ONCOLOGY.
No. 3
Supplement No. 3
Tailoring Treatment for Multiple Myeloma Patients With Relapsed and Refractory Disease
By Paul G. Richardson, MD1, Jacob Laubach, MD2, Constantine Mitsiades, MD, PhD3, Robert L. Schlossman, MD4, Deborah Doss, BSN, RN5, Kathleen Colson, RN5, Mary L. Mckenney, NP6, Kimberly Noonan, NP6, Diane L. Warren7, Irene M. Ghobrial, MD4, Nikhil C. Munshi, MD8, Kenneth Anderson, MD9 |
March 8, 2010
1Associate Professor of Medicine Harvard Medical School, Clinical Director, Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute
2Instructor of Medicine, Harvard Medical School Dana-Farber Cancer Institute
3Instructor of Medicine, Harvard Medical School
4Assistant Professor of Medicine, Harvard Medical School Dana-Farber Cancer Institute
5Research Nurse, Dana-Farber Cancer Institute
6Nurse Practitioner, Dana-Farber Cancer Institute
7Clinical Research Manager, Dana-Farber Cancer Institute
8Associate Professor of Medicine Harvard Medical School; Associate Director, Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute
9Professor of Medicine, Harvard Medical School; Director, Jerome Lipper Center for Multiple Myeloma Dana-Farber Cancer Institute, Boston, Massachusetts
One approach to the treatment of progressive MM is to consider strategies that lengthen TTP, even in the face of more modest ORR. For patients who responded to a first or subsequent line of treatment and have relapsed after > 1 year, it may be worthwhile to reintroduce the same regimen. Formal investigations have documented good results with bortezomib(Drug information on bortezomib) retreatment, as discussed above, and with second ASCT when TTP was ≥ 2 years.[33] Patients with TTP < 2 years after ASCT or < 1 year after melphalan(Drug information on melphalan) (Alkeran)/prednisone have poorer prognosis and are candidates for bortezomib- or lenalidomide-based combination therapy or clinical trials of novel agents.[34] Another individualized approach is based on type of prior therapy (Table 3). [6,8-10,18,21,22,26,33,35-40] The safety and efficacy of bortezomib and bortezomib-based regimens are similar in patients with and without renal impairment; moreover, bortezomib-based therapy rapidly reverses renal dysfunction in up to 40% of patients with relapsed and refractory MM.[41,42] A subgroup analysis of the APEX trial confirmed that the safety and efficacy of single-agent bortezomib are maintained regardless of renal dysfunction, even with baseline creatinine clearance (CrCl) < 30 mL/min.[43] Reflecting this, the FDA does not suggest bortezomib dosing adjustments for patients with renal insufficiency, including patients on dialysis.[15] According to a subgroup analysis of DOXIL-MMY-3001, both bortezomib/PLD and single-agent bortezomib can improve renal function among patients with baseline CrCl < 60 mL/min.[44] However, patients with renal dysfunction who received bortezomib/PLD were at increased risk of drug-related serious adverse events (28% vs 19% for CrCl < 60 and ≥ 60 mL/min, respectively). Patients with creatinine > 2.5 g/dL were excluded from the MM-009/010 trials, but those with CrCl < 50 mL/min could receive len/dex. Pooled analysis showed that patients with moderate (30 ≤ CrCl < 50 mL/min) or severe (CrCl < 30 mL/min) renal impairment responded to len/dex as well or better than to high-dose dexamethasone(Drug information on dexamethasone) alone.[45] Of 54 patients with renal dysfunction who were treated with len/dex, 78% had improvement in renal function within 4 months. In the expanded access program, lenalidomide ± dexamethasone or prednisone(Drug information on prednisone) was safe and effective when given to 23 patients with relapsed and refractory MM and renal impairment.[46] Compared with 46 patients with normal renal function, however, these patients had significantly higher rates of grade 3/4 thrombocytopenia. The NCCN guidelines on MM management recommend pamidronate (Aredia) or zoledronic acid(Drug information on zoledronic acid) (Zometa) for all myeloma patients with bone disease, including osteopenia (category 1 recommendation).[3] These bisphosphonates are associated with several important adverse events, so patients must be monitored closely. For instance, intravenous bisphosphonates can cause tubular necrosis and focal segmental glomerulosclerosis, and patients receiving them should undergo regular monitoring of urine creatinine and protein levels. Osteonecrosis of the jaw, a more recently recognized complication, is rare and manageable; the possibility of its development should not preclude judicious use of bisphosphonates, particularly in patients with severe bone disease. The American Society of Clinical Oncology recommends limiting the duration of bisphosphonate use to 2 years in patients with responsive or stable myeloma, with drug resumption if additional skeletal-related events occur.