Multiple Myeloma: Improved Treatment Sequencing Means Optimal Outcome

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Electron micrograph of a human plasma cell from bone marrow in multiple myeloma / Phototake
Electron micrograph of a human plasma cell from bone marrow in multiple myeloma / Phototake

Significant improvements in the understanding of the pathogenesis of multiple myeloma coupled with the development of new approaches to treatment are dramatically improving the outlook for many newly diagnosed patients with symptomatic multiple myeloma.

Now, clinicians have better therapeutic options and a deeper understanding of how to sequence them in order to optimize outcomes. Additionally, new treatment guidelines may help patients with low-risk disease avoid the harsh side effects of therapy.

Multiple myeloma is formed by malignant plasma cells.  The American Cancer Society (ACS) estimates there were will be 22,350 new cases diagnosed in 2013 and the disease is known to be slightly more common in men than in women; estimates note 12,440 cases are expected in men compared to 9,910 in women.  However, it is a relatively uncommon cancer with a lifetime risk estimated to be one in 149, according to the ACS.

Several recent studies have confirmed that maintenance therapy with lenalidomide (Revlimid®, Celgene Corporation) may significantly improve the time to progression and overall survival for a significant number of patients with this hematologic disease.  A phase 3, randomized, double-blind, placebo-controlled clinical trial that enrolled patients at 47 centers in the United States found that lenalidomide following induction therapy and hematopoietic stem-cell transplant reduced the risk of disease progression to 20% compared to placebo, which reduced the risk to 44%.1

Among 460 patients (median age, 59) in the trial, 231 were randomly assigned to the lenalidomide arm and 229 to the placebo arm.  All the patients had received prior autologous hematopoietic stem-cell transplantation and had stable (non-progressing) disease.  After a median follow-up of 34 months, the researchers found that 37% of the patients receiving lenalidomide experienced disease progression or had died compared to 58% of the patients in the placebo arm.

Medical oncologist/hematologist Jason Chandler, MD, from the West Clinic, Memphis, TN, said three new studies presented at the 2013 American Society of Clinical Oncology (ASCO) Annual Meeting support the use of lenalidomide in the maintenance setting after autologous stem cell transplant.2-4 These studies suggest that significant delays in disease progression may result from lenalidomide maintenance therapy. Dr. Chandler noted that these studies represent an important advancement in the ongoing effort to develop optimal therapies for multiple myeloma patients. 

“These studies provide a very important confirmation,” he told ChemotherapyAdvisor.com.  “On average, people have been living longer.  At each subsequent year, new agents keep coming out and many have different mechanisms of action.  Some of these agents come with fewer side effects and are more targeted.” 

Greater Benefits with Sequencing of Agents: A New Possibility

The new proteasome inhibitor carfilzomib (Kyprolis™, Onyx Pharmaceuticals) was approved by the United States Food and Drug Administration (FDA) last year to treat multiple myeloma. In addition, several other agents are showing considerable promise.

Another example is pomalidomide (Pomalyst®, Celgene Corporation), an immunomodulatory agent approved earlier this year for the treatment of multiple myeloma. A recent phase I study that enrolled 38 patients found that pomalidomide was safe and effective in patients with multiple myeloma who had experienced disease relapse after treatments with other agents, such as bortezomib and lenalidomide.5 The study showed that pomalidomide provided a minimal or better response for 42% of the patients, a partial response or better for 21%, and a complete response for 3% of the study population.  The agent was given in escalating doses, from 2 to 5 mg per day for 21 of 28 days, in combination with low doses of dexamethasone and it showed encouraging activity with an acceptable level of toxicity.

“We should be able to risk-stratify patients with multiple myeloma by cytogenetic and molecular analyses to be better able to determine appropriate drug combinations for these patients,” said Philip McCarthy, MD, Professor of Oncology at Roswell Park Cancer Institute, Buffalo, NY, in an interview with ChemotherapyAdvisor.com.

Dr. McCarthy added these agents are better tolerated than previous therapies and may provide greater efficacy in some subsets of patients.  Figuring out the best combinations based on side effect profiles and a potential drug benefit is paramount, he said. “Most of these drugs should be given in combination,” he noted.

Personalizing Therapy for Multiple Myeloma

A new set of guidelines, recently published in Mayo Clinic Proceedings, have been developed to better guide clinicians in the management of patients with multiple myeloma.6 The guidelines reflect the opinions of more than 20 myeloma specialists at the Mayo Clinic.

Lead author Joseph Mikhael, MD, a hematologist at the Mayo Clinic in Arizona, commented on how great progress has been made in understanding the disease and developing drug therapies over the past decade.  However, the medical community has not done a good job at optimizing therapy based on a patient's individual risk factors, which previously only included two groups: high risk and standard risk.

The new guidelines include a strong recommendation to enroll patients in clinical trials as the first option for therapy or supportive care and now separate patients into three risk groups: high-risk, intermediate-risk, and low-risk, determined by gene expression profiling. They also place a greater emphasis on delaying stem cell transplant, when possible, in favor of improved chemotherapy options. These guidelines will be regularly updated online (http://mSMART.org).

“The new drug combinations are very promising,” said Alexander Lesokhin, MD, a medical oncologist at Memorial Sloan-Kettering Cancer Center, New York, NY who specializes in treating patients with multiple myeloma and related disorders.  “I think we are in an era of a number of interesting drugs being developed and I think in the next 5 to 10 years there may be paradigm-shifting therapies available.”




References

1. McCarthy PL, Owzar K, Hofmeister CC, et al. Lenalidomide after stem-cell transplantation for multiple myeloma. N Engl J Med. 2012 May 10;366(19):1770-1781.

2. Boccadoro M, Cavallo F, Gay FM, et al. Melphalan/prednisone/lenalidomide (MPR) versus high-dose melphalan and autologous transplantation (MEL200) plus lenalidomide maintenance or no maintenance in newly diagnosed multiple myeloma (MM) patients. J Clin Oncol 31, 2013 (suppl; abstr 8509)

3. Palumbo A, Bringhen S, Rajkumar V, et al. Second primary malignancies (SPM) in newly diagnosed myeloma (MM) patients treated with lenalidomide (Len): Meta-analysis of 6,383 individual patient data (IPD). J Clin Oncol 31, 2013 (suppl; abstr 8517)

4. Kaufman JL, Willey J, Williams ME, et al. Risk-adapted maintenance therapy (MaintRx) after ASCT in first-line therapy for multiple myeloma (MM). J Clin Oncol 31, 2013 (suppl; abstr 8607)

5. Richardson PG, Siegel D, Baz R, et al. Phase 1 study of pomalidomide MTD, safety, and efficacy in patients with refractory multiple myeloma who have received lenalidomide and bortezomib. Blood. 2013 Mar 14;121(11):1961-1967.

6. Mikhael JR, Dingli D, Roy V, et al. Management of Newly Diagnosed Symptomatic Multiple Myeloma: Updated Mayo Stratification of Myeloma and Risk-Adapted Therapy (mSMART) Consensus Guidelines 2013. Mayo Clin Proc. 2013 Apr;88(4):360-76.

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