ubmslatePT-logo-ubm

PT Mobile Logo

Search form

Topics:

Current Challenges in the Management of Patients with Relapsed/Refractory Multiple Myeloma: Page 2 of 2

Current Challenges in the Management of Patients with Relapsed/Refractory Multiple Myeloma: Page 2 of 2

Comorbidities and Complications

Relapse in patients with renal failure

Renal dysfunction is common in patients with MM, resulting primarily from the toxic effects of monoclonal light chains on the kidney, and secondarily from hypercalcemia.[41] Dehydration, the use of nephrotoxic drugs (eg, aminoglycosides, nonsteroidal anti-inflammatory drugs [NSAIDs], contrast agents), and rarely, myeloma cell infiltration may also play a role.[41-43]

The efficacy and tolerability of bortezomib-based therapy appears to be good in patients with renal impairment[44] and can reverse renal failure in a substantial number of patients.[45,46] This suggests that bortezomib is an appropriate option for patients with relapsed/refractory MM who have renal failure.[2] Patients whose disease is refractory to, or who cannot tolerate, bortezomib may be candidates for thalidomide- or lenalidomide-based treatment.[2]

Renal excretion of thalidomide is limited, so dose adjustment is not necessary in patients with renal dysfunction.[41,47] However, there are few data on the efficacy of thalidomide in patients with relapsed/refractory MM and renal impairment. In a small series of patients with relapsed/refractory MM and renal failure who were receiving thalidomide alone or in combination with dexamethasone, 15 of 20 patients achieved a major (> 50% decrease in serum or urine M-protein) or minor (> 25% decrease) response.[48] Among these 15 patients, renal function normalized in 12 patients and improved in 2 patients.[48] Although lenalidomide was shown to be excreted renally in a pooled analysis of data from two phase III trials (MM-009 and MM-010), the degree of renal impairment had only a modest effect on the response to lenalidomide + dexamethasone.[49] Creatinine clearance improved in 72% of patients receiving lenalidomide and deteriorated in 1%.[49] However, significantly more patients with moderate or severe renal impairment developed thrombocytopenia or required dose adjustment because of adverse events, compared with patients without renal impairment (P < .05).[49] This suggests the need for dose adjustment of lenalidomide according to the degree of renal impairment, calculated using the Cockcroft-Gault formula.[50] Renal impairment may also limit the use of further cycles of autologous SCT in patients with relapsed/refractory MM because of the increased toxicity of high-dose induction therapy.[43] However, it may be attempted in patients younger than 60 years with chemosensitive disease and good performance status, using a high-dose regimen containing melphalan, 140 mg/m2.[43]

Relapse in patients at risk for venous thromboembolism

If a thalidomide-based or lenalidomide-based combination is indicated, patients at high risk for venous thromboembolism (VTE) should receive thromboprophylaxis with oral anticoagulants or low molecular weight heparin, and those at low risk (≤ 1 VTE risk factor) may receive aspirin prophylaxis.[51] The incidence of VTE with bortezomib is low (0.6% to 1.6%) and is unaffected by concomitant dexamethasone or erythropoietin use.[52]

Preliminary data with the next-generation PI carfilzomib suggest that it is associated with a low incidence of VTE,[53] similar to bortezomib. In a phase I study with the novel IMiD pomalidomide, VTE developed in 4 of 24 patients(16.7%),[54] but no VTE events were reported when pomalidomide was administered on alternate days in a second phase I study (n = 20).[55] Further data are needed to clarify the efficacy of daily or alternate-day dosing of pomalidomide in relation to the VTE risk.

Relapse in patients with peripheral neuropathy

Peripheral neuropathy is commonly associated with thalidomide and bortezomib therapies, so careful assessment of neurological function and potential subsequent dose modifications are important components of patient management when using both these agents.[2] Once patients have experienced peripheral neuropathy, they may be more susceptible to the condition as an adverse effect during subsequent therapy. However, the incidence of peripheral neuropathy with lenalidomide was low in the major phase III studies in patients with relapsed/refractory MM.[56,57] Therefore, lenalidomide-based therapy is an appropriate choice for patients with treatment- or disease-related peripheral neuropathy.[2] Of the emerging treatments for MM, carfilzomib appears to have a low potential for causing peripheral neuropathy (even in those with a history of neuropathy) and may be an alternative treatment option for susceptible patients.[53,58,59]

Relapse in patients with corticosteroid-associated toxicity

Patients with preexisting type 2 diabetes mellitus may be at risk for hyperglycemia if treatment includes corticosteroids.[60] Also, those who have developed corticosteroid-related toxicity during previous lines of therapy may benefit from regimens using only a low dose of prednisone; from a corticosteroid-sparing regimen such as bortezomib; or from IMiDs in combination with PLD, an anthracycline, or an alkylating agent.

