Introduction
Multiple myeloma (MM) is a clonal B cell malignancy characterized by a progressive clinical course, usually within 3 to 5 years from diagnosis. 1 The introduction of novel agents such as thalidomide, bortezomib or lenalidomide in the framework of high-dose or conventional chemotherapy programs has significantly improved patients’ outcome and survival. 2 Patients who are refractory or those who relapse after new agents-containing regimens, however, do still represent a therapeutic challenge, 3 especially in case of advanced age and presence of co-morbidities. Renal failure occurs in approximately 20–30% of MM patients at diagnosis and in more than 50% of patients with advanced disease. 4 Salvage therapy in these patients is difficult, due to the necessity to avoid potentially nephrotoxic drugs or compounds that are excreted by the kidney and, until a few years ago, the options were limited to VAD or other high-dose dexamethasone containing regimens. Recently, however, both thalidomide 5 and bortezomib 6 have proven effective in reverting renal failure in MM patients responding to treatment, with an acceptable toxicity profile. Lenalidomide is frequently considered a second-choice drug for MM patients with renal failure as it is catabolized through the kidney 7 and its use has been initially associated with an increased hematological toxicity in patients with impaired renal function. 8 – 11 Recent observations, however, have pointed out that improvement of renal function can be achieved, in case a response is obtained, 10 – 13 and that side effects are easily manageable in case a proper dose reduction is performed. 10 – 15 Aim of the present study was to investigate the efficacy and the toxicity profile of lenalidomide-dexamethasone combination in a series of elderly patients with advanced, relapsed or refractory multiple myeloma and renal failure.
Patients and Methods
Patients
Twenty consecutive patients (9 male, 11 female, median age = 76.5 years, range 68–85 years) with relapsed (n= 7) or refractory (n = 13) multiple myeloma with disease-related moderate to severe chronic renal failure, defined as creatinine clearance (Cr Cl) ≤ 50 ml/minute ( Table 1 ) received lenalidomide as salvage treatment at 5 Italian Centers. None of the patient had a pre-existent nephropathy such as nephroangiosclerosis, diabetes or AL-amyloidosis. Previous therapy (1–3 lines) included thalidomide in 9 patients (47%), bortezomib in 17 patients (84%) and autologous stem cell transplantation in 2 patients. Thirteen patients were refractory to the last administered therapy, either to bortezomib (10 patients) or to thalidomide (2 patients) or to both bortezomib and thalidomide (one patient). Eleven patients had a more severe impairment of renal function (CrCl < 30ml/min) and four of them were undergoing hemodyalisis.
Treatment
Lenalidomide was administered on days 1–21 of each 28-days course; dosing was chosen according to the extent of renal impairment, as previously reported. 15 Specifically, two patients with Cr Cl = 50ml/min were treated with full dose (25mg/day), 7 patients with Cr Cl < 30ml/min received 15mg every other day, patients undergoing hemodyalisis were treated at 5mg/day, the remaining patients received 10mg/day. Dexamethasone was used at 20mg/day once a week. All the patients received antithrombotic prophylaxis with either low-molecular weight heparin or aspirin, according to pre-treatment risk of venous thromboembolism, evaluated according to Dimopoulos et al. 16 Treatment was continued until disease progression or occurrence of grade > = 3 non-hematological toxicity.
Clinical and Laboratory Evaluation
Physical examination, quality of life assessment, blood cell counts, serum electrolytes, serum levels of immunoglobulins, serum creatinine, creatinine clearance and Bence-Jones proteinuria were evaluated before treatment and every other week thereafter. Toxicity and adverse events occurring during thalidomide therapy were evaluated according to the WHO grading system.
Assessment of Tumor Response
Response to lenalidomide was assessed after a minimum of 8 weeks; criteria for defining a complete response (CR), a very good partial response (VGPR) a partial response (PR) or a progressive disease (PD) were those reported by the International Myeloma Study Group 17 with the addition of minor response (MR) category, according to Kyle et al. 18
Renal Response
Improvement in renal function, i.e. complete, partial and minor renal response, were evaluated according to recently reported criteria. 19
Results
Response
All the patients but two completed at least 8 weeks of treatment; data were analyzed on an intention – to – treat basis. A ≥ partial response was observed in 8 patients (40%), one of whom obtained a complete response and one a very-good partial response. Four additional patients obtained a minor response, for an overall response rate of 60% ( Table 2 ). Maximal response was achieved after a median of 8 weeks. Median response duration was 16 months (range 2–19+ months) ( Figure 1A ). Seven patients (35%) were refractory to treatment, even though all of them showed a stable disease lasting an average 7.5 months.
