Br ie f Communicat ion

Renal transplant in plasma cell dyscrasias with lenalidomidetreatment after autologous stem cell transplantationANA SÁNCHEZ QUINTANA, PABLO RÍOS RULL, JOAQUÍN BREÑA ATIENZA and CRISTINA NOTARIO MCDONNELL

Department of Hematology and Hemotherapy, Hospital Universitario Nuestra Señora de la Candelaria, Santa Cruz de Tenerife, Spain

KEY WORDS:autologous stem cell transplantation,

lenalidomide, plasma cell dyscrasias, renal

transplantation.

Correspondence:Miss Ana Sánchez Quintana, Department of

Hematology and Hemotherapy, Hospital

Universitario Nuestra Señora de la Candelaria,

Carretera del Rosario n 145, 38010 Santa Cruz

de Tenerife, Canary Island. Spain. Email:

anasanchezquintana@gmail.com

doi:10.1111/nep.12116

Conflict of interest: The authors declare no

conflict of interest.

ABSTRACT:

Plasma cell dyscrasias (PCD) are a spectrum of diseases characterized byclonal proliferation of plasma cells secreting a monoclonal immunoglobulin.Although considered an incurable disease, a combination of autologousstem cell transplant with novel therapies, including lenalidomide, hasimproved the overall and progression-free survival of these patients. Renalimpairment is an important complication of the disease that, in some cases,progresses to end-stage renal disease. Due to the characteristics of PCD,traditionally these patients have not been candidates for renal transplanta-tion. However, treatment improvement allows a reconsideration of thisperception, especially in younger patients with good performance statusand treatment response. We report two cases of patients diagnosed withPCD undergoing renal transplantation after autologous stem cell transplan-tation, both cases under treatment with lenalidomide. We also report theirperioperative management and their outcome.

Plasma cell dyscrasias (PCD) are a spectrum of diseases char-acterized by clonal proliferation of plasma cells secreting amonoclonal immunoglobulin, the most common beingmultiple myeloma (MM). Although considered an incurabledisease, a combination of autologous stem cell transplant(ASCT) with novel therapies, including lenalidomide, hasimproved the overall and progression-free survival of thesepatients.1–4 Renal impairment (RI) is common in MM. It isdetected in 20–30% of cases at diagnosis and over 50%during the course of the disease. Although most patientsrecover normal renal function with treatment, some patients(2–3%) progress to end-stage renal disease, requiring hae-modialysis. RI is an important cause of morbidity and mor-tality in MM, producing a decline both in quality of life andsurvival rates.5–7 Due to the characteristics of PCD, tradition-ally these patients have not been candidates for renaltransplantation. Risk of recurrence affecting the allograft,increased infection susceptibility and poor prognosis havebeen the usual concerns. However, new drugs allow a recon-sideration of this perception, especially in younger patientswith good performance status and treatment response.8–10

In our experience, lenalidomide has allowed some patientsunder certain conditions to be considered for renal trans-

plantation. Lenalidomide is an antineoplastic, immunomo-dulatory and antiangiogenic drug. Most common side-effects are haematologic toxicity, infection susceptibilityand thromboembolic events. Due to its renal excretion, inpatients with renal failure it requires dosage adjustments toavoid toxicity. There is little experience in the perioperativemanagement of this drug, although the possibility ofincreased infection or impaired healing leads most centres todiscontinue the drug prior to a procedure. However, thetiming of a renal transplant from a cadaveric donor cannot bereliably predicted, so prior withdrawal of lenalidomide is notpossible.

Here we report on two patients diagnosed with PCDundergoing renal transplantation after ASCT, both undertreatment with lenalidomide. We also report theirperioperative management and their outcome. Table 1 sum-marises patient characteristics.