Relapse after transplantation

In patients who relapse after autologous SCT, treatment decisions will differ depending on the duration of remission following autologous SCT. In patients who relapse within 1 year of an autologous SCT, overcoming drug resistance should be a treatment goal, which may require multidrug therapy utilizing a combination of all potentially effective drugs.[3] Those who achieve a very good PR or CR to the drug cocktail may proceed to allogeneic SCT with reduced-intensity conditioning if a related or unrelated donor is available, or they may receive consolidation/maintenance therapy. Patients who relapse after prolonged remission (eg, 3 or 4 years) may undergo a second autologous SCT; suitable reinduction regimens in these patients may include the original effective treatment protocol or a different combination, usually including one of the novel agents.[3] Many patients fall into an intermediate category, in which their response to the initial SCT was neither brief nor prolonged (eg, 2 to 3 years). In these patients, we favor the sequential (rather than combined) use of novel agents as salvage therapy, switching to an alternative agent when the disease progresses. The possibility of a second transplant or even an allogeneic SCT can be discussed with these patients.[3]

FIGURE

Treatment Options for Patients With Relapsed/Refractory Multiple Myeloma

In patients relapsing after allogeneic transplantation, the first option is to consider whether graft vs host disease (GVHD) has developed. If it has not, the first choice would be to give donor lymphocyte infusions. If the patient has already experienced GVHD, the rescue therapy would be similar to that proposed in the general recommendation/treatment algorithm (Figure). Unfortunately, in many of these patients the allogeneic SCT was performed as a late salvage option, and these patients will have few alternatives left. Probably the best option will be to include them in an experimental trial, providing they meet the inclusion criteria for such a trial. Unfortunately, many experimental trials are very restrictive for patients with a previous allogeneic SCT.

Relapse in frail elderly patients

MM is predominantly a disease of the elderly (median age at diagnosis is 66 years).[61] With increasing survival duration, a higher proportion of the relapsed/refractory population will be in the older age group. However, elderly patients generally have poorer overall health status and more severe disease, making secondary treatment difficult.[62,63] Moreover, clinical trial data in elderly patients, particularly those who are also weak or ailing, are limited, making evidence-based treatment recommendations difficult. Physicians should base treatment decisions for older patients not just on the patient's chronologic age but also on his or her performance status, comorbidities, psychological state, and available social support.[2,63]

Treatment options for elderly patients are suggested in the Figure. Consideration should be given to dose-adjusted regimens such as low-dose dexamethasone or, preferably, prednisone in combination with oral cyclophosphamide or lenalidomide, with the alternative of thalidomide or weekly bortezomib.[2]

The Patient With Relapsed/Refractory Disease: A Treatment Algorithm

In patients with relapsed/refractory MM, one of the most relevant questions is whether to use all of the active drugs at the same time or sequentially. Moreover, it needs to be proved that the combination of a PI plus one IMiD is superior to the combination of either of the two drugs plus an alkylating agent or anthracycline with corticosteroids. In relapsed/refractory MM, four key factors should be assessed to determine the optimal treatment approach.

First, a comprehensive analysis of the patient's previous lines of therapy is vital. This should include the types of drugs and combinations used (eg, alkylating agents, immunomodulators, PIs), the degree and duration of response obtained, and adverse events experienced by the patient.[3] This will allow decisions about the possibility of retreatment with the same drug (alone or in combination, based on previous sensitivity) and avoid the use of agents with little or no effect and those with a known potential for toxicity in that patient. Second, the type of relapse should be considered: is this an aggressive or EM relapse? In those cases a more intensive therapeutic approach would usually be recommended. Third, the clinical situation (particularly comorbidities) and the patient's demographic and socioeconomic situation must be considered. Treatment of relapsed/refractory MM is particularly challenging because of the reemergence or worsening of disease-related complications, patient comorbidities, and cumulative toxicities resulting from previous lines of therapy. Therefore, it is important to take into account any comorbidities (eg, diabetes), performance status/quality of life, bone marrow reserve, renal function, previous toxicities (eg, peripheral neuropathy, VTE), age, life expectancy, insurance coverage, distance from hospital, and living situation (eg, availability of supportive care at home).[3] Fourth, future treatment options should be taken into consideration. For instance, how many treatment lines and new experimental agents are available at the local center or at the referral site for this patient? Also, the patient's cytogenetic profile may be considered, but current evidence for cytogenetic-based therapy in the context of relapsed MM is limited and is sometimes conflicting.[2]

