Transplant Onconephrology in Patients With Kidney Transplants

Abstract

Cancer is a leading cause of death in patients with kidney transplantation. Patients with kidney transplants are 10- to 200-times more likely to develop cancers after transplant than the general population, depending on the cancer type. Recent advances in cancer therapies have dramatically improved survival outcomes; however, patients with kidney transplants face unique challenges of immunosuppression management, cancer screening, and recurrence of cancer after transplant. Patients with a history of cancer tend to be excluded from transplant candidacy or are required to have long cancer-free wait time before wait-listing. The strategy of pretransplant wait time management may need to be revisited as cancer therapies improve, which is most applicable to patients with a history of multiple myeloma. In this review, we discuss several important topics in transplant onconephrology: the current recommendations for pretransplant wait times for transplant candidates with cancer histories, cancer screening post-transplant, post-transplant lymphoproliferative disorder, strategies for transplant patients with a history of multiple myeloma, and novel therapies for patients with post-transplant malignancies. With emerging novel cancer treatments, it is critical to have multidisciplinary discussions involving patients, caregivers, transplant nephrologists, and oncologists to achieve patient-oriented goals.

Graphical Abstract

Cancer is a leading cause of death in kidney transplant recipients. Recent advancements in cancer treatment have changed the landscape of pretransplant and post-transplant management. Recently, the Transplant Cancer Match Study showed that cancer incidence has not changed over the past 3 decades and patient outcomes (death with functioning allograft or death-censored allograft failure) have not changed except for patients with non-Hodgkin’s lymphoma.¹ Thus, there is an unmet clinical need to improve patient outcomes in kidney transplant recipients with cancer. In this review, we discuss important topics of transplant onconephrology, focusing on pretransplant wait time, management of multiple myeloma, cancer screening post-transplant, and emerging novel cancer therapies.

Pretransplant Wait Time for Prior Malignancies

Timing of transplantation in patients with a history of preexisting malignancy is of significant debate. Several guidelines have been proposed, with the most recent by Al-Adra and colleagues.^2,3 The guidelines are based on a consensus conference in 2019 between transplant professionals and oncologists. Although not comprehensive, they cover the most commonly encountered malignancies. The guidelines were predominantly based on cancer outcomes in the general population, as data in transplanted populations remain limited. Cancer risk stratification was based on TNM (tumor, node, metastasis) staging as well as recent advances including tumor marker analysis and epigenetics. In general, wait times are based on a benchmark of expected 5-year cancer survival rate of 80% or more. The suggested wait times range from no wait time to 2 years for low-grade disease and up to 5 years for high-grade disease. Below is a brief summary of proposed wait times based on cancer type (Table 1). Guidelines for stage 4 disease are not covered as in most cases these patients are not candidates for transplantation. For a more comprehensive review, it is suggested to reference the original manuscript.

Table 1.

Recommendation on Cancer-free Wait Time

Cancer Type	Classification	Recommended Wait*	Comments
Breast
	DCIS/stage 1	No wait
	Stage 2	1-2 years
	Stage 3	3-5 years
Colorectal
	Stage 1 (T1 or T2,N0,M0)	1-2 years
	Stage 2 (T3,N0,M0)	2 years
	Stage 2 (T4,N0,M0)	3-5 years	5 years for high-risk features
	Stage 3 (N+)	5 years
Anal
	Invasive, HPV-related	5 years
Prostate
	PSA < 10, Gleason < 6,T1-T2a	No wait	If nomogram CS death over 15 yrs < 10%
	PSA > 10, Gleason 7 (Grade 2,3) T2b	No wait
	PSA > 20 ng/mL, high volume Gleason 7	No wait	Treatment suggested
	Gleason 8-10, T3
Renal cell
	T1a (<4 cm) N0, M0	No wait
	T1b (>4 cm ≤ 7 cm) N0, M0, Fuhrman grade G1-2	No wait
	T1b (>4 cm ≤ 7 cm) N0, M0, Fuhrman grade G3-4	1-2 years
	T3 or T4 tumors	2 years minimum
Bladder
	Low risk NMIBC	6 months	If no recurrence at 6 months
	Intermediate risk NMIBC	6 months	If no recurrence at 6 months
	High risk NMIBC	2 years	After therapy
	Muscle invasive	2 years	After radical cystectomy
Gynecologic
	Stage 1A, 1B, grade 1-2 endometrial cancer without lymph-vascular space invasion	No wait
	Stage 1A. 1B, 1C grade 1-2 epithelial ovarian cancer
	Stage 1A1, 1A2 squamous/adenocarcinoma of the cervix
	Stage 1 and 2 endometrial cancer with risk factors and Stage 1b cervical cancer	2-3 years
	Serous, clear cell or carcinosarcoma of the uterus (all stages)	5 years
	Stage 3 grade 1-3 endometrial cancer of the uterus
	Stage 2,3 epithelial ovarian cancer
	Stage 2,3 squamous cell/adenocarcinoma cervical cancer
Non-small cell lung
	Early-stage disease (<1b)	3-5 years
	Stage 1b-3a	5 years
Melanoma
	In situ	No wait time
	Stages ≤ 2a	1 year
	Stage 3a	1-2 years
	Stage 2b, 2c, 3b	2-4 years
Lymphoma
		2 years after remission

Abbreviations: CS death, cancer-specific death; DCIS, ductal carcinoma in situ; NMIBC, non–muscle-invasive bladder cancer.

