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Kidney Transplant in the Era of Modern Therapy for Multiple Myeloma

Huskey, Janna L. MD1; Heilman, Raymond L. MD1; Khamash, Hasan MD1; Fonseca, Rafael MD1

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doi: 10.1097/TP.0000000000002449
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Multiple myeloma (MM) is a neoplastic proliferation of plasma cells in the bone marrow resulting in abnormal production of monoclonal immunoglobins leading to anemia, hypercalcemia, osteolytic bone lesions, and commonly renal impairment. Historically, individuals with MM and end stage renal disease (ESRD) were not considered candidates for kidney transplantation due to concerns for their overall poor prognosis, risk of disease recurrence, and increased risk of infection. However over the past 15 years, the survival of MM has greatly increased with the advent of an array of effective drugs and autologous stem cell transplantation (SCT). There have also been advances in the management of kidney transplant recipients, making it reasonable to consider these patients for transplantation. The goal of this review is to discuss the outcome of kidney transplantation in patients with advanced chronic kidney disease (CD) due to MM. In addition, we will review the advancement in therapy for MM over the years which has led to an improvement in patient survival. We will focus our discussion to MM patients with CKD related to cast nephropathy (CN) or monoclonal Ig kidney deposition disease (MIDD).

MM AND KIDNEY DISEASE

Renal involvement is common in patients with MM with about 25% of patients having renal impairment at time of presentation and 50% developing kidney disease during the course of their disease.1 These patients can present with several patterns of injury including CN, MIDD, or amyloidosis. Cast nephropathy is the most common pattern occurring in 40-63% of myeloma patients with renal involvement.1 Monoclonal immunoglobulin deposition disease occurs in 19% to 26% of patients with renal involvement and 7% to 30% will have amyloid kidney involvement. Patients with MIDD have a spectrum of hematologic disease, whereas the majority of patients with CN will meet the diagnostic criteria for MM. Cast nephropathy is primarily dictated by the formation of hyaline cylinders and proximal tubular damage caused by free light chains (LCs) in the urine (previously referred to as Bence-Jones proteinuria).

Cast nephropathy is recognized by highly refractile proteinaceous casts in the renal tubules which are usually associated with significant tubular inflammation.1 The mechanism of cast formation is due to the precipitation of filtered LC proteins with Tamm-Horsfall protein resulting in obstruction of the distal tubular lumen and reactive inflammation. Despite treatment with intravenous fluids, and possibly plasmapheresis to remove the free LC protein from the plasma, more than half of patients with CN do not recover kidney function and will be left with advanced CKD including ESRD. In MIDD, monoclonal immunoglobulins are deposited in the kidney along the glomerular and tubular basement membranes, leading to proteinuria and progressive CKD.

Historically, kidney transplantation has not been widely incorporated in the management of patients with MM and ESRD because of the poor prognosis of patients with MM and significant CKD. Tsakiris and colleagues2 found that individuals with ESRD due to MM on renal replacement therapy had an unadjusted median survival of 0.91 years on dialysis compared to 4.46 years in non-MM patients. There was a 2.77 higher risk of death compared with patients without MM with malignancy being the most common cause of death (36.1%) followed by cardiovascular causes (17.2%) and infection (14.7%). A more recent analysis of patients with ESRD from monoclonal gammopathies between the years of 2002 and 2011 found a median survival of 18.4 months for individuals with ESRD due to LC deposition disease (LCDD) and 16.1 months for those with CN. Independent risk factors for death were increasing age, frailty, congestive heart failure, and initiation of dialysis with a catheter, whereas the year of initiation of renal replacement therapy and higher blood pressure were associated with lower mortality. The most common cause of death in both groups was malignancy (32.6% for LCDD and 41.5% in CN).3