We recently proposed a management algorithm for patients with relapsed/refractory MM that takes into account many of these factors (see Figure).[2] In elderly patients, considerations of quality of life and cost constraints should be carefully weighed. At the initial relapse, the first choice should be to use a new class of drug or a drug combination that is different from the one used for induction, unless the first remission was long enough (progression-free interval > 6 to 9 months) to merit consideration of retreatment with the same regimen. In patients under treatment with a single agent (eg, maintenance with low-dose lenalidomide) who are showing nonaggressive disease progression, the possibility of adding another agent (eg, dexamethasone ± an alkylating agent) before switching to another class of drug can be considered. At second or subsequent relapse, usually after a patient has been treated with bortezomib and at least one IMiD, enrollment in a clinical trial with experimental agents should be encouraged. If the patient is not a candidate for active therapy, palliative treatment with oral cyclophosphamide (50 mg daily) and prednisone (30 mg on alternating days) could be considered.

Conclusion

Choosing an appropriate treatment for patients with relapsed/refractory MM is a complex task requiring consideration of numerous patient-, treatment-, and disease-related factors. Disease- and treatment-related complications, patient comorbidities, and patient age can all affect treatment choices, as can the magnitude and duration of response to previous therapies. Novel agents have transformed the range of treatment options available, and new agents under development offer the opportunity to further expand these choices and improve the therapeutic options for patients with relapsed/refractory MM.

Acknowledgments: The authors would like to thank Catherine Rees, PhD, and Yvonne Yarker, PhD, on behalf of Fishawack Communications for their assistance with manuscript development. This editorial support was funded by Onyx Pharmaceuticals.

Pages

References

REFERENCES

1. Kumar SK, Rajkumar SV, Dispenzieri A, et al. Improved survival in multiple myeloma and the impact of novel therapies. Blood. 2008;111:2516-20.

2. van de Donk NW, Lokhorst HM, Dimopoulos M, et al. Treatment of relapsed and refractory multiple myeloma in the era of novel agents. Cancer Treat Rev. 2011;37:266-83.

3. San Miguel JF. Relapse/refractory myeloma patient: potential treatment guidelines. J Clin Oncol. 2009;27:5676-7.

4. Durie BG, Harousseau JL, Miguel JS, et al. International uniform response criteria for multiple myeloma. Leukemia. 2006;20:1467-73.

5. National Comprehensive Cancer Network (NCCN). Clinical Practice Guidelines in Oncology. Multiple Myeloma. Version 1.2011. National Comprehensive Cancer Network. 2010.

6. Palumbo A, Facon T, Sonneveld P, et al. Thalidomide for treatment of multiple myeloma: 10 years later. Blood. 2008;111:3968-77.

7. Hicks LK, Haynes AE, Reece DE, et al. A meta-analysis and systematic review of thalidomide for patients with previously untreated multiple myeloma. Cancer Treat Rev. 2008;34:442-52.

8. Vogl DT, Stadtmauer EA, Richardson PG, et al. Impact of prior therapies on the relative efficacy of bortezomib compared with dexamethasone in patients with relapsed/refractory multiple myeloma. Br J Haematol. 2009;147:531-4.

9. Wang M, Dimopoulos MA, Chen C, et al. Lenalidomide plus dexamethasone is more effective than dexamethasone alone in patients with relapsed or refractory multiple myeloma regardless of prior thalidomide exposure. Blood. 2008;112:4445-51.

10. Barlogie B, Tricot G, Anaissie E, et al. Thalidomide and hematopoietic-cell transplantation for multiple myeloma. N Engl J Med. 2006;354:1021-30.

