagnostics, Meylan, France) with a threshold of positivity at 0.8 U/mL. 270 samples were analyzed in duplicate with the 2 assays, by 2 independent labs. Data were reported and statistically analyzed by the clinical research team. 17 results were discordant including 12 with Abbott IgG test undetectable and Roche IgG+M detectable, and 5 with Abbott test detectable and Roche undetectable. After the first dose of BNTCV, 72/147 (49%) pts were seroconverted, including 7/18 (39%) with CLL, 27/63 (43%) with NHL, 10/14 (71%) with MGUS, 17/34 (50%) with MM and 11/18 (61%) with SMD. The median levels of the AcAS response for pts were 0 (range 0-40 000 AU/mL) for the AdviseDX test as compared to 12 normal subjects (mean 257 AU/mL, range 226-283), and 0 U/mL (range 0-2500) for the Elecsys test. 49/75 (65%) of untreated pts were seroconverted after the 1 st dose as compared to 26/72 (36%) of treated patients (p<0.001), with rituximab or ibrutinib as negative factors in addition to low gammaglobulin level (<5g/L, p=0.019), similarly to the IgG level. Analysis of CRP levels, circulating lymphocyte counts, and lymphocyte subpopulations will be performed. After the second dose of BNTCV, 50 pts have currently been tested, with only 25 additional pts seroconverted. The median levels of the AcAS response for pts were 310 AU/mL (range 62-11760) for the AdviseDX test as compared to 12 normal subjects (mean 6725 AU/mL, range 3002-9787), and 1250 U/mL (range 0.87-2500) for the Elecsys test. The 25 patients who were not seroconverted after the 2nd dose received a 3rd dose of BNTCV, including 8 with MM, 9 with NHL, 5 with CLL, 1 with MGUS (with polyneuropathy under daratumumab) and 2 with SMD. Currently, 9 pts were tested after the 3 rd dose. AcAS levels were respectively 268 AU/mL for 1 MM treated by daratumumab, 103 and 313 AU/mL for 2 MM under carfilzomib, 1622 AU/mL for 1 untreated SMD, 29100 AU/mL for 1 untreated MGUS, 537 AU/mL for 1 CLL and 2 negative NHL. In conclusion, there is a need to follow AcAS for pts having HM including SMD after BNTCV aiming to adapt vaccine strategy including a 3 rd dose and eventual recall. As some pts are always negative after a 3 rd dose, vaccination strategy could be discussed by using different combinations of vaccine or the addition of immune adjuvant in a more personalized medicine. In addition, the usage of telemedicine connecting system may help to follow the early tolerance and to improve the pts' adherence. Disclosures Rossi: NPO Petrovax Pharm: Consultancy; LEO Pharma: Consultancy; EUSA Pharma: Consultancy; E-SANA Inc: Other: Co-founder of E-SANA Inc .