Novel carbapenem-β-lactamase inhibitor combination, imipenem/relebactam (IMI-REL), has been recently approved for treatment of infections with limited or no alternative treatment options. In this study, we described the emergence of the IMI-REL-resistance in a KPC-producing Klebsiella pneumoniae (KPC-Kp) strain collected from a hematological patient with no evidence of prior colonization. Interestingly, IMI-REL-resistance was associated with meropenem/vaborbactam (MER-VAB) cross-resistance but was not associated with cross-resistance to ceftazidime/avibactam (CAZ-AVI). Although treatment with CAZ-AVI and gentamicin completely eradicated the infection due KPC-Kp cross-resistance to IMI-REL and MER-VAB, the patient became colonized subsequently by KPC-Kp strains susceptible to IMI-REL and MER-VAB. Whole-genome sequencing performed by hybrid approach using Illumina and Oxford Nanopore platforms demonstrated that all KPC-Kp strains isolated from hematological patient belonged to the ST512 and were clonally related. Analysis of antimicrobial and porins genes demonstrated that cross-resistance to IMI-REL and MER-VAB was associated with increased blaKPC-3 copy number and truncated OmpK35 and OmpK36 with GD134-135 insertion. Phylogenetic analysis demonstrated that KPC-Kp cross-resistance to IMI-REL and MER-VAB was clonally related to a KPC-Kp resistant to IMI-REL as previously described, demonstrating the spread of this multidrug resistant clone in the hematological unit. In conclusion, the results presented in this study reported the emergence of cross-resistance to MER-VAB and IMI-REL in a KPC-Kp strain isolated from a hematological patient and highlight the potential development and diffusion of new multidrug resistance traits.