Usually, yes. Isthmus comes through Latin from the Greek isthmos, a neck or narrow passage. For the Greeks, the Isthmus was the narrow neck of land at Corinth that joins the Peloponnese to the rest of Greece.
The letters sthm make a hard cluster: s, th and m with no vowel between them. Most speakers simply drop the th, as they do in asthma. Oxford lists only IS-mus, and so does Cambridge's American dictionary.
Cambridge's main entry gives ISTH-mus, with the th, so that form is correct as well. If you are unsure, say IS-mus. It is easier, and it is the form both dictionaries accept.