England forwards Nathan Hughes and Courtney Lawes are both set for an extended period on the sidelines after undergoing surgery.
Both had operations this week on knee injuries sustained during Saturday's 22-16 defeat by France in Paris.
Wasps No 8 Hughes limped off in the 24th minute at the Stade de France after taking a heavy blow to his left knee and is expected to miss 12 weeks while recovering from surgery.
Northampton forward Lawes, who finished the match, will require 14 weeks of rehabilitation.
Their recovery timelines mean both will miss the remainder of the season for their respective clubs. They are also very doubtful to participate in England's summer tour of South Africa.
Eddie Jones' side will face the Springboks in a three-Test series in Johannesburg (9 June), Bloemfontein (16 June) and Cape Town (23 June).