MARTA Q LACY.
Professor of Medicine
Division of Hematology
Mayo Clinic College of Medicine
Rochester, Minnesota

Relapse remains a significant clinical problem for multiple myeloma. Nearly all patients eventually relapse, and, although survival rates are improving and treatment options continue to grow, the move to upfront combination therapy does limit options in relapse. FDA approved options for relapsed multiple myeloma include the immunomodulatory agents thalidomide and lenalidomide and the proteasome inhibitors, bortezomib and carfilzomib (for patients who have received at least 2 prior therapies including treatment with bortezomib and an immunomodulatory agent).

For patients not resistant or refractory to immunomodulatory agents and proteasome inhibitors, there are effective choices. However, for patients who have failed thalidomide, lenalidomide, and bortezomib survival is low.¹ Disease-, regimen-, and patient-related factors contribute to therapy selection in relapse. Disease-related factors include risk as assessed by FISH and cytogenetics and duration of response to initial therapy. Patient-related factors include comorbidities, age, and performance status. Regimen-related factors include prior drug exposure, toxicity of the regimen, the mode of administration, and whether the patient has had a previous stem cell transplant. These factors should be carefully weighed when making treatment decisions for relapsed myeloma patients.

At diagnosis, Mr Johnson had no high-risk molecular markers and excellent renal function. In this setting, at Mayo, we prefer to start with lenalidomide and dexamethasone because it has high remission rates, is oral, well tolerated, and unlikely to induce peripheral neuropathy. When using lenalidomide in patients with no personal history of VTE, we favor prophylaxis with aspirin at 325 mg daily. We would use IV bisphosphonates monthly for 12 months and quarterly for 1 additional year. In patients with low-risk disease, we consider risks and benefits of maintenance therapy. If maintenance therapy is chosen, consider limiting the duration to 12-24 months. 

At relapse, if our patient had a good response and a long duration of remission (> 12 months), we favor re-introduction of the initial regimen. If the patient has suboptimal response or a short remission duration, we would change the class of drug used (eg, if initially treated with an immunomodulatory agent [thalidomide, lenalidomide], we would switch to proteasome inhibitor [bortezomib, carfilzomib]. If initially treated with a proteasome inhibitor, we would switch to an immunomodulatory agent). In this particular case, we would need to factor in that the patient now has renal failure and a new bone lesion. We generally re-introduce bisphosphonates quarterly at relapse in patients with new bone lesions. However, since this patient has renal failure, we would wait for renal improvement and favor pamidronate over zoledronic acid with a reduced dose of 30 mg (from 90 mg).¹ Also due to the renal status of this patient, full-dose lenalidomide should not be used. I would favor switching to bortezomib because it can be used at full dose. However, dose-adjusted lenalidomide is also an option.² A second ASCT may also be considered, especially if the initial remission was extremely long (eg, > 4 years).
 

Thomas G. Martin III, MD
Clinical Professor of Medicine
Multiple Myeloma Translational Initiative
UCSF Medical Center, University of California, San Francisco
San Francisco, California

Mr Johnson's presentation was fairly typical and consistent with standard risk myeloma. At UCSF, we would consider this young (< 60 years), standard risk patient to be an excellent candidate for autologous transplantation at presentation. Therefore, we would avoid melphalan containing therapy and limit upfront lenalidomide therapy to 4-6 cycles thus allowing ample marrow reserve for stem cell collection. Lenalidomide/dexamethasone, bortezomib/dexamethasone, and/or lenalidomide with bortezomib would all be considered excellent upfront therapy options. Appropriate supportive care measures would be oral calcium and vitamin D and IV bisphosphonates. Patients receiving proteasome inhibition should receive anti-viral prophylaxis to prevent zoster reactivation and patients receiving immunomodulatory agents should receive venous thromboembolism (VTE) prophylaxis. Patients at increased risk for VTE should receive therapeutic warfarin, while low-risk patients, such as this one, can receive aspirin (325 mg) daily. In patients treated with autologous transplantation, we favor lenalidomide maintenance based on the CALGB 100104 and French randomized post-transplantation maintenance trials.^1,2 The median time to progression in the CALGB study was almost double for the lenalidomide arm (46 months) versus the placebo arm (27 months). The optimal duration of maintenance therapy remains unclear but we attempt to continue maintenance in this setting for at least 1 year and often for 2-3 years depending on tolerability and count suppression.

