The purpose of this study is to test the safety of a study drug called KRT-232 (AMG 232) when used in combination with a standard treatment regimen for relapsed or refractory multiple myeloma. The standard treatment is with the drugs carfilzomib, lenalidomide, and dexamethasone (KRd).

Different doses of KRT-232 (AMG 232) will be tested to see which dose is safer in people when used with standard doses of carfilzomib, lenalidomide, and dexamethasone. Another purpose of this study is for researchers to learn whether a biomarker can help predict which patients will respond well (have tumor shrinkage) from the combination of KRT-232 (AMG 232) and KRd.

KRT-232 (AMG 232) is considered investigational, which means it has not yet been approved by the U.S. Food and Drug Administration. Carfilzomib, lenalidomide, and dexamethasone (KRd) are approved by the FDA, but are considered investigational in combination with the study drug.

Participants are assigned to a study group based on when they enroll and will be discussed with the study team. In Part I, different doses of the study drug KRT-232 (AMG 232) will be given to several study participants in combination with standard doses of carfilzomib, lenalidomide, and dexamethasone. The first several study participants will receive the lowest dose of KRT-232 (AMG 232). If the KRT-232 (AMG 232) does not cause serious side effects, it will be given to other study participants at a higher dose. The doses will continue to increase for every group of study participants until side effects occur that require the dose to be lowered.

In Part 2, participants will receive KRT-232 (AMG 232) at the dose that was tolerated in combination with carfilzomib, lenalidomide, and dexamethasone in Part 1. 
   
KRT-232 (AMG 232) is taken by mouth on an empty stomach at least 2 hours after a meal and 2 hours before the next meal with a full glass of water. Carfilzomib is given through a vein, lenalidomide is taken by mouth with or without food, and dexamethasone is either given through the vein or taken by mouth. A pill diary will be provided to ensure that are the medications are taken by mouth as instructed.

Participants will receive KRT-232 (AMG 232) in combination with carfilzomib, lenalidomide, and dexamethasone for up to 18 cycles which is approximately 18 months (1 cycle = 4 weeks), followed by KRT-232 (AMG 232), lenalidomide, and dexamethasone as long as the treatment is being tolerated and the myeloma is controlled.
   
Participants will also receive genetic testing on their myeloma at the time of study enrollment. The results of this testing may give the study team information on whether or not KRT-232 (AMG 232) has a chance to be effective, although the results of this testing may not be available until after you begin therapy. If the results of this testing show that it is unlikely a participant would benefit from KRT-232 (AMG 232), they will be removed from the study after the first cycle (4 weeks) of treatment with KRd + KRT-232 (AMG 232), and will continue on KRd alone as per the standard treatment for relapsed or refractory myeloma.