^*Wait times begin after therapy, if therapy is warranted.

Breast Cancer.

Prognostic staging was based on the American Joint Committee on Cancer (AJCC)’s staging manual, 8th edition and include tumor receptor status (ER+/HER2 +). Based on excellent 5-year survival in low-risk disease, it is suggested that there is no recommended wait time for ductal carcinoma in situ (DCIS) and stage 1 disease. For stage 2 disease, a wait time of 1-2 years was suggested and 3-5 years for stage 3 disease. It is suggested that patients with inflammatory cancer or stage IV disease do not undergo transplantation.

Colorectal Cancer.

Prognostic staging was based on the AJCC’s staging manual which was recently refined with emphasis on histopathologic and molecular features. Low-risk features include microsatellite instability without BRAF mutation, while high-risk features include lymphovascular invasion, perineural invasion, mucinous or signet histology, poorly differentiated histology, bowel obstruction, tumor perforation, < 12 lymph nodes examined, and tumor deposits. The suggested wait time for stage 1 disease is 1 year, 2 years for T3 stage 2 disease, and 3-5 years for T4 stage 2 disease or if high-risk features are present. A wait time of 5 years is suggested for stage 3 disease (node-positive disease).

Anal Cancer.

Squamous cell anal cancer accounts for a small portion of gastrointestinal cancers, but it is often associated with human papilloma virus (HPV). Owing to the possibility of worse viral control through immunosuppression, careful consideration before transplant is suggested. For invasive HPV-related anal cancer, the suggested wait time is 5 years.

Prostate Cancer.

Prostate cancer is considered low risk for progression even with immunosuppression. For this reason, wait imes tend to be very short except for high-grade disease. There is no suggested wait time for cancers limited to the prostate. The authors go on to state that surveillance alone is reasonable for most prostate cancers. Treatment is suggested before transplant for high-volume intermediate risk or high risk. These cancers include prostate-specific antigen (PSA) is > 20 ng/mL, high-volume Gleason 7 disease, or any Gleason 8-10 disease.

Renal Cell Carcinoma.

There is no required wait time for small (< 4 cm) incidental renal cell carcinoma (RCC) after resection. For cancers staged T1b (tumor > 4 cm ≤ 7 cm) with Fuhrman grade 1-2, there is nowait time. With 3-4 Fuhrman grade, 1-2 years ofwait time is recommended. For T3 or T4 tumors, a minimum wait time of 2 years is suggested.

Bladder Cancer.

In patients with localized non–muscle-invasive bladder cancer (NMIBC), ecurrence rate is very high, but progression is low. These cancers can often be treated locally. For low-risk NMIBC, patients should have surveillance at 6 months after resection. If no recurrence, transplantation can be performed without further wait. The same is suggested for intermediate-risk NMIBC. For high-risk NMIBC, a wait time of at least 2 years is advised after local and intravesical therapy. In patients with muscle-invasive bladder cancer, transplantation can be considered 2 years after radical cystectomy.

Gynecological Cancers (Endometrial, Ovarian, and Cervical).

These cancers were grouped together based on classification by the International Federation of Gynecologic Oncology. These cancers were classified by 5-year risk of recurrence: low risk (<5%), intermediate risk (5-15%), high risk (>30%), and very high (>80%). There is no suggested waiting time for low-risk disease, which included most stage 1 gynecologic cancers without risk factors, 2-3 years for intermediate-risk disease which included stage I and II endometrial cancer with risk factors and Ib cervical cancer, and 5 years for high-risk disease. Transplantation was not recommended for very high-risk cancers.

Non-Small Cell Lung Cancer.

These cancers remain the leading cause of cancer-related mortality in the US, with most recurrences occurring in the first 2 years after treatment. However, late metastatic recurrences are not uncommon. Therefore, it is suggested that patients with early-stage disease that responded to treatment can be considered transplant candidates after 3-5 years but with caution.

Melanoma.

Owing to recent advances, the prognosis of melanoma has dramatically improved. Wait time of 1 year is suggested in all stages IIa or less, whereas 2-4 years of wait time is suggested for stages IIIb or less. There was no consensus reached for stages above IIIb. These wait times are in stark difference to prior recommendations. It is important to note that much of the improvement in melanoma therapy may be attributed to immune checkpoint inhibitors (ICIs) which increase risks of rejection after transplant. Response to ICIs also suggests that melanoma is a particularly immune-sensitive disease, meaning there is significant potential to worsen melanoma after initiating immunosuppression for transplantation.

Lymphoma.

Several types of lymphoma exist from acute and aggressive to indolent. In general, treated patients with progression-free survival at 2 years have above 80% 5-year cancer-free survival. For this reason, it is suggested that patients with a history of most lymphomas may be transplanted after 2 years from therapy.

Screening for Cancer After Transplantation

After kidney transplantation, cancer occurs at twice the standardized incidence of the general population, and therefore, screening for cancer after transplantation is of utmost importance.⁴ Society recommendations for cancer screening vary.⁵ In general, cancer screening should follow the recommendations for the general population with a few exceptions.

Skin and Lip Cancer.

The most common skin cancers seen are cutaneous squamous cell carcinoma (cSCC) and basal cell carcinoma. Melanoma also occurs more commonly after transplantation. It is therefore advised that skin cancer screening occur annually in all transplant recipients by a physician with experience in skin cancer.⁶

Urologic Malignancies.