NEW THERAPIES FOR MM

Eleven new drugs have been approved by the Food and Drug Administration for the treatment of myeloma since 1999 and were added to already existing options, including dexamethasone, alkylators, bendamustine, and other chemotherapeutic agents. These drugs have improved the average survival of patients from a median survival of 29 months in 1998 to over 8 years for those that are recently diagnosed.4,5 A newly diagnosed patient who undergoes optimal induction therapy, followed by an SCT and maintenance, their time to next treatment can be documented to be 5 years from therapy initiation.6 Two of the most active combinations for the treatment of relapsing disease (defined as 1-3 prior lines of therapy), carfilzomib plus lenalidomide and dexamethasone and daratumumab plus lenalidomide and dexamethasone can be said to contribute each to at least 2 more years of disease control.7,8 In total, that means that the average myeloma patient can look forward to a survival of 8 to 9 years.4 Before the advent of these novel therapeutics, myeloma was mostly treated with steroids and alkylators. The use of SCT became the standard of care for suitable candidates; mostly healthy and fit individuals under the age of 75. Even with this strategy older studies document the possibility of myeloma being a curable condition. One study published in 2011 demonstrates that among those treated with high-dose melphalan and who achieve a complete response, there is a 30% possibility of not having progression at 20 years.9 In that study, the induction therapy (treatments before transplant) was much less effective than what is used nowadays, and only 30% of patients achieved a complete response after SCT. With use of the best regimens in 2018 the proportion of patients achieving a complete response is closer to 60%, so if the arithmetic remains true myeloma should be curable in at least 20% of cases, perhaps more. The progression of hematological malignancies to become considered “curable” seems to occur when regimens start achieving complete response rates of close to 50%, and does not follow a linear progression. Given the number of new MM therapies that have significantly improved overall outcomes, it is quite possible that we are very close to finding a cure for a larger fraction of patients. It should be noted that even patients who achieve very deep responses, including a complete response, can ultimately relapse and die from their disease.

Despite these advances, subsets of patients with high-risk disease do not enjoy long-term survival.10,11 Many systems exist to classify patients as having high risk versus other, but the majority incorporate genetic markers; fluorescence in situ hybridization or gene expression profiling.11,12 Patients with high-risk disease have a greater likelihood of early relapse and disease progression. In general, patients with high-risk MM can be expected to have a survival of less than 5 years, with a prominent component of mortality being present during the first 2 years after diagnosis. Conversely, patients who do not harbor high-risk markers can be logically expected to be overrepresented among long-term survivors. The cumulative burden of treatment toxicity or need of medical supportive measures (eg, hemodialysis) is thus greater in those that live many years after diagnosis. Strategies to ameliorate this added burden would be welcomed by patients and physicians.

There are 3 new main groups of drugs used for the treatment of myeloma; proteasome inhibitors (PIs), immunomodulatory drugs (IMIDs) and monoclonal antibodies (Figure 1). PIs (bortezomib, carfilzomib, ixazomib, and other drugs in development) revolutionized the treatment of myeloma by creating endoplasmic reticulum stress and apoptosis due to the high rate of production of immunoglobulin molecules by myeloma cells.13 Immunomodulatory drugs are drugs derived from thalidomide and include lenalidomide, pomalidomide, and others in development.14-16 Immunomodulatory drugs are oral agents that can be used over an extended period because of their tolerance profile and have been used successfully in combination and as part of maintenance after SCT.6,17,18 Both IMIDs and PIs are interesting in that they target the normal biology of plasma cells, a biology that is retained in the clonal plasma cells, and one that creates cell vulnerabilities. Immunomodulatory drugs are pleiotropic in their mechanism of action but contain an immune stimulant component that will be of relevance as one considers these drugs in the setting of organ transplantation. Another class of drugs includes the monoclonal antibodies, some target CD38 (daratumumab and isatuximab)19 and others target SLAMF7 (elotuzumab).20 Daratumumab has direct cytotoxic activity against myeloma cells and has been used alone or in combination. Daratumumab may have some immune modulating activity, but this knowledge is still in development. Elotuzumab has no single-agent activity and has been used mostly in combination with lenalidomide and dexamethasone. Lastly, corticosteroids are almost always used as part of combinations used for the treatment of myeloma because they are cytotoxic to plasma cells and increase antimyeloma activity of most drugs.

