Treating Earlier to Avoid Progression to Multiple Myeloma 


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Ruben Niesvizky, MD

With an expanded list of drugs to treat multiple myeloma, experts are interested in whether treating precursor diseases to multiple myeloma can prevent progression to full-blown myeloma. In addition, new drugs are entering the armamentarium for treating multiple myeloma, noted Ruben Niesvizky, MD, Associate Professor of Medicine at Weill Medical College of Cornell University and at NewYork Presbyterian Hospital/Weill Cornell Medical Center in New York,1 at the Chemotherapy Foundation Symposium XXXI, held recently in New York.

Precursors and Sequelae

“Most multiple myeloma has a precursor disorder, either smoldering myeloma or monoclonal gammopathy of undetermined significance. Someone should capitalize on those stages to see if the natural history of the disease can be altered,” said Dr. Niesvizky.

Patients with multiple myeloma can develop renal failure, myelosuppression, bone disease, and hypercalcemia, he continued. “It is disappointing that after all these years and advances we are now first trying to address disease in early stages. If we could intervene earlier we might be able to impact disease progression. We need drugs with low toxicity and high efficacy,” he said.

“Now that good drugs are available, and we can characterize higher-risk patients with smoldering myeloma, we need to address this question,” he added.

Smoldering Myeloma Study

Although the definition of high risk is a moving target, patients with one of the following abnormalities are considered high-risk: bone marrow plasma cells ≥ 10%, ≥ 95% aberrant antigenic features by immunophenotyping, or abnormal free light chain ratio.

A recent study looked at whether treatment of high-risk patients with smoldering myeloma would slow the progression to multiple myeloma, and increase survival, response rate, duration of response, and safety.2 The study randomly assigned 119 patients—60 to treatment with lenalidomide (Revlimid) and dexamethasone followed by lenalidomide maintenance for 2 years, and 59 to no treatment.

In an intent-to-treat analysis with a median follow-up of 40 months, the time to progression to multiple myeloma was superior in the treatment arm: Median time to progression was not reached in the treatment arm vs 21 months in the control group (P < .001). Treatment was also associated with an overall survival advantage; 3-year overall survival was 94% in the treated arm vs 80% in the no-treatment arm (P = .03).

“This study opens a new window of opportunity to initiate research in precursor disorders and perhaps prevent the evolution of the disease,” Dr. Niesvizky told the audience.

He said that two trials of treatment are currently accruing patients with smoldering myeloma. One is evaluating a combined regimen of carfilzomib (Kyprolis), lenalidomide, and dexamethasone in smoldering myeloma, and the other is a biomarker study of the investigational monoclonal antibody elotuzumab in high-risk smoldering myeloma. He encouraged audience members to enroll patients in these trials.

New Drugs for Multiple Myeloma

Turning to treatment advances in multiple myeloma, he noted that the disease is heterogeneous, and genomic profiling makes it clear that there is no one single treatment target. Multiple myeloma is characterized by multiple genetic abnormalities, and no single drug can address these. Further complicating treatment, the genetic heterogeneity is present at all stages of the disease, and different genetic abnormalities are evident at different stages. The majority of patients with multiple myeloma relapse after an initial response to therapy, and by that time, the disease has evolved into a more aggressive cancer.

Pomalidomide (Pomalyst), carfilzomib, and clarithromycin are being studied in various combinations with other myeloma drugs to see if outcomes can be improved. Pomalidomide has achieved an objective response rate of about 30% in relapsed/refractory multiple myeloma and about 60% in early relapse in phase II trials.3

The combination of clarithromycin, lenalidomide, and dexamethasone is undergoing phase II study in multiple myeloma patients (80% refractory). With this triplet, objective response rate was 57% and clinical benefit rate (ie, complete response, partial response, and stable disease) was 66%. Progression-free survival was a median of 8.67 months, whereas it is typically about 4 months in refractory patients, Dr. Niesvizky said.4

Carfilzomib is undergoing phase II testing in combination with lenalidomide and low-dose dexamethasone. Median duration of response is about 2 years, and median progression-free survival is 15.4 months.5 Front-line therapy with carfilzomib plus lenalidomide achieved an objective response rate of 97%, and at 24 months, 94% of patients were alive.6

A study in Europe showed that combined carfilzomib, melphalan, and prednisone achieved an objective response rate of 91% as front-line therapy in multiple myeloma patients, including those at high risk.7 The phase III CLARION study will compare carfilzomib, melphalan, and prednisone vs bortezomib (Velcade), melphalan, and prednisone in transplant-ineligible patients with newly diagnosed multiple myeloma.8

Disclosure: Dr. Niesvizky reported no potential conflicts of interest.

References

1. Niesvizky R: Trials of new agents in multiple myeloma. 2013 Chemotherapy Foundation Symposium. Presented November 6, 2013.

2. Mateos MV, Hernandez M-T, Giraldo P, et al: Lenalidomide plus dexamethasone for high-risk smoldering multiple myeloma. N Engl J Med 369:438-447, 2013.

3. Richardson PG, Mark TM, Lacy MC: Pomalidomide: New immunomodulatory agent with potent antiproliferative effects. Crit Rev Oncol Hematol 88(suppl 1):S36-S44, 2013.

4. Mark TM, Rodriguez M, Shah M, et al: (Clarithromycin/[Biaxin®], pomalidomide, dexamethasone) therapy in relapsed or refractory multiple myeloma. Blood 118(ASH Annual Meeting Abstracts):Abstract 635, 2011.

5. Wang M, Martin T, Bensinger W, et al: Phase 2 dose-expansion study (PX-171-006) of carfilzomib, lenalidomide and low-dose dexamethasone in relapsed or progressive multiple myeloma. Blood 122:3122-3128, 2013.

6. Jakubowiak AJ, Dytfeld D, Griffith KA, et al: A phase 1/2 study of carfilzomib in combination with lenalidomide and low-dose dexamethasone as a frontline treatment for multiple myeloma. Blood 120:1801-1809, 2012.

7. Moreau P: CMP—carfilzomib (CFZ) plus melphalan-prednisone (CMP)—in elderly patients with newly diagnosed multiple myeloma (NDMM): Results of a phase 1/2 trial. 2013 Congress of the European Hematology Association. Abstract P224. Presented June 14, 2013.

8. Phase 3 study of carfilzomib, melphalan, prednisone vs bortezomib, melphalan, prednisone in newly diagnosed multiple myeloma (CLARION). Available at www.clinicaltrials.gov. Accessed November 21, 2013.


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Commenting on the evidence for treating precursor myeloma in the study by Mateos et al,Kenneth C. Anderson, MD, Kraft Family Professor of Medicine at Harvard Medical School and Director of the Jerome Lipper Multiple Myeloma Center and LeBow Institute for Myeloma Therapeutics at Dana-Farber Cancer ...

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