No clear guidelines exist for RCC screening of native kidneys after transplantation. Patients with retransplant acquired cystic kidney disease, prior RCC, and analgesic abuse may benefit from screening ultrasonography every 1-3 years after transplantation.^7,8 Transplant recipients with new-onset hematuria should also be evaluated for a urologic malignancy.

Table 2 summarizes recommendations from the American Society of Transplantation (AST) and Kidney Disease: Improving Global Outcomes (KDIGO).^6,9

Table 2.

Recommendation on Cancer Screening After Kidney Transplantation

Screening	KDIGO	AST
Skin/lip	Annual examination	Annual examination
Anogenital		Annual examination
Pelvic exam/Pap smear	Every 3 years	Annually
Mammogram	Annually > age 40	Every 1-2 years
PSA/DRE	Not recommended	Annually age > 50
Colorectal	Same as general population	Same as general population
Lymph node exam		Every 3 months in the first year then annually

Abbreviations: AST, American Society of Transplantation; DRE, digital rectal exam; KDIGO, Kidney Disease: Improving Global Outcomes; PSA, prostate-specific antigen.

Immunosuppression and Cancer Risk

One of the most important risks for cancer after transplantation relates to immunosuppression. There are several manners in which immunosuppression can increase the risk for cancer including reduced immune surveillance, impaired defense mechanism against oncogenic viruses, and drug-specific pathways. The importance of total immunosuppression in cancer risk is highlighted by historic data that suggest heart transplant patients have a higher incidence of malignancy than kidney transplant recipients.^10,11 Similarly, several studies have suggested increased risk for malignancy, in particular post-transplant lymphoproliferative disorders (PTLDs), in patients who have received lymphocyte depletion induction therapy.^12,13 Higher doses of antilymphocyte preparations may also predispose them to post-transplant malignancy.¹⁴ Lymphodepleting induction agents are in contrast to nondepleting agents, such as the IL-2 receptor antibodies, which have not been associated with an increased risk of cancer.

Although net immunosuppression is a risk for post-transplant malignancy, maintenance immunosuppressives differ in neoplastic potential.

Calcineurin Inhibitors.

Both tacrolimus and cyclosporine are associated with an increased risk for malignancy. Several mechanisms have been implicated such as increased production of cytokines including transforming growth factor (TGF)-beta, vascular endothelial growth factor (VEGF), and IL-6. Calcineurin inhibitors also reduce the ability to repair radiation-induced DNA damage important in the pathogenesis of skin cancer.¹⁵ Dantal and colleagues found a lower incidence of malignancy with low-dose cyclosporine than with high-dose cyclosporine.¹⁶ Another study initially suggested a higher incidence of malignancy with tacrolimus over cyclosporine, but was later thought to be related to tacrolimus dose rather than a drug-specific effect.¹⁷

Antimetabolites.

Azathioprine has been implicated in the development of post-transplant malignancy, especially nonmelanoma skin cancer. This may be related to impaired radiation-induced DNA repair and increased development of microsatellite DNA instability.^18,19 Mycophenolate analogs however (mycophenolate mofetil [MMF] and mycophanolic acid [MPA]) have not been found to independently increase the risk for malignancy. In fact, it has been suggested that the incidence of post-transplant malignancy has decreased after introduction of MMF.²⁰ It is unclear if there are specific antitumor properties of MMF or if simply less rejection results in less overall net immunosuppression.

Mammalian Target of Rapamycin Inhibitors.

Several registry-based studies suggest that mammalian target of rapamycin (mTOR) inhibitors may decrease the incidence of post-transplant malignancy compared with other immunosuppressive regimens.^21,22 In fact, everolimus has been used to treat hormone receptor–positive, HER2-negative breast cancer, neuroendocrine tumors, and RCC (brand name Afinitor®). In addition, several case series have reported full resolution of post-transplant Kaposi sarcoma by switching from a calcineurin inhibitor to sirolimus.²³ In the TUMORAPA study, conversion to sirolimus significantly reduced the risk for cSCC relapse compared with calcineurin inhibitors.²⁴ However, a recent study found higher mortality in transplant patients on mTOR inhibitors despite a lower rate of malignancy.²⁵ Antitumor mechanisms include reduced TGF-beta and IL-10 production, direct antitumor effect by inhibiting the mTOR pathway, inhibition of p70 S6K cancer cell proliferation, and inhibition of tumor angiogenesis by decreasing VEGF signaling.^26–31

Belatacept.