FIGURE 1
FIGURE 1:
This figure shows the various mechanisms of action of the medications used in the treatment of MM. MOA, mechanism of action; IKZF1/3, names for the genes Ikaros and Aiolos; ER, endoplasmic reticulum.

KIDNEY TRANSPLANTATION AND MM

There are several case reports describing the outcomes of kidney transplantation in MM with CKD (Table 1).21-28 The early literature described a limited number of patients treated with chemotherapy followed by kidney transplantation months or years after the MM was in remission. Because these series were older, many of these patients were treated with melphalan and dexamethasone to obtain remission of the MM. More recently Lum et al describe 2 patients treated with bortezomib and dexamethasone followed by living donor kidney transplant after the MM was in remission.28 Of the 16 patients treated with chemotherapy alone followed by kidney transplantation, 6 had relapse of MM and 1 was in partial remission. At least 6 (38%) died of infection complications.

TABLE 1
TABLE 1:
Kidney transplant after chemotherapy for MM

An additional unique strategy includes nonmarrow ablative therapy with the transplant of HLA identical stem cell and kidney transplant from the same donor for patients with ESRD and MM (Table 2).29-32 There have been several publications from the same group which were recently reviewed by Baraldi et al.33 This group has treated 16 patients with this strategy. There were 13 patients with MM and ESRD in this cohort. One patient died with recurrent myeloma, 3 had partial remission of the MM, and 9 achieved a complete remission. Interestingly, 10 patients achieved operational tolerance allowing for the complete withdrawal of immunosuppression. However, 6 developed graft versus host disease necessitating the reinitiation of immunosuppression. A more recent study found that individuals who achieved tolerance after HSCT and kidney transplant had better renal function compared to standard living donor transplantation over a period of 250 patient years with no episodes of allograft loss. However, it should be noted that none of the individuals had MM.34 Although this last strategy appears to be effective, it requires the availability of an HLA-identical donor which limits this option and allogeneic stem cell transplant is not favored as a mainstream option by most MM specialists. The results of this approach is more important from the evidence it provides, demonstrating that tolerance can be achieved in many of these patients but this option is not available to the majority of patients with MM and ESRD because of the lack of an HLA-identical donor. Most clinical guidelines do not suggest the option of allogeneic transplantation as primary treatment for MM.

TABLE 2
TABLE 2:
Simultaneous HLA identical kidney and SCT for MM

A more relevant strategy is the treatment with chemotherapy and SCT to obtain remission of the MM followed by kidney transplantation (Table 3).35,36,38-42 The toxicity associated with SCT appears to be higher in patients with advanced CKD even despite the use of reduced dose conditioning.43 These case series describe a total of 14 patients with MIDD treated with the strategy of SCT followed by kidney transplantation. Of these 14 patients, one had a relapse of MIDD, 2 had a partial response and the remainders appear to have obtained complete response of the MM. One patient with partial remission before transplant had progression of MM 6 months after kidney transplantation despite maintenance therapy with bortezomib. Initially, therapy consisted of lenalidomide plus dexamethasone and later switched to carlfizomib, cyclophosphamide, and dexamethasone for disease progression. Despite hematologic progression, the creatinine was stable at 1.3 md/dL with no evidence of recurrent renal disease or rejection.42 One patient received maintenance therapy with lenalidomide after kidney transplantation without apparent rejection.41 Based on these limited data, it appears that the outcomes are better with a treatment strategy that includes SCT with consideration for maintenance therapy after kidney transplant. The clear corollary to this is that effective therapeutic strategies that can control the growth of myeloma cells and can reduce the serum concentration of the free LCs are likely to result in benefits for renal function.

