What are the adverse side effects of treating advanced stage multiple myeloma with Ipilimumab (Yervoy) and Nivolumab (Opdivo)?

Adverse Side Effects of Ipilimumab Plus Nivolumab in Advanced Multiple Myeloma

Critical Limitation: No Evidence for Multiple Myeloma

The combination of ipilimumab plus nivolumab is not approved or studied for advanced stage multiple myeloma, and therefore specific adverse event data for this indication does not exist. The available evidence pertains exclusively to other malignancies including renal cell carcinoma, melanoma, non-small cell lung cancer, mesothelioma, colorectal cancer, and esophageal cancer 1, 2.

General Adverse Event Profile from FDA-Approved Indications

Since no multiple myeloma-specific data exists, the following represents the adverse event profile from FDA-approved uses, which may inform potential toxicities if this combination were used off-label:

Overall Toxicity Burden

Treatment-related adverse events occur in 91-95% of patients receiving ipilimumab plus nivolumab, with grade 3-4 events occurring in 46-59% of patients 1, 3, 4. This represents substantially higher toxicity than either agent alone 1, 5.

• Treatment discontinuation due to adverse events occurs in 22-36% of patients 1, 4
• Treatment-related deaths occur in approximately 1-2% of patients 1, 4
• Emergency department visits related to immune-related adverse events occur in 50% of patients 4
• Hospitalization for immune-related adverse events is required in 36% of patients 4

Immune-Related Adverse Events by Organ System

Gastrointestinal Toxicity

• Diarrhea occurs in 22-46% of patients (grade 3-4: 2-16%) 1, 2
• Colitis occurs in approximately 8% of patients with ipilimumab monotherapy 5
• Nausea occurs in 22-24% of patients 2
• Abdominal pain occurs in 10-15% of patients 2

Dermatologic Toxicity

• Rash occurs in 31-34% of patients (grade 3-4: 2.7-3.1%) 1, 2, 5
• Pruritus occurs in 17-27% of patients 2, 5
• Dermatitis occurs in 10% of patients 5

Hepatic Toxicity

• Elevated AST occurs in 38-39% of patients (grade 3-4: 6-7%) 1, 2
• Elevated ALT occurs in 33-37% of patients (grade 3-4: 6-7%) 1, 2
• Hepatitis occurs in approximately 3% of patients with nivolumab monotherapy 5
• Hepatic function abnormalities requiring hospitalization occur in 2.8% of patients 2

Endocrine Toxicity

• Hypothyroidism occurs in 14-15% of patients 1, 2
• Hypophysitis occurs in 4% of patients with ipilimumab monotherapy 1, 5
• Adrenal insufficiency requiring hospitalization occurs in 2.5% of patients 2
• Hyperglycemia occurs in 6-43% of patients (grade 3-4: 0.8-4.3%)** 2, 5

Pulmonary Toxicity

• Pneumonitis occurs in 3-7% of patients and represents one of the most serious complications 1
• Dyspnea occurs in 16-27% of patients (grade 3-4: 2.3-3.2%) 1
• Cough occurs in 9-23% of patients 1

Renal Toxicity

• Nephritis can occur, with particular concern in patients with a single kidney 1
• Increased creatinine occurs in 15-20% of patients (grade 3-4: 0.3-0.7%) 1, 2

Musculoskeletal Toxicity

• Musculoskeletal pain occurs in 8-14% of patients 2
• Arthralgia occurs in 12-13% of patients 1, 5

Timing and Resolution of Adverse Events

Grade 3-4 immune-related adverse events typically occur with median onset ranging from 3.1 weeks (skin) to 16.3 weeks (renal) 1, 6.

• Median time to resolution ranges from 1.9 weeks (renal) to 4.5 weeks (pulmonary) 6
• Resolution rates range from 79-100% with appropriate management, excluding endocrine toxicities 6
• Late-onset immune-related adverse events can occur more than 16 weeks after the last treatment dose in 13% of patients who discontinued therapy early 4

Management Requirements

High-dose corticosteroids are required in 35-72% of patients who develop immune-related adverse events 1, 4.

• Infliximab or mycophenolate for steroid-refractory toxicity is required in 25% of patients 4
• For grade 3 immune-related adverse events, therapy should be held and high-dose oral steroids initiated with tapering over 4-6 weeks once symptoms resolve 1
• For grade 3-4 toxicities, permanent discontinuation is generally recommended 1

Laboratory Abnormalities

Hematologic abnormalities include lymphopenia (43-50%, grade 3-4: 8-13%), anemia (43-52%, grade 3-4: 2.4-7%), and thrombocytopenia (12%, grade 3-4: 1%) 2.

Metabolic abnormalities include hyponatremia (32-45%, grade 3-4: 8-11%), hyperkalemia (23-30%, grade 3-4: 1.6-4.1%), and hypocalcemia (28-32%) 1, 2.

Critical Clinical Caveat

This combination is not standard therapy for multiple myeloma and should only be considered in the context of a clinical trial. The adverse event profile described above derives from other malignancies and may not accurately predict toxicity in multiple myeloma patients, who often have different baseline characteristics including bone marrow compromise, renal dysfunction, and prior treatment exposure 1, 2.