Illustrative case Series

Management of Multiple Myeloma in the Oldest Old

By Bindu Kanapuru, MD, Institute for Advanced Studies in Aging and Geriatric Medicine, Falls Church, VA. Dr. Kanapuru reports no financial relationships relevant to this field of study.

An 88-year-old woman with history of hypertension, chronic kidney disease with baseline creatinine of 1.8 meq/dL, and osteoarthritis was seen in the emergency room for worsening pain in the right shoulder and fatigue over 2 weeks. Her son denied any recent illnesses, falls, changes in appetite, or change in urinary or bowel habits. He reported that his mother was able to perform her daily activities but has a sedentary lifestyle. Laboratory investigations in the emergency room revealed hemoglobin of 7.0 g/dL, calcium level of 12.0 mg/dL, total protein of 7.0 g/dL, albumin of 3.0 g/dL, and creatinine of 2.0 meq/dL. X-ray of the right shoulder revealed a lytic lesion in the upper end of the right humerus without apparent fracture. Also present was a serum M-spike of 3.5 g/dL with an associated immunofixation pattern consistent with an IgG lambda monoclonal protein. Quantitative IgG level was of 3460 mg/dL, whereas immunoglobulin A and immunoglobulin M (IgA; IgM) levels were both found to be 80 mg/dL (normal IgG, 640-1430 mg/dL; IgA normal, 70-300 mg/dL, normal IgM, 20-140 mg/dL). Serum lambda light chains were elevated to 2030 mg/dL, but kappa light chains were reduced. Beta-2 microglobulin was very high at 28.0 mg/L. A bone marrow biopsy showed infiltration with 65% plasma cells (some very dysplastic in appearance) consistent with a diagnosis of multiple myeloma.

How Should This 88-year-old Woman Be Treated for Her Multiple Myeloma?

Multiple myeloma is a malignant disorder of B cells characterized by proliferation of plasma cells in the bone marrow and is predominantly a disease of the elderly. The median patient age at diagnosis is 70 years. The incidence rates in those aged 50-54 is less than 10%; rates steadily increase with age and are greater than 35% in the elderly over 80 years of age.1 The proportion of newly diagnosed patients over 80 years of age between 1950-1959 and 2000-2005 has grown dramatically and will likely continue to grow as the population ages. Over the past 2 decades, survival for myeloma has improved by 10% for patients aged 50-59 years and by 5% 60-69 years of age. However, there has been only a modest increase in survival in the 70-79 year old age group and no improvement in survival for those over 80 years of age. Older myeloma patients have less favorable features at presentation such as high International Staging System (ISS) and Durie- Salmon stage as well as other adverse features such as low hemoglobin and poor performance status.2 Although these factors alone may account for the poor survival seen in the very old, it turns out that age alone has been found to be an independent risk factor for reduced survival by multivariate analysis. Whether this is related to increased toxicity from chemotherapy or inadequate therapy is unclear.

Clinical trials for myeloma have traditionally considered those over the age of 65 years to be "elderly," and protocols with representative numbers of typical octogenarians have been very few. Although chronological age should not be used to exclude patients from standard treatments, increased comorbidities and frailty in the oldest-old necessitate a modified approach. Melphalan and prednisone have been the standard therapy against which novel agents have been compared for the elderly patients. Current recommendation for those over 65 years old include Melphalan, prednisone, thalidomide (MPT); Bortezomib, melphalan, prednisone (VMP); and lenalidomide, dexamethasone (RD or Rd).

Meta-analyses of trials evaluating MPT vs MP have demonstrated a significant improvement in progression-free survival (PFS: MP 14.9 months and for MPT 20.3 months) and a trend toward benefit in overall survival. Most of the trials analyzed included participants younger than 75 years of age and with good performance status. In the Nordic trial which included > 20% of patients over 80 years of age and 30% of the participants with WHO performance status 3 or 4 the median PFS with MPT (10 months vs 6 months) was much shorter for those over 75 years of age than for those 65-75 years of age. No survival benefit to MPT over MP was observed and there was an increased risk of toxic deaths observed in those over 75 years of age.4 Peripheral neuropathy and neutropenia were significantly increased in the MPT arm than MP in the IFM01/01 trial in which > 36% of patients were over 80 years of age, albeit with good performance status.5 In the HOVON 49 trial, which enrolled more than 50% of the participants older than 75 years of age but less than 10% of the patients had PS of 3, a shorter EFS was observed in these patients without any survival benefit.6