Renal Response
Recovery of a normal renal function, defined as creatinine clearance ≤ 60ml/min was observed in 4 out of 8 responding patients (20% of the whole population). Three patients showed an increase in CrCl from < 30 to > 30ml/min (partial response). One further responding patient who was dependent on chronic hemodyalysis showed an improvement of renal function and dyalisis was withdrawn (minor response). No improvement of renal function was observed in patients who were refractory to lenalidomide + dexamethasone therapy.
Toxicity
Toxic effects that were recorded in this series of patients were comparable to those observed in patients with a normal renal function. Neutropenia was the most commonly observed side effect (35% of the patients), although only 3 patients experienced grade ≥3 infections. No patient showed grade ≥3 thrombocytopenia. Dose reduction was necessary in 3 patients while therapy was interrupted after 1 21-day cycle in 2 patients, due to tremors and dizziness (1 patient) and stroke (1 patient), this latter patient received low-molecular heparin prophylaxis. Another patient interrupted the treatment after 5 cycles due to recurrent severe infections
Patient Status and Survival
After 8 months median follow up, 2/8 responding patients showed disease progression; 1 of them died. Five additional non responding patients have died. Overall survival averages 9 months ( Figure 1B ). No second primary tumor was observed.
Discussion
Recently published reports have demonstrated that lenalidomide-based drug combinations are highly effective in in pre-treated advanced MM. 20 Major concerns were risen regarding the use of the drug in patients with renal failure. Although a direct damage to the kidney has not been demonstrated in MM, worsening of renal function has been described in patients with AL. amyloidosis. 21 Lenalidomide is excreted by the kidney, so that its clearance decreases in patients with renal failure, with a consequent 6–12 hours increase in plasma half-life and area-under the curve (AUC). 7 Retrospective evaluation of relapsed/refractory MM patients with some degree of renal impairment treated with full dose Lenalidomide in the context of clinical trials including mainly patients with normal renal function 10 , 11 confirmed the efficacy of the drug but also the occurrence of hematological toxicity, mainly thrombocytopenia that can potentially lead to more frequent treatment discontinuations. Later reports 12 – 14 that were mainly focused on patients with renal failure showed that a proper dose reduction can limit hematological toxicity. We further tested this latter hypothesis by analyzing the data obtained in 20 elderly patients with MM and renal insufficiency. Taking into account that the median age of our patients was higher (76.5 years) than that reported by other studies 10 – 11 , 14 – 15 the first, and most significant observation, is that the drug appeared to be safe, as side effects and toxicity, both hematological and non hematological, were not different or more severe than those observed in patients with a normal renal function. Even though karyotype evaluation was not carried out in our patients, their prognosis can be classified as poor ( high International staging system score, high percentage of thalidomide and/or bortezomib resistance); in spite of that, 40% of the patients obtained at least a partial response, and this figure is similar to that reported in relapsed-refractory patients with a normal renal function, treated with lenalidomide-dexamethasone combination. 20 Overall, a renal response was achieved in eight patients, all of whom showing some degree of disease response. We can thus assume that renal response is strictly dependent on the attainment of a disease response that is a reduced production of light chains, and not on a direct effect on the inflammatory mechanisms that contribute to the pathogenesis of myeloma kidney as it has been described for bortezomib. 22 A bortezomib-containing regimen is generally considered the first choice therapeutic approach for patients with renal failure and MM, either newly diagnosed or relapsed/refractory. All the same however, our study and others 10 – 14 showed that lenalidomide-based drug combination can induce a response even in bortezomib refractory patients, thus indicating that a lenalidomide-based approach should not be overlooked, especially in elderly patients. Oral administration and, above all, the absence of toxic effects that are encountered upon thalidomide or bortezomib therapy, such as lethargy, constipation and peripheral neuropathy, render the drug convenient for long-term use, especially in elderly patients. 23 Our results, although obtained in a small series of patients, confirm that lenalidomide + dexamethasone can represent a useful therapeutic tool for elderly patients even in case of renal failure, provided an appropriate dose reduction and close monitoring of side effects.
Acknowledgements
Work supported in part by RiminiAil. The authors gratefully thank Alfredo Grattini for data collection and technical assistance
Competing interests: The authors have declared that no competing interests exist.