11. Sonneveld P, Hajek R, Nagler A, et al. Combined pegylated liposomal doxorubicin and bortezomib is highly effective in patients with recurrent or refractory multiple myeloma who received prior thalidomide/lenalidomide therapy. Cancer. 2008;112:1529-37.

12. Guglielmelli T, Bringhen S, Rrodhe S, et al. Previous thalidomide therapy may not affect lenalidomide response and outcome in relapse or refractory multiple myeloma patients. Eur J Cancer. 2011;47:814-18.

13. Richardson PG, Blood E, Mitsiades CS, et al. A randomized phase 2 study of lenalidomide therapy for patients with relapsed or relapsed and refractory multiple myeloma. Blood. 2006;108:3458-64.

14. Avet-Loiseau H, Soulier J, Fermand JP, et al. Impact of high-risk cytogenetics and prior therapy on outcomes in patients with advanced relapsed or refractory multiple myeloma treated with lenalidomide plus dexamethasone. Leukemia. 2010;24:623-8.

15. Madan S, Lacy MQ, Dispenzieri A, et al. Efficacy of retreatment with immunomodulataory drugs (IMiDs) in patients receiving IMiDs for initial therapy of newly diagnosed multiple myeloma. Blood. 2011;118:
1763-5.

16. Guglielmelli T, Petrucci MT, Saglio G Palumbo A. Thalidomide after lenalidomide: a possible treatment regimen in relapsed refractory multiple myeloma patients. Br J Haematol. 2010;152:108-10.

17. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low dose dexamethasone (pom/dex) is active and well tolerated in lenalidomide refractory multiple myeloma (MM). Leukemia. 2010;24:1934-9.

18. van de Donk NW, Wittebol S, Minnema MC Lokhorst HM. Lenalidomide (Revlimid) combined with continuous oral cyclophosphamide (Endoxan) and prednisone (REP) is effective in lenalidomide/dexamethasone-refractory myeloma. Br J Haematol. 2010;
148:335-7.

19. Richardson PG, Weller E, Jagannath S, et al. Multicenter, phase I, dose-escalation trial of lenalidomide plus bortezomib for relapsed and relapsed/refractory multiple myeloma. J Clin Oncol. 2009;
27:5713-9.

20. Sood R, Carloss H, Kerr R, et al. Retreatment with bortezomib alone or in combination for patients with multiple myeloma following an initial response to bortezomib. Am J Hematol. 2009;84:657-60.

21. Petrucci MT, Blau IW, Corradini P, et al. Efficacy and safety of re-treatment with bortezomib (Velcade©) in patients with multiple myeloma: results from a prospective international phase II trial. 50th Annual Meeting of the American Society of Hematology; December 6-9, 2008; San Francisco, CA. Blood; 2008. Abstract 3690.

22. Richardson P, Jagannath S, Hussein M, et al. Safety and efficacy of single-agent lenalidomide in patients with relapsed and refractory multiple myeloma. Blood. 2009;114:772-8.

23. Jagannath S, Vij R, Stewart K, et al. Final results of PX-171-003-A0, part 1 of an open-label, single-arm, phase II study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). 45th Annual Meeting of the American Society of Clinical Oncology; May 20, 2009; Orlando, FL. J Clin Oncol; 2009. Abstract 8504.

24. Siegel D, Wang M, Kaufman J, et al. Results of an ongoing open-label, phase 2 study of carfilzomib in patients with relapsed and/or refractory multiple myeloma (MM). 33rd World Congress of the International Society of Hematology; Jerusalem, IL. 2010. Abstract 399.

25. Siegel DS, Martin T, Wang M, et al. Results of PX-171-003-A1, an open-label, single-arm, phase 2 (ph 2) study of carfilzomib (CFZ) in patients (pts) with relapsed and refractory multiple myeloma (MM). 52nd Annual Meeting of the American Society of Hematology; December 4-7, 2010; Orlando, FL. Blood; 2010. Abstract 985.

26. Kumar S, Blade J, Goldschmidt H, et al. Natural history of multiple myeloma relapsing after therapy with IMiDs and bortezomib: a multicenter international myeloma working group study. 51st Annual Meeting of the American Society of Hematology; December 5-8, 2009; New Orleans, LA. Blood; 2009. Abstract 2878.