TABLE 3
TABLE 3:
Chemotherapy and ASCT followed by kidney transplant

One important caveat is that IMIDs have been anecdotally reported to be associated with an increased risk of rejection and allograft loss of solid organ transplants. Lum and colleagues44 recently published a case report of a patient that developed MM 5 years after receiving a kidney transplant for polycystic kidney disease. She was treated with lenalidomide and dexamethasone for MM and 5 weeks after therapy she developed acute kidney injury with an allograft biopsy showing Banff IIA acute cellular rejection and antibody-mediated rejection which was treated with IVIG and thymoglobulin with improvement in renal function. Rice et al45 reported on a patient who underwent combined heart kidney transplant for AL amyloidosis. Several heart and kidney biopsies were negative for rejection and 101 days after transplant she was started on lenalidomide in preparation for SCT. Eight days after initiating lenalidomide she developed fevers, pulmonary infiltrates and ultimately a fatal cardiac arrest. The autopsy showed severe acute cellular rejection, necrosis, and arteritis in the heart and renal allografts. Xie et al46 described a patient who developed MM after receiving a heart transplant for AL amyloidosis who was treated with bortezomib, cyclophosphamide, and dexamethasone (CyBorD) therapy followed by a stem cell transplant. His antiproliferative agent was discontinued, and 2 years after his heart transplant, he was started on lenalidomide for treatment of his AL amyloidosis, approximately 1 month later, he developed grade IIIr (severe) acute cellular rejection of his heart. Although no precise quantification of this risk exists, these case reports highlight clinical scenarios where the initiation of therapy with lenalidomide leads to acute organ rejection. This could be “bioplausible” given that others have reported that IMIDs augment immune function. Several studies have shown that IMIDs can enhance immune responses, including augmented response to vaccination, leading to higher protective titers.16,47,48 Studies have shown that lenalidomide quickly increases natural killer (NK) cell toxicity and activation, increase CD3+/CD8+ T cells, and CD4+ and CD8+ interferon-gamma secreting cells. This results in an increase in cytokine excretion as well as inhibition of the PD-1/PDL-1 axis which ultimately can lead to acute inflammation and rejection.44,45,49 Although these immunomodulatory effects are beneficial in the treatment of MM, they can have a detrimental effect on a solid organ transplant and therefore should be used with caution. However, given the threat that myeloma poses to a person, if down the line an IMID is needed for recurrent or progressive disease, it should be considered after careful discussion with the patient regarding the potential risks versus benefit.

At our center, we have transplanted 4 patients with a prior history of MM. A 36-year-old man with ESRD due to MIDD achieved remission with lenalidomide and bortezomib and subsequently underwent living donor kidney transplant. He received basiliximab induction therapy with tacrolimus and mycophenolate mofetil for maintenance immunosuppression. Four months after kidney transplant, he received SCT for recurrent MM and did well for 2 years but had aggressive recurrent disease requiring a variety of chemotherapeutic agents and repeat SCT. His last kidney biopsy was 2 years after kidney transplant which showed no evidence of recurrence. His creatinine 5 years postkidney transplant was 1.8 mg/dL, but unfortunately, he developed progressive MM and passed away 5.5 years after transplant. The second case is a 44-year-old woman with ESRD due to MIDD treated with CyBORD (bortezomib, cyclophosphamide, and dexamethasone) followed by SCT with lenalidomide maintenance. One year later, she underwent living donor kidney transplant with alemtuzumab induction therapy followed by tacrolimus and mycophenolate mofetil for maintenance therapy. Three years after kidney transplant, she had MM recurrence treated with pomalidomide and bortezomib with complete remission. Six years after transplant, she continues to do well with Cr 0.9. The third case is a 60-year-old woman with ESRD due to MIDD who received vincristine, adriamycin, and dexamethasone chemotherapy followed by SCT complicated by recurrence which was successfully treated with lenalidomide. Three years later, she received a dual extended criteria donor deceased donor kidney transplant with alemtuzumab induction. She was unable to tolerate mycophenolate mofetil and was maintained on tacrolimus and prednisone. Eight months after kidney transplant, she had recurrence of her MM and was started on lenalidomide; however, due to drug side effects, she was switched to ixazomib 22 months later. Unfortunately, she had disease progression and was transitioned to pomalidomide which she took for 18 months at which time her disease progressed again, and she was recently started on daratumumab. Her creatinine early after transplant was 1.3 mg/dL but is currently 4.1 mg/dL at 4 and half years after transplant. Her last kidney biopsy 2 years after kidney transplant (Cr 2.8 mg/dL) showed severe interstitial fibrosis and tubular atrophy but no evidence of MM. The last case is a 70-year-old man with ESRD due to focal segmental glomerular sclerosis and a history of MM. His MM was treated with bortezomib followed by an SCT. He had recurrent disease requiring a variety of chemotherapeutic agents and was in partial remission before his kidney transplant. He received a deceased donor kidney transplant with basiliximab induction therapy and tacrolimus, mycophenolate mofetil, and prednisone for maintenance immunosuppression. Approximately 10 months after kidney transplant, he was started on pomalidomide for progressive MM. He quickly developed acute kidney injury requiring a renal allograft nephrectomy and the pathology showed diffuse cortical necrosis, thrombotic changes, and endotheliitis secondary to rejection.