References
1 Kyle RA Rajkumar SV Multiple myeloma N Engl J Med 2004 351 1806 1873 10.1056/NEJMra041875 15509819
2 Kumar SK Rajkumar SV Dispenzieri A Lacy MQ Hayman SR Buadi FK Zeldenrust SR Dingli D Russell SJ Lust JA Greipp PR Kyle RA Gertz MA Improved survival in multiple myeloma and the impact of novel therapies Blood 2008 111 2516 2520 10.1182/blood-2007-10-116129 17975015 PMC2254544
3 Kumar SK Lee JH Lahuerta JJ Morgan G Richardson PG Crowley J Haessler J Feather J Hoering A Moreau P LeLeu X Hulin C Klein SK Sonneveld P Siegel D Blade J Goldschmidt H Jagannath S San Miguel J Orlowski R Palumbo A Sezer O Rajkumar SV Durie BG Risk of progression and survival in multiple myeloma relapsing after therapy with ImiDs and bortezomib: a multicenter international myeloma working group study Leukemia 2012 26 149 157 10.1038/leu.2011.196 21799510 PMC4109061
4 Dimopoulos MA Terpos E Chanan-Khan A Leung N Ludwig H Jagannath S Niesvizky R Giralt S Fermand JP Blade J Comenzo RL Sezer O Palumbo A Harousseau JL Richardson PG Barlogie B Anderson KC Tosi P Cavo M Rajkumar SV Durie BG San Miguel J Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International myeloma working group J Clin Oncol 2010 28 4976 4984 10.1200/JCO.2010.30.8791 20956629
5 Tosi P Zamagni E Tacchetti P Ceccolini M Perrone G Brioli A Pallotti MC Pantani L Petrucci A Baccarani M Cavo M Thalidomide-Dexamethasone as Induction Therapy before Autologous Stem Cell Transplantation in Patients with Newly Diagnosed Multiple Myeloma and Renal Insufficiency Biol Blood Marrow Transplant 2010 16 1115 1121 20197100 10.1016/j.bbmt.2010.02.020
6 Chanan-Khan AA Kaufman JL Metha J Richardson PG Miller KC Lonial S Munshi NC Schlossman R Tariman J Singhal S Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study Blood 2007 109 2604 2606 10.1182/blood-2006-09-046409 17138816
7 Chen N Lau H Kong L Kumar G Zeldis JB Knight R Laskin OL Pharmacokinetics of lenalidomide in subjects wiyh various degrees of renal impairment and in subjects on hemodialysis J Clin Pharmacol 2007 47 1466 1475 10.1177/0091270007309563 17954615
8 Niesvizky R Naib T Christos PJ Jayabalan D Furst JR Jalbrzikowski J Zafar F Mark T Lent R Pearse RN Ely S Leonard JP Mazumdar M Chen-Kiang S Coleman M Lenalidomide-induced myelosuppression is associated with renal dysfunction: adverse events evaluation of treatment-naïve patients undergoing front-line lenalidomide and dexamethasone therapy Br J Haematol 2007 138 640 643 10.1111/j.1365-2141.2007.06698.x 17686058
9 Chen C Reece DE Siegel D Niesvizky R Boccia RV Stadtmauer EA Abonour R Richardson PG Matous J Kumar S Bahlis NJ Alsima M Vescio R Coutre SE Pietronigro D Knight RD Zeldis JB Rajkumar V Expanded safety experience with with lenalidomide plus dexamethasone in relapsed or refractory multiple myeloma Br J Haematol 2009 146 164 170 10.1111/j.1365-2141.2009.07728.x 19545290 PMC2728892
10 Dimopoulos M Alegre A Stadtmauer EA Goldschmidt H Zonder JA de Castro CM Masliak Z Reece D Olesnyckyj M Yu Z Weber DM The efficacy and safety of lenalidomide plus dexamethasone in relapsed and/or refractory multiple myeloma patients with impaired renal function Cancer 2010 116 3807 3814 10.1002/cncr.25139 20564094 PMC2970911
11 Klein U Neben K Hielscher T Heiss C Ho AD Goldschmidt H Lenalidomide in combination with dexameyhasone: effective regimen in patients with relapsed or refractory multiple myeloma complicated by renal impairment Ann Hematol 2011 90 429 43 10.1007/s00277-010-1080-4 20857112