Belatacept was initially found to result in an elevated risk for PTLDs, especially with central nervous system involvement.³² Many of these cases occurred in patients who were Epstein-Barr virus (EBV) seronegative, and belatacept now carries a black box warning against its use in such individuals. Long-term extension studies in EBV-positive patients suggest a similar incidence of malignancy as other immunosuppressive agents.³³

Post-Transplant Lymphoproliferative Disorder

Post-transplant lymphoproliferative disorder (PTLD) is a serious complication after transplantation, associated with cumulative exposure to immunosuppression. The prevalence of PTLD is 1-2%, and the mortality is as high as 50%. PTLD occurs in two phases, with one peak in early phase (predominantly EBV-positive, 1-2 years after transplant), and the other peak in late phase (mostly EBV-negative, 7-10 years after transplantation).³⁴ The clinical presentation of PTLD varies from asymptomatic mononucleosis to advanced lymphoma. Lymphoproliferative disease is commonly found in the gastrointestinal tract and central nervous system, and the symptoms at presentation can be nonspecific. Risk factors for PTLD include EBV status mismatch (ie, donor EBV positive to recipient EBV negative), lymphocyte-depleting induction, and pediatric transplantation.³⁵ Treatment approach involves the reduction of immunosuppression, which may achieve objective response rate of 30-40% with an accompanied risk of acute rejection.^36,37 With no randomized trials to guide the reduction of immunosuppression, discontinuation of antimetabolite agents and reduction of calcineurin inhibitors are common.³⁸ If there is no improvement with immunosuppression reduction, additional therapy with chemo/targeted therapy should be considered. The therapeutic approach includes an anti-CD20 agent (eg, rituximab) with or without cytotoxic chemotherapy. A recent phase II study showed rituximab alone or in combination with R–CHOP (rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone) achieved complete remission in 25% of patients.³⁷

More recently, cellular therapies have become available for PTLD: EBV-directed cytotoxic T-cell therapy (EBV-CTL) and chimeric antigen receptor (CAR)-T therapy. EBV-CTL is indicated in patients with EBV-positive PTLD, refractory to other conventional chemotherapy/targeted therapy. Engineered allogeneic EBV-CTL is manufactured and infused in the patients. One product uses HLA-matched EBV-CTL, which achieved objective response rate of 64% at 5 weeks and 52% in 6 months.³⁹ Another product of pooled third party EBV-CTL was tested in pediatric patients, achieving complete remission in 7 and partial response in 1 out of 11 patients.⁴⁰ Another emerging cellular therapy for PTLD is CAR-T therapy. CAR-T cells are the manufactured cellular product derived from patients’ T cells, expressing engineered chimeric antigen receptors (CARs) to target cancer cells. CAR-T therapy has been approved by the FDA for diffuse large B-cell lymphoma (DLBCL)⁴¹ and multiple myeloma⁴² in nontransplant patients and showed promise in refractory cases. However, CAR-T therapy in solid organ transplant patients is challenging owing to presumed higher risk of rejection while on minimal immunosuppression and concern for concomitant immunosuppression therapy, which could theoretically increase in the chance of manufacturing failure of CAR-T therapy. CAR-T therapy consists of multiple steps (Fig 1): leukocyte mobilization, leukapheresis, ex vivo CAR-T manufacturing, lymphodepleting chemotherapy, and CAR-T infusion. In nontransplant patients, acute kidney injury (AKI) and electrolyte abnormalities are common after CAR-T.^43,44 In patients with kidney transplants, in addition to AKI risk, the risk of rejection is thought to be highest in the peri-infusion process. To mitigate rejection while keeping CAR-T effective, several immunosuppression modifications are considered. First, to collect functional T cells by leukapheresis, the immunosuppression should be reduced beforehand, as T cells may be functionally exhausted in the presence of immunosuppression. Some experts suggest reduction to a single agent, prednisone 5-10 mg daily. Second, several days before CAR-T cell infusion, patients receive lymphocyte-depleting therapy with cyclophosphamide with or without fludarabine, which can work as immunosuppressants and may help mitigate the risk of rejection. Third, after the infusion, cytokine release syndrome (CRS) is a common complication. Anti-IL-6 agent (eg, tocilizumab) is approved to treat severe, life-threatening CRS,⁴⁵ and it could potentially help prevent rejection in transplant patients. Krishnamoorthy and colleagues reported 3 cases of PTLD where immunosuppression was not reduced, but all suffered from AKI and poor tumor response.⁴⁶ Mamlouk and colleagues reported another 3 cases with relatively good response in cancer without rejection.⁴⁷ Another group reported similar efficacy without allograft rejection⁴⁸ (Table 3). The data of CAR-T therapy in transplant are evolving, and more studies are needed.

Figure 1.

CAR-T therapy in patient with kidney transplants. Immunosuppression agents need to be minimized 2-3 weeks before leukapheresis (1), to ensure the efficacy of CAR-T manufacturing (2). Lymphodepleting chemotherapy (3) will be administered 3-5 days before CAR-T infusion (4). Risk of acute kidney injury (AKI) and rejection is high during peri-infusion period, along with cytokine release syndrome (CRS). Anti-IL-6 treatment can be used for treatment of CRS.

Table 3.