Early studies have noted an increased risk of infections after kidney transplant in patients with MM. In our limited experience, infections were not a major complication. One patient who was cytomegalovirus mismatch at the time of transplant developed cytomegalovirus viremia and another patient with a history of coronary artery disease developed an infected foot ulcer. The most common complication posttransplant has been recurrent or progressive MM requiring treatment. Three of the 4 patients received an IMID after kidney transplant. Two of these patients have tolerated the therapy for at least a year without rejection, whereas one lost his allograft due to acute rejection despite standard immunosuppression. Immunologic risk and immunosuppression were similar among the 3 patients, making it unclear the difference in outcome. It is possible that additional immunosuppression from bortezomib helped prevent rejection in one of the patients; however, the second patient has tolerated IMIDs for several years now without additional agents aside from her transplant immunosuppressive medication. It is also unclear whether the pharmacologic immunosuppression will increase the risk of disease recurrence after effective initial treatment, although MM is not considered a malignancy of increased incidence in immunosuppressed states.

CURRENT RECOMMENDATIONS FOR KIDNEY TRANSPLANTATION IN PATIENTS WITH MM

Promulgating that renal transplantation is a reasonable option for MM patients' needs to rest on the assertion that there will be enough survival postkidney transplantation for the transplant to be considered valuable. Determining patients according to their genetic risk category seems to be the best, albeit imperfect, method to select individuals with a greater likelihood of long-term survivorship and transplant value. Nevertheless, genetic factors alone can only explain a fraction of the heterogeneity of outcomes. A new arbitrary system that further enhances this discriminatory process would seem to be warranted for better selecting patients. In addition to these aforementioned genetic factors, other factors can help identify individuals with a high risk of rapid progression and include a high lactate dehydrogenase, presence of extramedullary disease, poor performance status, persistent disease post-SCT in positron emission tomography imaging, and rapid relapse. Some of these factors are cross-sectional, and some require longitudinal surveillance. The greatest conundrum is how long to make this period of relapse-free survival to maximize benefit. Too short a period and there is a greater risk of failing to detect someone with an early relapse. Too long a period of surveillance and the time represented by area under the curve will be diminished for those who could benefit from earlier kidney transplantation (Figure 2). There is no prospective study that addresses this question, and by necessity, selection criteria will be arbitrary.

FIGURE 2
FIGURE 2:
In this figure, we show the conceptual framework upon which one could make decisions about when to offer kidney transplantation. We have arbitrarily divided patients with MM into 3 groups. Patients who have standard-risk disease and that have achieved excellent levels of response, as determined by having a negative test in an MRD-negative assay. These patients could be considered after 6 months after initial antimyeloma therapy (including SCT) for renal transplantation. At the other end of the spectrum, we see patients with high-risk myeloma that still have evidence of residual disease, and as a group they are least likely to benefit from kidney transplantation given their shorter survival. Renal transplantation should be considered carefully, and in our opinion only after it is clear that the disease has been well controlled, and that the response is durable. In between are patients who have either high-risk disease and negative MRD assays, or patients who have standard risk disease but remain positive for MRD, but that otherwise had no evidence of overt disease. These patients could be considered for renal transplant after 12 months of therapy. HR-MM, high-risk MM; SR-MM, standard-risk MM.