12 Ludwig H Zojer N Renal recovery with lenalidomide in a patient with bortezomib-resistant myeloma Nat Rev Oncol 2010 7 289 294 10.1038/nrclinonc.2010.31 20351701
13 de la Rubia J Roig M Ibanez A Garcia I Vera JA Aguilar C Del Campo R Gonzales N Martinez R Palomera L Picon I Rodriguez JN Sanz M Activity and safety of lenalidomide and dexamethasone in patients with multiple myeloma requiring dialysis: a Spanish multicenter retrospective study Eur J Haematol 2010 85 363 365 10.1111/j.1600-0609.2010.01500.x 20662900
14 Oehrlein K Langer C Sturm I Ponisch W Hahn-Ast C Kuhn S Weisel KC Successful treatment of patients with multiple myeloma and impaired renal function with lenalidomide: results of 4 german centers Clin Lymphoma, myeloma and leukemia 2012 12 191 196 10.1016/j.clml.2012.01.001 22341857
15 Dimopoulos MA Terpos E Goldschmidt H Alegre A Mark T Niesvizky Treatment with lenalidomide and dexamethasone in patients with multiple myeloma and renal impairment Cancer Treat Rev 2012 38 1012 1019 10.1016/j.ctrv.2012.02.009 22609463
16 Dimopoulos MA Palumbo A Attal M Beksac M Davies FE Delforge M Einsele H Hajek R Harousseau JL Leal Da Costa F Ludwig H Mellqvist UH,m Morgan GJ San Miguel JF Zweegman S Sonneveld P Optimizing the use of lenalidomide in relapsed or refractory multiple myeloma: consensus statement Leukemia 2011 25749 760 10.1038/leu.2011.3 21293488
17 Durie BG Harousseau JL Miguel JS Bladé J Barlogie B Anderson K Gertz M Dimopoulos M Westin J Sonneveld P Ludwig H Gahrton G Beksac M Crowley J Belch A Boccadoro M Cavo M Turesson I Joshua D Vesole D Kyle R Alexanian R Tricot G Attal M Merlini G Powles R Richardson P Shimizu K Tosi P Morgan G Rajkumar SV International uniform response criteria for multiple myeloma Leukemia 2006 20 1467 1473 10.1038/sj.leu.2404284 16855634
18 Kyle RA Rajkumar SV Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma Leukemia 2009 23 3 9 10.1038/leu.2008.291 18971951 PMC2627786
19 Dimopoulos MA Roussou M Gkotzamanidou Nikitas N Psimenou E Mparmaparoussi D Matsouka C Spyropoulou-Vlachou M Terpos E Kastritis E The role of novel agents on the reversibility of renal impairment in newly diagnosed symptomatic patients with multiple myeloma Leukemia 2013 27 423 429 10.1038/leu.2012.182 22763386
20 Dimopoulos M Spencer A Attal M Prince HM Harousseau JL Dmoszynska A San Miguel J Hellman A Facon T Foa R Corso A Masliak Z Olesnyckyi M Patin J Zeldis JB Knight RD Lenalidomide plus dexamethasone for relapsed or refractory multiple myeloma N Engl J Med 2007 357 2123 2132 10.1056/NEJMoa070594 18032762
21 Specter R Sanchorawala V Seldin DC Shelton A Fennessey S Finn KT Zeldis JB Dember LM Kidney disfunction during lenalidomide treatment for AL amyloidosis Nephrol Dial Transplant 2011 26 881 886 10.1093/ndt/gfq482 20693160 PMC3108346
22 Sarkozi R Perco P Hochegger K Enrich J Wiesinger M Pirklbauer M Eder S Rudnicki M Rosenkranz AR Mayer B Schramek H Bortezomib-induced survival signals and genes in human proximal tubular cells J Pharmacol Exp Ther 2008 327 645 656 10.1124/jpet.108.142604 18776064
23 Palumbo A Bringhen S Ludwig H Dimopoulos MA Bladé J Mateos MV Rosi-ol L Boccadoro M Cavo M Lokhorst H Zweegman S Terpos E Davies F Driessen C Gimsing P Gramatzki M Hàjek R Johnsen HE Leal Da Costa F Sezer O Spencer A Beksac M Morgan G Einsele H San Miguel JF Sonneveld P Personalized therapy in multiple myeloma according to patient age and vulnerability: a report of the European Myeloma Network (EMN) Blood 2011 118 4519 4529 10.1182/blood-2011-06-358812 21841166