Case Series of CAR-T Therapy in Solid Organ Transplant

Baseline Characteristics					Disease Characteristics			Therapies Before CAR-T	Immunosuppression Management	CAR-T Adverse Events and Outcomes
Publication	Case #	Age, Gender	Organ Transplant	Immunosuppression	Time from tx (years)	Timor EBV Static	Pathology			CRS Grade	Outcomes
Krishnamoorthy	1	54M	DDKT/Pancreas	Tac/Aza/Pred	20	Negative	DLBCL-GCB	Rituximab alone, R–CHOP	Low-dose tac, pred	1	Death at day 115 due to refractory PTLD
	2	54F	Heart	Tac/MMF/Pred	26	Negative	DLBCL-non-GCB	R–CHOP, R-ICE, lenalidomide	switched from tac tosirolimus	2	AKI requiring RRT, death at day 44 due to GI bleed from refractory PTLD
	3	71M	DDKT	Tac/Aza/Pred	10	Negative	DLBCL-non-GCB	R–CHOP, R-DHAX, ibrutinib.	Stopped	3	AKI requiring RRT, aspergillus pneumonia, VRE bacteremia, death at day 15 from refractory PTLD
Mamlouk	4	38M	Kidney	Tac/MMF/Pred	10	Negative	DLBCL-GCB	R-EPOCH, R-GEM-Ox	M MF. On low dose pred	1	Rejection at 16 weeks, CR at 1 month, up to 7 mo.
	5	44M	Kidney	Sirolimus/Pred	10	Negative	DLBCL-GCB	R–CHOP	Stopped	1	Pneumonia, AW, CR at 1 mo. Relapse at 34 week
	6	41M	Kidney	Sirolimus/Pred	7	Negative	DLBCL-GCB	R-EPOCH, R-GDP, R- ESHAP, Pola-BR	Stopped sirolimus, on low dose pred	None	PR at 1 mo. PD at 3 mo.
Luttwak	7	69 M	DDKT	Tac	25	Negative	DLBCL-GCB	R-daEPOCH, R-GDP, Pola-BR	Tac (2 ng/mL)	1	CR at 1 mo. Relapse at 3 mo.
	8	50F	DDKT	Tac	5	Negative	DLBCL-GCB	R–CHOP, R-ICE + ASCT, gemcitabine	Tac (2 ng/mL)	2	CR at 1 mo. Sustained at 3 mo.
	9	66M	Liver	Tac	8	Negative	DLBCL-non-GCB	R–CHOP, ICE, radiotherapy	Tac (2 ng/mL)	1	PR at 1 mo. Sustained at 3 mo.
Dang	10	17F	Heart	Tac/Pred	0.3	Positive	DLBCL-non-GCB	CYVE, O-ICE, radiation, EBV-CTL, radiation	Pred, low dose tac (1-2 ng/mL)	1	CR at 1 mo. Sustained at 6 mo.
Wang	11	3M	Liver	Tac/Pred	1.8	Positive	Burkitt lymphoma	R–CP, CP, radiation	Pred	2	CR at 2 mo. Sustained at 16 mo.

Abbreviations: ASCT, autologous stem cell transplantation; Aza, azathioprine; CR, complete response; DDKT, deceased kidney transplant; DLBCL, diffuse large B-cell lymphoma; EBV-CTL, EB virus-specific cytotoxic T cell therapy; GCB, germinal center B cell; GDP, gemcitabine, carboplatin and dexamethasone; MMF, mycophenolate mofetil; PR, partial response; PD, progressive disease; Pola-BR, polatuzumab vedotin, bendamustine, rituximab; R–CHOP: rituximab, cyclophosphamide, vincristine, doxorubicin, and prednisone; R-daEPOCH, rituximab, dose-adjusted etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin; R-DHAX, Rituximab, dexamethasone, cytarabine, and oxaliplatin; R-EPOCH, rituximab, etoposide, prednisone, vincristine, cyclophosphamide, and doxorubicin; R-ESHAP, rituximab, etoposide, methylprednisolone,cytarabine, cisplatin; R-GEM-Ox, rituximab, gemcitabine, oxaliplatin; R-ICE, Rituximab, ifosfamide, carboplatin, and etoposide; RRT, renal replacement therapy; Tac, tacrolimus.

Adapted from Schreiber et al.¹¹⁰

Multiple Myeloma, Amyloid Light-chain Amyloidosis, and Kidney Transplantation

Patients with end-stage kidney disease (ESKD) from multiple myeloma (MM) have poor outcomes on dialysis.⁴⁹ Decourt and colleagues showed an adjusted hazard ratio of death of 2.18 in patients with ESKD from monoclonal gammopathies compared with controls.⁴⁹ MM has traditionally been a contraindication to kidney transplantation, owing to reported high relapse rates and high risk of allograft loss.⁵⁰

Over the past 2 decades, there have been extraordinary advancements in the management of this disease with 11 new drugs approved by the FDA improving the average median survival of MM from 20 months to 8 years.^51,52 These drugs can be divided into three groups: proteasome inhibitors (PIs), immunomodulatory drugs, and monoclonal antibodies. The current treatment algorithm for newly diagnosed MM relies on eligibility for auto-stem cell transplantation (ASCT). Eligibility is affected by age, comorbidities, and performance status.⁵³ In ASCT-eligible patients, induction with bortezomib, lenalidomide, and dexamethasone (VRD) is preferred, followed by ASCT and lenalidomide maintenance. In patients with AKI, cyclophosphamide is used for induction instead of lenalidomide.⁵³ In a recent study, the addition of a fourth agent for induction, the monoclonal antibody against CD38 (daratumumab) to VRD, showed added benefit, with more than 90% of patients achieving a very good partial remission (VGPR) or better.⁵⁴

In addition, a powerful prognostic staging system for MM, the Revised International Staging System for Multiple Myeloma (R–ISS) has emerged as the predominant staging tool used by hematologists. Patients with R–ISS stages 1, 2, and 3 had 5-year overall survival rates of 82%, 62%, and 40%, respectively.⁵⁵ Furthermore, sensitive minimal residual disease (MRD) assays detecting low levels of disease in bone marrow samples with next-generation flow cytometry or next-generation VDJ (variability, diversity, and joining) sequencing have been added to response criteria used by hematologists.⁵⁶

Now armed with effective treatment regimens achieving high remission rates, excellent prognostic tools that can aid in risk stratification, and assays that can assess remission on molecular levels, transplant centers should revisit kidney transplantation as feasible and, in many cases, the optimal treatment for ESKD in patients with MM.