At relapse, Mr Johnson has developed significant renal insufficiency and this prevents the use of full-dose lenalidomide, as lenalidomide clearance is primarily renal. Since Mr Johnson's remission lasted 24 months, one could choose to use either dose-reduced lenalidomide, or a bortezomib-containing regimen. There are a number of reports describing improved renal function in patients receiving early bortezomib administration and no increased toxicity. Consequently, we would likely recommend a bortezomib-based regimen, like cyclophosphamide, bortezomib, and dexamethasone (CyBorD) in this case. One should consider re-instituting bisphosphonate therapy once the renal function improves (unless the renal insufficiency is due to hypercalcemia for which bisphosphonates should be used right away). At relapse, one always needs to consider toxicity from prior therapy. Since the patient has a history of neuropathy, we would choose to administer bortezomib at weekly intervals and by subcutaneous injection. If the neuropathy increases, option would include switching to carfilzomib or lenalidomide-based therapy.

Mr Johnson - Challenge Question-Commentary

Katherine Sanvidge Shah, PharmD, BCOP
Hematology/Oncology Pharmacy Specialist
Emory University Hospital
Winship Cancer Institute
Atlanta, Georgia

I agree with holding off on bisphosphonate therapy until Mr Johnson's renal function improves. One exception would be if he were hypercalcemic at relapse. In this case, we would give full-dose therapy x 1 dose (for hypercalcemia of malignancy). If the renal function does not improve, we would consider dose-reduced zoledronic acid or pamidronate for the treatment of his lytic disease. At first relapse for this patient, we would also favor adding bortezomib into the treatment regimen of this patient as he has not previously received a proteasome inhibitor as dose reductions are not required with renal insufficiency (ie, exhibits good renal data), though we likely would have used bortezomib in the upfront setting.

Mr Johnson - Idea Exchange #1

 

Monitoring

Martha Q. Lacy, MD

For patients like Mr Johnson who achieve a CR, what do you monitor and how often?

Thomas G. Martin III, MD

Once a patient has achieved remission following upfront therapy, it is important to follow their myeloma for evidence of relapse. Early recognition of disease relapse often can prevent morbid complications including hypercalcemia, compression fractures, and renal failure. For patients on maintenance therapy, we will follow their CBC including neutrophil and platelet counts every 4-6 weeks and adjust dosing accordingly. A history and physical exam and laboratories including serum protein electrophoresis, quantitative immunoglobulins, serum immunofixation electrophoresis, and serum free light chains can be followed every 12 weeks. We will follow 24-hour urine tests (TP, UPEP, UIFE) every 12 weeks if a patient has had disease that is only assessable by urine tests (this is rare). We perform bone marrow biopsies every 12-18 months unless the patient has truly nonsecretory disease for which BMB exams are performed every 3-6 months. We rarely performed routine skeletal surveys but prefer PET/CT or total body MRI exams, every 12-18 months.

Elizabeth Bilotti, MSN, RN, APN

For patients who have achieved a CR post-transplant, we would follow every 3 months or as clinically indicated for reported symptoms, with a change in the frequency of assessments at the time signs of relapse became present. Evaluation would include full laboratory assessment (CBC, chemistry panel, quantitative immunoglobulins, SPEP, free light chain analysis, serum immunofixation with 24-hour urine analysis as appropriate ‒ UTP, UPEP, and urine immunofixation on a 24-hour urine). Radiographic imaging and BM biopsy would be determined based upon medical necessity and only used routinely in patients with non-secretory disease.