27. Lacy MQ, Hayman SR, Gertz MA, et al. Pomalidomide (CC4047) plus low-dose dexamethasone as therapy for relapsed multiple myeloma. J Clin Oncol. 2009;27:5008-14.

28. Siegel D, Wang L, Orlowski RZ, et al. PX-171-004, an ongoing open-label, phase II study of single-agent carfilzomib (CFZ) in patients with relapsed or refractory myeloma (MM): updated results from the bortezomib-treated cohort. Blood (ASH Annual Meeting Abstracts). 2009;114:Abstract 303.

29. Krejci M, Adam Z, Buchler T, et al. Salvage treatment with upfront melphalan 100 mg/m2 and consolidation with novel drugs for fulminant progression of multiple myeloma. Ann Hematol. 2010;89:483-7.

30. Varettoni M, Corso A, Pica G, et al. Incidence, presenting features and outcome of extramedullary disease in multiple myeloma: a longitudinal study on 1003 consecutive patients. Ann Oncol. 2010;21:
325-30.

31. Katodritou E, Gastari V, Verrou E, et al. Extramedullary (EMP) relapse in unusual locations in multiple myeloma: is there an association with precedent thalidomide administration and a correlation of special biological features with treatment and outcome? Leuk Res. 2009;33:1137-40.

32. Raanani P, Shpilberg O, Ben-Bassat I. Extramedullary disease and targeted therapies for hematological malignancies—is the association real? Ann Oncol. 2007;18:7-12.

33. Rosinol L, Cibeira MT, Blade J, et al. Extramedullary multiple myeloma escapes the effect of thalidomide. Haematologica. 2004;89:832-6.

34. Damaj G, Mohty M, Vey N, et al. Features of extramedullary and extraosseous multiple myeloma: a report of 19 patients from a single center. Eur J Haematol. 2004;73:402-6.

35. Biagi JJ, Mileshkin L, Grigg AP, et al. Efficacy of thalidomide therapy for extramedullary relapse of myeloma following allogeneic transplantation. Bone Marrow Transplant. 2001;28:1145-50.

36. Yasuda H, Ando J, Sato E, et al. Successful treatment of extramedullary tumors with low-dose thalidomide in patients with multiple myeloma. Intern Med. 2010;49:2617-20.

37. Ali R, Ozkalemkas F, Ozkan A, et al. Bortezomib and extramedullary disease in multiple myeloma: the shine and dark side of the moon. Leuk Res. 2007;
31:1153-5.

38. Chim CS, Hwang YY, Pang C , Shek TW. Restoration of chemosensitivity by bortezomib: implications for refractory myeloma. Nat Rev Clin Oncol. 2009;6:
237-40.

39. Dytfeld D, Matuszak M, Lewandowski K, Komarnicki M. Bortezomib in combination with thalidomide and dexamethasone—a successful treatment regimen in refractory extramedullary multiple myeloma. Ann Hematol. 2008;87:253-4.

40. Dimopoulos MA, Kastritis E, Christoulas D, et al. Treatment of patients with relapsed/refractory multiple myeloma with lenalidomide and dexamethasone with or without bortezomib: prospective evaluation of the impact of cytogenetic abnormalities and of previous therapies. Leukemia. 2010;24:1769-78.

41. Dimopoulos MA, Kastritis E, Rosinol L, et al. Pathogenesis and treatment of renal failure in multiple myeloma. Leukemia. 2008;22:1485-93.

42. Gay F, Palumbo A. Management of disease- and treatment-related complications in patients with multiple myeloma. Med Oncol. 2010;27(suppl 1):S43-52.

43. Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010;28:
4976-84.

44. San-Miguel JF, Richardson PG, Sonneveld P, et al. Efficacy and safety of bortezomib in patients with renal impairment: results from the APEX phase 3 study. Leukemia. 2008;22:842-9.

45. Chanan-Khan AA, Kaufman JL, Mehta J, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood. 2007;109:2604-6.

46. Ludwig H, Drach J, Graf H, et al. Reversal of acute renal failure by bortezomib-based chemotherapy in patients with multiple myeloma. Haematologica. 2007;92:1411-4.

47. Gay F, Palumbo A. Multiple myeloma: management of adverse events. Med Oncol. 2010;27:646-53.

48. Tosi P, Zamagni E, Cellini C, et al. Thalidomide alone or in combination with dexamethasone in patients with advanced, relapsed or refractory multiple myeloma and renal failure. Eur J Haematol. 2004;73:98-103.