DESCRIPTIVE CASES

The first patient was a 38-year-old male with light chaindeposition disease (Randall type) diagnosed by renal biopsyin the context of acute renal failure and nephrotic range

bs_bs_banner

Nephrology 18 (2013) 641–643

© 2013 The AuthorsNephrology © 2013 Asian Pacific Society of Nephrology 641

proteinuria. Monoclonal component was not observed inserum or urine. Bone marrow aspirate showed 10% infiltra-tion by plasma cells with a pathological immunophenotype(CD 138 positive, CD 38 weak positive, CD 56 negative, CD19 negative) in 86% of the cells. Fluorescence in situ hybridi-zation (FISH) was also performed on plasma cells, demon-strating the presence of t (11; 14) in 22%, which confirmedthe clonality of the process.

The patient received high-dose dexamethasone and inten-sification of treatment with ASCT. During ASCT his renalfunction worsened and he remained dialysis-dependent.Eight months later a biological progression was detected, solenalidomide was started with doses adjusted as for patientson haemodialysis (5 mg/day). Due to haematological toxicitymultiple dose adjustments were required. A completeresponse (CR) was achieved and maintained for 4 years, sothe patient was considered a suitable candidate for renaltransplantation. Lenalidomide treatment was discontinuedthe day of surgery and resumed 10 days later without majorcomplications. Since then, a dose escalation was performedfrom 5 mg to 25 mg with acceptable haematologic toxicity.He received steroids and tacrolimus as immunosuppressantdrugs. One month after the transplant an acute rejection wassuspected so treatment with mycophenolate mofetil wasstarted. However, rejection was not confirmed, so thiswas discontinued. Eight years after diagnosis the patientremains in CR with a functional allograft and withlenalidomide as maintenance therapy (10 mg/day).

The second patient was a 44-year-old female with Bence-Jones MM, stage IIIB, who required haemodialysis ever sincediagnosis. She was treated with VAD chemotherapy (vincris-tine, adriamycin and dexamethasone) and intensificationwith ASCT, achieving a very good partial response (VGPR).

On day +100 maintenance treatment was started with tha-lidomide. Two years later thalidomide was replaced bylenalidomide because of secondary neuropathy and with theaim of improving the response obtained in order to assess thefeasibility of a renal transplant. The treatment was started atan adjusted dose of 5 mg/day, which required reduction(5 mg dialysis days) due to haematologic toxicity. After 2years on lenalidomide, a VGPR was sustained. Due to thestabilization of the disease the patient was accepted for renaltransplantation. Transplant was performed without furthercomplications, discontinuing the cycle of lenalidomide onthe day of surgery. Fifteen days post transplant, lenalidomide5 mg per day was resumed with good tolerance. Steroids andtacrolimus were used as primary immunosuppression. Thepatient continues with VGPR 7 years after diagnosis and 3years after renal transplant, receiving 10 mg/day lenali-domide as maintenance therapy and with no signs of allo-graft rejection.

DISCUSSION

These cases demonstrate that renal transplantation in PCDpatients may be considered as a therapeutic option, espe-cially in dialysis-dependent younger patients with a goodperformance status and if sustained remission can beachieved. It has been demonstrated that this procedureimproves the quality of life and even produces higher sur-vival rates than dialysis.11 Furthermore, by increasing renalclearance, better tolerance to subsequent treatments can beachieved. As an example, our two patients were receivinglenalidomide prior to renal transplant with difficult manage-ment due to haematologic toxicity. After renal transplanta-tion, lenalidomide was restarted at the prior dose, but in bothcases a progressive increase was possible in the absence oftoxicity.

Despite the limited experience of the perioperative man-agement, lenalidomide was discontinued on the day of trans-plantation, and resumed once the patients were able totolerate oral diet. No problems were found in healing, infec-tious or thrombotic complications postoperatively.

Immunosuppressive therapy with steroids and tacrolimusfor prophylaxis of solid organ rejection was used in bothcases. After 4 and 3 follow-up years respectively, no signifi-cant infections or ongoing rejection episodes were noted.Although an acute rejection was suspected in one case, it wasnot confirmed. Neither patient developed cytomegalovirus(CMV) infection/disease or evidence of polyoma virusnephropathy.