[47] Prior to bisphosphonate initiation, patients should obtain a comprehensive dental examination, with particular attention paid to the presence of active infections and sites at high risk for infection. The novel agents themselves are important components of the management of bone disease. According to in vivo and correlative clinical studies, bortezomib both inhibits osteoclasts (ie, bone-resorbing cells) and activates osteoblasts (ie, bone-forming cells).[48-52] There is also promising in vitro evidence that lenalidomide inhibits osteoclast differentiation.[53,54] As patients live longer with improved control of their disease, extramedullary myeloma has become an increasingly important challenge. Involvement is usually multifocal, response to conventional chemotherapy is generally poor, and resistance to treatment is frequent.[55] Response of extramedullary disease to thalidomide(Drug information on thalidomide) may be limited,[55-57] but thalidomide can be used successfully in combination with other agents. Bortezomib seems to be active in extramedullary disease, although the numbers of patients formally studied to date has been small[58] and there is preliminary evidence that lenalidomide is active in extramedullary disease when combined with bortezomib and dexamethasone.[59] Extramedullary disease thus remains particularly difficult to treat in the context of advanced myeloma, and clearly more so than extramedullary disease seen at diagnosis. Patients with relapsed and refractory MM who have extramedullary disease should also be strongly encouraged to participate in clinical trials when appropriate, and off protocol typically need combination approaches including both novel agents and chemotherapy when feasible. The potential to improve responses and survival in patients with relapsed and refractory MM has increased with the introduction of novel therapies. The NCCN-recommended approaches for treating relapsed and refractory MM with bortezomib and/or lenalidomide are single-agent bortezomib, single-agent lenalidomide, bortezomib/dexamethasone, bortezomib/PLD, len/dex, and RVD. Ongoing research into drug resistance, side-effect management, and optimal sequencing of available therapies should inform decisions about future treatment choices for individual patients with relapsed and refractory MM. Participation in clinical trials remains a key priority in accomplishing these goals and provides patients with options that may be especially effective in the face of resistant disease. In this context, a number of new approaches—such as inhibiting heat shock protein 90, histone deacetylase, AkT, and mammalian target of rapamycin (Figure 1), as well as using monoclonal antibodies—show great promise. The need for continuing research on this patient population — and the continued development of new agents—including second-generation proteasome inhibitors, new immunomodulatory agents, and other small molecules—remain paramount.[60]
Financial Disclosure: Dr. Richardson has served on advisory boards for Celgene and Millennium. Dr. Laubach has no potential conflicts of interest to disclose. Dr. Mitsiades has received research support from Amgen, AVEO, EMD Serono, OSI, and Sunesis, and has received honoraria from Bristol-Myers Squibb, Merck, Millennium, and Novartis. Dr. Schlossman has served on speakers' bureaus for Celgene and Millennium. Ms. Doss has served on speakers' bureaus for Celgene and Millennium. Ms. Colson has served on advisory boards for Millennium. Ms. McKenney, Ms. Noonan, and Ms. Warren have no potential conflicts of interest to disclose. Dr. Ghobrial has served on advisory boards for Celgene; has served on speakers' bureaus for Celgene, Millennium, and Novartis; and has received honoraria from Celgene, Millennium, and Novartis. Dr. Munshi has served on advisory boards for Celgene, Millennium, and Novartis. Dr. Anderson has served on advisory boards for, and has received research support and honoraria from, Celgene, Millennium, and Novartis. Acknowledgements: The authors gratefully thank Katie Redman for administrative assistance and Faith Reidenbach for assistance with drafting the manuscript. Address all correspondence to: Paul G. Richardson, MD, Associate Professor of Medicine Harvard Medical School Dana-Farber Cancer Institute 44 Binney St Dana 1B02 Boston, MA 02115 e-mail: paul_richardson@dfci.harvard.edu
Multiple Myeloma Therapy Supplement
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Guidance for Using Newer NCCN-Recommended Salvage Therapies in Patients With Multiple Myeloma Depending on Prior Therapy
Synergistic Anti-MM Activity
