Charles Grodin’s Death From Multiple Myeloma

Actor Charles Grodin has died at the age of 86. The actor, who was known for many of his performances, including “The Heartbreak Kid,” “Beethoven,” “Midnight Run,” and “Heaven Can Wait,” died from multiple myeloma. Grodin died May 18, at his home in Connecticut.

Besides his stage and screen work, Grodin was known as a frequent late night-TV guest. He made 17 appearances on “Late Night With David Letterman” and 36 appearances on “The Tonight Show Starring Johnny Carson.”

Tributes to the actor included those from Steve Martin: “So said [sic] to hear. One of the funniest people I ever met.”

Kathy Griffin added, “I loved Charles Grodin so much. He would bust my balls and give me so much shit in a way that left me no choice but to giggle with glee. Never mean spirited, just quick and brilliant.”

Mia Farrow, who appeared with Grodin in “Rosemary’s Baby,” tweeted, “At first Charles Grodin was Dr. Hill to me, then through the decades he was my pal, ‘Chuck’, unfailingly kind, direct, funny – a gifted, gentle man.”

There was even one from Miss Piggy, with whom Grodin revealed a brief tryst: “My beloved Charles Grodin was a fabulous friend to moi onscreen and off. Debonair, handsome, talented, charming – and great taste! I’ll miss him dearly.”

Multiple Myeloma

Multiple myeloma is a form of cancer that occurs due to abnormal and uncontrolled growth of plasma cells in the bone marrow. There are several types of plasma cell neoplasms. These diseases are all associated with a monoclonal (or myeloma) protein (M protein). They include monoclonal gammopathy of undetermined significance (MGUS), isolated plasmacytoma of the bone, extramedullary plasmacytoma, and multiple myeloma.

Patients with MGUS have an M protein in the serum without findings of multiple myeloma, macroglobulinemia, amyloidosis, or lymphoma and have fewer than 10% of plasma cells in the bone marrow. A clinically similar group of patients are diagnosed as having smoldering myeloma (SMM), also referred to as indolent disease. SMM is defined as a monoclonal (M) protein ≥3 g/dL and/or 10 to 60 percent bone marrow plasma cells but no end-organ damage (lytic lesions, anemia, renal disease, or hypercalcemia) that can be attributed to the underlying plasma cell disorder or other myeloma-defining events, and no amyloidosis. The risk of progression to multiple myeloma is higher for patients with SMM than for those with MGUS (10% in the first 10 years, vs 1% respectively).

According to the National Cancer Institute’s Surveillance, Epidemiology, and End Results Program (SEER), it is estimated that there will be 34,920 new cases of myeloma in the U.S. in 2021, and 12,410 deaths. The 5-year relative survival rate is 55.6% based on data from 2011-2017. The 5-year survival rate for those with localized disease at the time of diagnosis is 77.5%. Unfortunately, localized disease is only found in 4% of patients.

Factors associated with an increased risk of developing multiple myeloma include increasing age, male sex, African-American race, radiation exposure, a family history of the condition, obesity, and/or a personal history of monoclonal gammopathy of undetermined significance (MGUS).

Symptoms

The specific symptoms of the condition result from abnormal and excessive growth of plasma cells in the bone marrow. Excess plasma cells form tumors in the bone and cause bones to become weak and easily broken. The abnormal growth of plasma cells also makes it more difficult for the bone marrow to make healthy blood cells and platelets. In addition, the plasma cells produced in multiple myeloma produce abnormal antibodies that the immune system is unable to use. These abnormal antibodies build up in the body and cause a variety of problems.

In some cases, multiple myeloma is not associated with any signs and symptoms. When present, the most common symptom is anemia, which can be associated with fatigue, shortness of breath, and dizziness. Other features of the condition may include:

• Bone pain
• Nausea
• Constipation
• Loss of appetite
• Frequent infections
• Weight loss
• Excessive thirst
• Weakness and/or numbness in the arms and legs
• Confusion
• Abnormal bleeding
• Weak bones that may break easily
• Difficulty breathing

Diagnosis

A diagnosis of multiple myeloma may be suspected based on the presence of characteristic signs and symptoms. Additional testing can then be ordered to confirm the diagnosis, including:

• Specialized blood tests including immunoglobulin studies, complete blood count with differential, and blood chemistry studies (especially serum calcium and renal function tests)
• Urine tests such as immunoglobulin studies and a 24-hour urine test
• Bone marrow aspiration and biopsy
• Imaging studies such as a skeletal bone survey, MRI, CT scan, and/or PET scan

Treatment

The major challenge in treating plasma cell neoplasms is separating the stable asymptomatic group of patients who do not require immediate treatment from patients with progressive symptomatic myeloma who may need to be treated immediately. MGUS or smoldering myeloma must be distinguished from progressive myeloma.

Patients with symptomatic advanced disease require treatment. Treatment most often is directed at reducing the tumor cell burden and reversing any complications of disease, such as renal failure, infection, hyperviscosity, or hypercalcemia, with appropriate medical management.

Current therapy for patients with symptomatic myeloma can be divided into the following categories:

• Induction therapies
• Consolidation therapies, which are less applicable for the very elderly
• Maintenance therapies
• Supportive care, such as bisphosphonates

Newly diagnosed patients who require therapy fall into two categories: the younger fit patient who is transplant-eligible or the older more unfit patient with comorbidities who is not transplant eligible. Patients younger than age 65 are usually considered younger and fit, while patients older than age 75 are usually not transplant eligible.

The younger fit patient will receive induction chemotherapy with a triple-drug (triplet) approach that includes bortezomib in the absence of a clinical trial. The most commonly used triplets include:

• VRd: lenalidomide + dexamethasone
• CyBorD: cyclophosphamide + bortezomib + dexamethasone. This regimen is preferred in the presence of significant renal dysfunction (creatinine clearance less than 45 cc/min). If the renal function recovers rapidly, some clinicians switch to VRd.

After 4 to 8 months of therapy, responding patients usually undergo ASCT (autologous stem cell transplantation) consolidation. After recovery from the ASCT, maintenance therapy is then implemented until the time of relapse. At relapse, subsequent therapies are applied sequentially by using previously successful drugs (if the interval of time since previous exposure is more than 1 year) or newer drugs not previously tried.

The older, less fit patient will receive induction chemotherapy with a triplet (as described for the younger fit patient) plus the monoclonal antibody to CD38, daratumumab, or with a doublet and daratumumab, which might be better tolerated. Therapy is continued until maximal response and then maintenance therapy is applied until relapse. At relapse, subsequent therapies are applied sequentially (as described for the younger fit patient).

After the initial treatment, maintenance therapy is often given to help keep the disease in remission for a longer time. Several types of treatment are being studied for this use, including:

• Chemotherapy
• Immunotherapy (interferon or lenalidomide)
• Corticosteroid therapy
• Targeted therapy with a proteasome inhibitor (bortezomib or ixazomib)

Prognosis

Multiple myeloma is highly treatable but rarely curable. The median survival in the pre-chemotherapy era was about 7 months. After the introduction of chemotherapy, prognosis improved significantly with a median survival of 24 to 30 months and a 10-year survival rate of 3%. Even further improvements in prognosis have occurred because of the introduction of newer biologic therapies and better salvage options, with median survivals now exceeding 60 to 90 months.

Michele R. Berman, MD, is a pediatrician-turned-medical journalist. She trained at Johns Hopkins, Washington University in St. Louis, and St. Louis Children’s Hospital. Her mission is both journalistic and educational: to report on common diseases affecting uncommon people and summarize the evidence-based medicine behind the headlines.