Unfortunately, most of the available data on kidney transplantation for patients with ESKD from MM have come from case reports and small case series. Several of the reports include patients who have not been treated with ASCT, or whose regimens did not include the current standard of care. Supplemental Table is adapted from a recent descriptive literature review of all case reports and series and lists the MM and kidney transplant outcomes of patients treated with ASCT⁵⁷ (Supplemental Table).

Similar to MM, amyloid light-chain (AL) amyloidosis has also been a contraindication to kidney transplantation owing to its reported high relapse rates and worse overall survival.⁵⁸ However, also similar to MM, the prognosis for patients with AL amyloidosis has improved as it has become a more treatable disease using many of the same agents as those used for MM. A recent study evaluated the outcomes of 49 patients with AL amyloidosis and kidney transplants and found 1-, 3-, and 5-year graft survival to be 94%, 89%, and 81%, respectively.⁵⁹ The median patient survival from kidney transplantation was 10.5 years. Those patients who achieved a complete remission (CR) or VGPR fared better than those with partial response or no response (NR) after treatment for amyloidosis, which is confirmed in another observational study from UK.⁶⁰

No streamlined protocols are available for the pre–kidney transplant clearance of and post–kidney transplant management of patients with ESKD from multiple myeloma or AL amyloidosis. In the next section, we will illustrate UCSF’s approach to patients with ESKD from MM. A similar strategy is used for patients with ESKD from AL amyloidosis, but given the variable involvement of multiple organ systems in AL amyloidosis, our approach is less protocolized with these patients and, along with our oncology colleagues, clearance is on case-by-case basis.

Medical Evaluation and Kidney Transplant Clearance for Patients with ESKD from MM.

Timing of kidney transplantation for patients with ESKD from MM is critical. For most malignancies, the more time that has transpired since achieving a remission, the less likely the malignancy will relapse. On the contrary, MM is a disease characterized by multiple remissions and relapses, with a first relapse usually occurring approximately 3-4 years after the initial diagnosis.^53,61 Therefore, according to Huskey and colleagues, a strategy of transplanting patients with low-risk myeloma earlier after ASCT and higher risk patients later (or never) should be implemented.⁶² The strategy at UCSF is to wait 1 year after a successful ASCT with the patient having achieved a VGPR or CR before kidney transplantation. Clearance by hematology is required using their expertise to risk stratify and select appropriate candidates (Table 4).

Table 4.

Kidney Transplant Candidate Criteria and Post-Transplant Management for Individuals with Plasma Cell Dyscrasias¹⁰⁹

Transplant Candidate Criteria
1. Living donor or estimated time to deceased donor transplant less than or equal to 2 years
2. No ABO incompatible donors or positive crossmatch
3. Confirmed CR or VGPR for 1 year post-ASCT
4. Bone marrow biopsy within 4 months of kidney transplant (within 1 year if deceased donor transplant)
5. PCD labs within 4 weeks of kidney transplant (within 6 months if deceased donor transplant)
6. Clearance by oncology
7. Fat pad biopsy and cardiac MRI to evaluate for amyloidosis
8. Kidney and bladder ultrasound to evaluate for GU malignancy
9. Hold IMiD for 4 weeks and proteasome inhibitor for 2 weeks pre-transplant (avoid regimens containing IMiDs if possible in deceased donor recipients)
Post-Transplant Management
1. Induction therapy for kidney transplant per PRA
2. Maintenance immunosuppressive regimen consisting of tacrolimus, mycophenolate, and prednisone. Lower dose mycophenolate after re-initiation of PCD-directed therapy
3. Use of PCP prophylaxis and HSV prophylaxis indefinitely due to increased state of immunosuppression from PCD-directed therapy
4. Preferentially treat with proteasome inhibitor or CD38 inhibitor for maintenance, restarting at 2-3 weeks post-transplant
5. More aggressive screening for malignancies including kidney/bladder ultrasound every 1-3 years to rule out urologic malignancy

Abbreviations: ASCT, autologous stem cell transplant; CR, complete response; GU, genitourinary; ImiD, imide; MRI, magnetic resonance imaging; PCD, plasma cell dyscrasia; PCP, pneumocystis pneumonia; PRA, panel reactive antibody; VGPR, very good partial response.

All candidates for kidney transplantation at UCSF will have undergone the current recommended 3-4 drug regimen for induction followed by ASCT.⁵³ Consideration of the number of early relapses and treatment regimens needed to achieve a VGPR or CR is important as treatment regimens for relapses usually need to include 2 or more drugs that the patient is not refractory to.^53,63–65 Therefore, having multiple available agents after kidney transplantation to treat relapses is essential to optimizing kidney transplant outcomes.