Lenalidomide is an immunomodulatory drug, which hasbeen associated with a higher incidence of infection andsecond primary malignancies. Despite this, lenalidomide isalso known to enhance T-and NK-cell activity against PCDcells, so it hypothetically may increase the risk of rejection.Although there is little experience regarding the use oflenalidomide in transplant recipients, we believe that stand-

Table 1 Patient characteristics

Case 1 Case 2

Sex Male Female

Age 38 44

Diagnosis Randall BJ MM κHaemodialysis After AHCT At diagnosis

Treatment Dexamethasone

ASCT

VAD

ASCT

ASCT response CR VGPR

Time between transplants

(years)

4 4

Donor Cadaveric Cadaveric

Follow-up after renal

transplant (years)

4 3

Immunosuppression Steroids

Tacrolimus

Mycophenopate

mofetil (1 month)

Steroids

Tacrolimus

ASCT, autologous stem cell transplant; BJ MM, Bence-Jones Multiple Myeloma;

CR, complete response; VAD, vincristine, adriamycin and dexamethasone;

VGPR, very good partial response.

A Sánchez Quintana et al.

© 2013 The AuthorsNephrology © 2013 Asian Pacific Society of Nephrology642

ard immunosuppression must be maintained; however,patients should be monitored closely for evidence of infec-tion or the development of malignancy.

In conclusion, this experience supports the feasibility ofrenal transplantation for younger patients with PCD under-going ASCT who achieve a satisfactory response. Thesepatients may also benefit from novel agents such aslenalidomide after ASCT to maintain or even improve theinitial response. Lenalidomide did not increase surgical com-plications or post-transplant toxicity, although the side-effects in combination with standard immunosuppressivetreatment remain to be fully evaluated.

REFERENCES

1. Brenner H, Gondos A, Pulte D. Expected long-term survival of

patients diagnosed with multiple myeloma in 2006–2010.

Haematologica 2009; 94: 270–95.

2. Kumar SK, Rajkumar SV, Dispenzieri A et al. Improved survival in

multiple myeloma and the impact of novel therapies. Blood 2008;

111: 2516–20.

3. McCarthy PL, Owzar K, Hofmeister CC et al. Lenalidomide after

stem-cell transplantation for multiple myeloma. N. Engl. J. Med.

2012; 366: 1770–81.

4. Attal M, Lauwers-Cancer V, Marit G et al. Lenalidomide

maintenance after stem-cell transplantation for multiple myeloma.

N. Engl. J. Med. 2012; 366: 1782–91.

5. Eleutherakis-Papaiakovou V, Bamias A, Gika D et al. Renal failure

in multiple myeloma: Incidence, correlations, and prognostic

significance. Leuk. Lymphoma 2007; 48: 337–241.

6. Torra R, Blade J, Cases A et al. Patients with multiple myeloma

requiring long-term dialysis: Presenting features, response to

therapy, and outcome in a series of 20 cases. Br. J. Haematol. 1995;

91: 854–9.

7. Penfield JG. Multiple Myeloma in end-stage renal disease. Semin.

Dial. 2006; 19: 329–34.

8. Bansal T, Garg A, Snowden JA, McKane W. Defining the role of

renal transplantation in the modern management of multiple

myeloma and other plasma cell dyscrasias. Nephron Clin. Pract.

2012; 120: c228–c235.

9. Wirk B. Renal failure in multiple myeloma: A medical emergency.

Bone Marrow Transplant. 2011; 46: 771–83.

10. Van Bommel EFH. Multiple myeloma treatment in

dialysis-dependent patients: To transplant or not to transplant?

Nephrol. Dial. Transplant. 1996; 11: 1486–7.

11. Nayak L, Lazarus HM. Renal allografts in plasma cell myeloma

hematopoietic cell graft recipients: On the verge of an explosion?

Bone Marrow Transplant. 2013; 48: 338–45.

Renal transplant in plasma cell dyscrasias

© 2013 The AuthorsNephrology © 2013 Asian Pacific Society of Nephrology 643