The VISTA trial, which evaluated the benefit of adding bortezomib to Melphalan and prednisone in older patients, included 30% over 75 years of age and approximately 30% with Karnofsky performance status < 70%. The median time to progression was significantly improved (7.4 months) and median survival was not reached in those who received bortezomib. However, subgroup analysis showed that the significant benefit in survival was confined to those less than 75 years of age. In fact, 3-year overall survival (OS) in those older than 75 years age receiving MPT was 55.5%, which was similar to 3-year OS in all patients who received MP.7

Lenalidomide in combination with low- or high-dose dexamethasone was evaluated in a randomized trial that included > 50% of patients over 65 years of age. Although the low-dose dexamethasone regimen was associated with lower response rates, 1-year overall surviavl was significantly improved and treatment-related toxicity was significantly reduced. In the subgroup of patients over 70 years of age, the low-dose dexamethasone regimen did have relatively high response rates; however, PFS was slightly inferior compared to the overall population (25.3 months vs 22 months). Incidence of grade 3-4 hematological toxicity was 59% in the Rd group compared to 78% in the RD group. Firm evidence that these results can be applied to those over 80 years of age or those with poor performance status is lacking.

Based on the above discussion, the optimal management of the very elderly with myeloma remains to be defined. The novel drugs, although promising, have no definite survival benefit, have a less pronounced effect on PFS, and are associated with greater toxicity in the very old. Initiating treatment with Melphalan/prednisone is still a very reasonable therapy in these patients. Single-agent dexamethasone or prednisone are very active in multiple myeloma and should also be considered in frail elderly patients, especially acknowledging that treatment goals are directed at palliation with the least risk of toxicity. That stated, careful monitoring for side effects and dose modifications are essential to reduce the adverse effects from hyperglycemia, gastritis, edema, and bone loss. Different schedules of dexamethasone and prednisone are published and can be used based on the tolerance of the patient.8,9

Dose reductions or schedule modifications in the frail and very elderly may reduce toxicity without compromising efficacy. Weekly bortezomib with cautious dose adjustments for hematological and non-hematological toxicity may turn out to be an effective approach. The European Myeloma Network suggested stratifying patients for treatment based on age > 75 years, frailty, comorbidity, disability, or presence of grade 3-4 non-hematological toxicities.8 They recommended reduced dose treatment if even one or more of the above risk factors were present. Other authors have given recommendations on dose reductions in the very elderly or in poor performance status patients with starting dose of thalidomide at 50 mg or 100 mg, lenalidomide 10-15 mg. Again, these are recommendations derived more from anecdotal experience than randomized clinical trials, and without such evidence, clinical judgment is required.

Inasmuch as disease-directed treatments are untested in frail-elderly and are likely to have some associated toxicity and only modest efficacy, offering supportive care alone may be the best choice. Included would be appropriate management of infections, anemia, and palliative radiation for symptomatic bone lesions.

Case Continued

The patient was started on dexamethasone 20 mg daily for 4 days and this was to be repeated in 2 weeks. She received H2 receptor blockers for gastritis prophylaxis, packed red blood cell transfusions, intravenous fluids, and reduced dose bisphosphonates based on her creatinine clearance. An appointment was also made for palliative radiation to painful rib lytic lesions.

References

1. Howlader N, et al, eds. SEER Cancer Statistics Review, 1975-2008, National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2008/, based on November 2010 SEER data submission, posted to the SEER web site, 2011.

2. Ludwig H, et al. Myeloma in patients younger than age 50 years presents with more favorable features and shows better survival: An analysis of 10,549 patients from the International Myeloma Working Group. Blood 2008;111:4039-4047.

3. Brenner H, et al. Recent major improvement in long-term survival of younger patients with multiple myeloma. Blood2008;111:2521-2526.

4. Waage A, et al. Melphalan and prednisone plus thalidomide or placebo in elderly patients with multiple myeloma. Blood2010;116:1405-1412.

5. Hulin C, et al. Efficacy of melphalan and prednisone plus thalidomide in patients older than 75 years with newly diagnosed multiple myeloma: IFM 01/01 Trial. J Clin Oncol 2009;27:3664-3670.

6. Wijermans P, et al. Phase III study of the value of thalidomide added to melphalan plus prednisone in elderly patients with newly diagnosed multiple myeloma: The HOVON 49 study. J Clin Oncol 2010;28:3160-3166.

7. Mateos M, et al. Bortezomib plus melphalan and prednisone compared with melphalan and prednisone in previously untreated multiple myeloma: Updated follow-up and impact of subsequent therapy in the Phase III VISTA trial. J Clin Oncol 2010;28:2259-2266.

8. Palumbo A, et al. Personalized therapy in multiple myeloma according to patient age and vulnerability: A report of the European Myeloma Network (EMN). Blood 2011;118:4519-4529.

9. Mehta J, et al. How I treat elderly patients with myeloma. Blood 2010;116:2215-2223.