For patients with a living donor, IMIDs (thalidomide, lenalidomide, pomalidomide) are held for 4 weeks before their surgery to minimize the risk of thrombotic-related complications perioperatively.⁶⁶ To minimize cytopenias immediately after transplantation, PIs are held (bortezomib, carfilzomib, and ixazomib) for 2 weeks before transplantation. Induction therapy with anti-thymocyte globulin or basiliximab is based on the current institutions’ protocols and is based primarily on calculated panel reactive antibody (cPRA). All patients are maintained on triple therapy with a calcineurin inhibitor, antimetabolite, and prednisone. Steroid-inclusive regimens are implemented, and mTOR inhibitors are avoided mainly to combat the cytopenias that are likely to develop in the setting of the combination of myeloma therapies and antirejection therapies. The antimetabolite dose is reduced once maintenance therapy for myeloma is reinstituted after transplantation, which is usually at 2-4 weeks after transplant.

Maintenance Therapies for Myeloma After Kidney Transplantation.

Multiple studies have demonstrated improved progression-free and overall survival with maintenance therapy after ASCT with IMIDs and PIs.^67–69 Studies evaluating the role of monoclonal antibodies for maintenance after ASCT are ongoing.⁶⁷ In addition to antirejection therapies, most patients with kidney transplants with ESKD from MM will require maintenance therapy for myeloma as well. Intensified immunosuppression in this context may lead to increased risk of infectious complications as well as cytopenias. For the increased infectious risk, patients remain indefinitely on herpes simplex virus (HSV) prophylaxis and pneumocystis prophylaxis after kidney transplant.

There is also the added risk of rejection that has been reported in solid organ transplant recipients treated with immunomodulatory agents after transplantation.^70–73 Despite this documented risk, not all transplant patients treated with IMIDs after solid organ transplant reject.⁶² Transplant centers can still consider using these agents, with careful monitoring, after transplantation.⁶² Bortezomib has been studied in patients with kidney transplants for the treatment of antibody-mediated rejection, and for this reason, PIs are the preferred class of drugs for maintenance therapy after kidney transplant at UCSF.⁷⁴ The anti-CD38 monoclonal antibody daratumumab is also being actively studied in patients with kidney transplants for desensitization and for antibody-mediated rejection and may play a role in maintenance therapy for MM.^67,75,76 However, its potential to inhibit T regulatory cells may promote alloimmune activity against the graft in the form of cell-mediated rejection.²⁷ Finally, anti–B-cell maturation antigen (BCMA) CAR T cell is an exciting advancement in the field of MM; however, owing to its immunomodulatory effects, it may not be an appropriate agent for solid organ transplant recipients because of the risk of rejection.^42,46,77

Other Considerations: Malignancy Screening.

Several of the agents used to treat MM are also associated with secondary malignancies.^78,79 For patients with kidney transplants with MM, the risk for de novo malignancies may be compounded by these factors and current guidelines for screening after kidney transplant may not be sufficient. In addition to currently recommended cancer screening, at UCSF, we screen patients with MM for urologic malignancies with urinalyses looking for microscopic hematuria and native and kidney transplant ultrasounds every 1-3 years.^5,80

Advancements in risk stratification, molecular detection of residual disease, and therapies associated with high remission rates have made transplant centers reconsidering kidney transplantation as a feasible option for the treatment of ESKD in patients with MM and AL amyloidosis. A multidisciplinary team of transplant nephrologists and hematologists is critical for the identification of ideal candidates before transplantation and the complex management of patients after transplantation.

Treatment of Cancers After Transplantation: Novel Cancer Therapies

Treatment of cancer after transplant can be challenging owing to kidney allograft dysfunction. It is common to develop cancer more than 10 years after transplant, and kidney function may be marginal by the time cancer therapy begins. Cytotoxic chemotherapy, molecular targeted therapy, and radiotherapy are the most common therapeutic approaches in patients with kidney transplants with cancer. As kidneys are a major elimination pathway for many antineoplastic drugs and their metabolites, dose adjustment may be necessary depending on kidney function. In nontransplant patients, dose adjustment is made based on the creatinine clearance (Cockcroft-Gault), Chronic Kidney Disease Epidemiology Collaboration equation (CKD-EPI), or Modification of Diet in Renal Disease (MDRD).^81,82 However, these estimations have not been validated in kidney transplant recipients with one functioning kidney Thus, unintentional overdosing or underdosing of chemotherapy may be common. Besides the dose adjustment, nephrologists and oncologists should be aware of the treatment-associated adverse events. For example, platinum agents can cause tubular injury, hypomagnesemia, and proximal tubular dysfunction (ie, Fanconi-like syndrome), as it does in nontransplant patients. Tyrosine kinase inhibitors (TKIs), including anti-VEGF antibodies, can be associated with hypertension and proteinuria. The mechanism of proteinuria caused by TKIs are thought to be due to the combination of reduction of nitric oxide production and endothelial injury⁸³ and thus often accompanied with hypertension. This is important when patients develop proteinuria while on mTOR inhibitor, as proteinuria due to mTOR inhibitor is not usually associated with hypertension. Furthermore, it is notable that many patients with kidney transplants are on calcineurin inhibitors and may be at a higher risk of endothelial injury/thrombotic microangiopathy (TMA) when treated with chemotherapeutic agents such as gemcitabine (Table 5).

Table 5.