49. Dimopoulos M, Alegre A, Stadtmauer EA, et al. The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple myeloma patients with impaired renal function. Cancer. 2010;116:3807-14.

50. Dimopoulos MA, Palumbo A, Attal M, et al. Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement. Leukemia. 2011;25:749-60.

51. Palumbo A, Rajkumar SV, Dimopoulos MA, et al. Prevention of thalidomide- and lenalidomide-associated thrombosis in myeloma. Leukemia. 2008;22:
414-23.

52. Lonial S, Richardson PG, San Miguel J, et al. Characterisation of haematological profiles and low risk of thromboembolic events with bortezomib in patients with relapsed multiple myeloma. Br J Haematol. 2008;143:222-9.

53. Singhal SB, Siegel DS, Martin T, et al. Pooled safety analysis from phase (ph) 1 and 2 studies of carfilzomib (CFZ) in patients with relapsed and/or refractory multiple myeloma (MM). 52nd Annual Meeting of the American Society of Hematology; December 4-7, 2010; Orlando, FL. Blood; 2010. Abstract 1954.

54. Schey SA, Fields P, Bartlett JB, et al. Phase I study of an immunomodulatory thalidomide analog, CC-4047, in relapsed or refractory multiple myeloma. J Clin Oncol. 2004;22:3269-76.

55. Streetly MJ, Gyertson K, Daniel Y, et al. Alternate day pomalidomide retains anti-myeloma effect with reduced adverse events and evidence of in vivo immunomodulation. Br J Haematol. 2008;141:41-51.

56. Dimopoulos M, Spencer A, Attal M, et al. Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma. N Engl J Med. 2007;357:
2123-32.

57. Weber DM, Chen C, Niesvizky R, et al. Lenalidomide plus dexamethasone for relapsed multiple myeloma in North America. N Engl J Med. 2007;357:2133-42.

58. Vij R, Kaufman JL, Jakubowiak A, et al. Carfilzomib: high single-agent response rate with minimal neuropathy even in high-risk patients. 52nd Annual Meeting of the American Society of Hematology; December 4-7, 2010; Orlando, FL. Blood; 2010. Abstract 1938.

59. Martin T, Singhal S, Vij R, et al. Baseline peripheral neuropathy does not impact the efficacy and tolerability of the novel proteasome inhibitor carfilzomib (CFZ): results of a subset analysis of a phase 2 trial in patients with relapsed and refractory multiple myeloma (R/R MM). 52nd Annual Meeting of the American Society of Hematology; December 4-7, 2010; Orlando, FL. Blood; 2010. Abstract 3031.

60. Chen CI, Nanji S, Prabhu A, et al. Sequential, cycling maintenance therapy for post transplant multiple myeloma. Bone Marrow Transplant. 2006;37:
89-94.

61. Kyle RA, Gertz MA, Witzig TE, et al. Review of 1027 patients with newly diagnosed multiple myeloma. Mayo Clin Proc. 2003;78:21-33.

62. Mehta J, Cavo M, Singhal S. How I treat elderly patients with myeloma. Blood. 2010;116:2215-23.

63. Palumbo A, Gay F. How to treat elderly patients with multiple myeloma: combination of therapy or sequencing. Hematology Am Soc Hematol Educ Program. 2009;566-77.

64. Anderson KC, Kyle RA, Rajkumar SV, et al. Clinically relevant end points and new drug approvals for myeloma. Leukemia. 2008;22:231-9.

65. Kyle RA, Rajkumar SV. Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma. Leukemia. 2009;23:3-9.

66. Niesvizky R, Richardson PG, Rajkumar SV, et al. The relationship between quality of response and clinical benefit for patients treated on the bortezomib arm of the international, randomized, phase 3 APEX trial in relapsed multiple myeloma. Br J Haematol. 2008;
143:46-53.

67. Rajkumar SV, Harousseau JL, Durie B, et al. Consensus recommendations for the uniform reporting of clinical trials: report of the International Myeloma Workshop Consensus Panel 1. Blood. 2011;
117:4691-95.

 
Loading comments...

By clicking Accept, you agree to become a member of the UBM Medica Community.