Anticancer Agents and Major Renal Complications

Anticancer Agents	Renal Complications
Gemcitabine, VEGF inhibitors, TKIs	Thrombotic microangiopathy (TMA)
CAR-T therapy	CRS, acute kidney injury, vasodilation, decreased cardiac output, capillary leak syndrome.
High dose IL-2	Acute allograft rejection
IMiD (lenalidomide, pomalidomide, thalidomide)	Acute allograft rejection
Interferon alpha	Acute allograft rejection
Immune checkpoint inhibitor (anti-CTLA-4, anti-PD-1, anti-PD-L1)	Acute allograft rejection, glomerulonephritis

Abbreviations: CAR, chimeric antigen receptor; CLTA-4, cytotoxic T-lymphocyte-associated protein 4; CRS, cytokine release syndrome; IMiD, immunomodulatory drug; PD-1, program cell death protein-1; PD-L1, program death ligand-1; TKI, tyrosine kinase inhibitor; VEGF, vascular endothelial growth factor.

Besides cytotoxic chemotherapy and molecular targeted therapy, immunomodulating agents have been introduced and associated with an increased risk of rejection, such as immunomodulatory drugs (IMiD, eg, lenalidomide) for MM,^70,73,84,85 and interferon alpha^86,87 for RCC. Lenalidomide contributes to direct phosphorylation of CD28 and induce T-cell activation.⁸⁸ Moderate- to high-dose IL-2 therapy has been used in metastatic RCC and melanoma and is associated with cytokine storm and capillary leak. Given well-described roles of IL-2 in maintaining allograft tolerance, high-dose IL-2 is considered a relative contraindication in transplant patients⁸⁹ (Table 5).

Immune checkpoint inhibitors (ICIs) have become standard of therapy for many cancers.⁹⁰ However, ICIs are associated with high risk of acute rejection of the transplant organ. Initially, ipilimumab (anti-CTLA4) was reported to be safe to use in transplant,⁹¹ but later, pembrolizumab (anti-PD-1) was associated with a higher risk of rejection.⁹² This has been supported by mouse transplant models suggesting both PD-1 and PD-L1 are essential to achieve allograft tolerance.^93–95 More recently, Abdel-Wahab and colleagues reported the risk factors and survival benefit in solid organ transplant patients.⁹⁶ The rejection rate was 41%, and the overall survival was worse in the patients with allograft rejection. A meta-analysis by d’Izarny-Gargas and colleagues also confirmed the high risk of acute rejection (39.8%) in patients with kidney transplants.⁹⁷ The median overall survival of the patients receiving ICIs seemed comparable (36 weeks) with historical cohorts. More recently, a multicenter observational study investigated the efficacy and safety of ICIs in kidney transplant recipients.⁹⁸ Estimated risk of acute rejection was 42%, with median ICI to rejection time being 24 days. The rejection risk was lower if the patients were on a higher number of immunosuppressants (eg, three-agent immunosuppression) and mTOR inhibitors. In patients with advanced cSCC, the overall survival in those receiving ICIs was significantly longer than that of historical cohorts of advanced cSCC who did not receive ICIs. Currently, there is no consensus on how to manage immunosuppression to mitigate acute rejection while achieving effective tumor response. There are several ongoing clinical trials to investigate immunosuppression strategies in patients with kidney transplants. One approach is to continue tacrolimus (NCT03816332)⁹⁹ for those with skin cancer (cSCC, melanoma, basal cell carcinoma, Merkel cell carcinoma) treated with ipilimumab and/or nivolumab. Another approach includes combination of mTOR inhibitor and dynamic steroid dosing for cSCC treated with cemiplimab (NCT04339062).¹⁰⁰ In this study, the patients receive prednisone minipulse synchronizing with the infusion, modified from a previously reported approach.¹⁰¹ Another safety monitoring study of those with various cancer species treated with nivolumab is ongoing (ANZCTR CA209-993ISR).¹⁰² A targeted gene expression analysis of kidney allograft biopsies suggested that interferon signaling pathway, particularly the expression level of IFI27, is associated with ICI-associated rejection,¹⁰³ and further research on biomarkers is awaited to better understand the mechanism of ICI-associated rejection. Donor-derived cell-free DNA has been used as a biomarker for rejection in setting of ICI use,^104,105 although the optimal interval of monitoring is unclear at this point. Interestingly, acute rejection can still occur in patients on dialysis with previously failed allograft. In these cases, patients developed allograft pain and fever 2-4 weeks after the first cycle of checkpoint therapy, owing to intolerant allograft symptoms.^106–108 In summary, as therapeutic options for cancer expand, specific considerations of immunomodulatory effects of cancer treatment are needed in patients with kidney transplants (Fig 2).

Figure 2.

Complexity of immune checkpoint inhibitor use in patients with kidney transplants. The figure highlights the complexity of immune suppression–associated adverse effects (eg, cancers [left] and infections [middle]) and benefits (eg, achieving allograft tolerance [right]). Abbreviation: PTLD, post-transplant lymphoproliferative disorder.

CONCLUDING REMARKS

The treatment options for cancers are rapidly evolving. Transplant centers should revisit their current protocols regarding pretransplant cancer-free wait times and reassess patient populations that were previously excluded from kidney transplantation owing to histories of cancer. Multidisciplinary decision-making among the patient, caretaker, oncologist, and transplant nephrologist is extremely important in ensuring appropriate pretransplant and post-transplant care.

CLINICAL SUMMARY.

• Cancer-free wait time and cancer screening strategies after transplant are opinion-based, and more data are needed.

• Careful strategies may enable kidney transplantation in patients with multiple myeloma.

• Novel cancer therapies with potential immunomodulatory effects need to be used with caution.