A novel approach to gauge the progress of initial treatment for MM is the use of minimal residual disease (MRD) measurements of the bone marrow.50 Methods to do so include flow cytometry, polymerase chain reaction and next-generation sequencing. While there is no universally accepted threshold most believe a level of at least of 10−5 is desirable and preferable at 10−6. One could postulate that achievement of MRD-negative status could be used as a selection criteria for renal transplant candidates.50 A drawback to this criterion is that the fraction of patients achieving MRD-negative status, as determined by either method, can be small and thus transplant would be denied to many suitable candidates who could live for many years, even when they could harbor a small amount of residual clonal cells in their bone marrow.9 Nevertheless, achieving MRD negativity in those with standard risk is a major prognostic factor and would identify patients with an excellent prognosis50 (Figure 1). Among those with high-risk disease, achieving and sustaining deep responses has been previously documented to be associated with improved outcomes.51 Likewise, patients who have high-risk markers and who do not achieve MRD-negative status are at high risk of early relapse and thus would be premature to recommend kidney transplantation to them. It is possible that MRD determinations will need to be done longitudinally in those receiving a kidney transplant to monitor the depth of responses.

One therapeutic option that has greatly improved survival of MM is maintenance therapy post-SCT.6,17,18 Several randomized studies show that lenalidomide improves progression-free survival, and one study showed an improvement in overall survival.6,17,18,52 A recent meta-analysis has shown that maintenance with lenalidomide can improve overall survival by over 2 years. We recently reported, using real world data, similar improvements in time to next treatment.6 This creates a conundrum when considering kidney transplant for MM patients. It is indisputable that IMIDs at large are a great part of the improvements in survival seen for MM patients, and yet they pose potential risks for those with solid organ transplants. One option to avoid IMIDs, at least earlier in the course after kidney transplant, could be to use other drugs previously explored as maintenance for MM. These drugs could include bortezomib, ixazomib and daratumumab. A recent press released has revealed that ixazomib improved progression-free survival as a maintenance drug in a phase 3 trial, but specifics were not reported. Also, for the subset of patients that harbor t(11;14), one could make the reasonable postulate to use venetoclax as a maintenance drug, given its oral route of administration and its growing recognition as useful for this patient subpopulation.53,54 Also, one could consider omission of maintenance therapy if someone has MRD-negative status after SCT. If the patient progresses on an IMID-free regimen, then it would seem reasonable to initiate the best next line of therapy against MM, even if that included an IMID and its associated risk of organ rejection.

Patients who have MM and kidney transplantation should be monitored carefully with close interaction between the transplant team and the hematologist. They should have free LCs and serum protein electrophoresis checked at a minimum of every 3 months with the caveat that they may need more frequent monitoring if there is a recurrence and treatment is being initiated. In addition, many of the drugs used to treat MM can have immunosuppressive effects and interact with transplant related medications so a multidisciplinary approach is essential. Over time, many myeloma regimens can produce profound hypogammaglobulinemia, also a consideration for a patient who is already receiving immunosuppression and is at an increased risk of infection. For individuals on MM therapy, appropriate infection prophylaxis should be initiated as recommend by hematology.

CONCLUSIONS

Despite advancements in the treatment for MM, CKD remains a common complication. While individuals with MM and ESRD have inferior outcomes compared to patients without MM, their survival has improved over the years. Individuals being referred for kidney transplant with a history of MM should be evaluated by a hematologist to risk stratify their MM and determine the current status of their disease. Active MM should be treated with induction therapy followed by SCT with consideration for maintenance therapy in individuals being considered for kidney transplantation. Individuals with low risk disease should wait a minimum of 6 months after SCT before proceeding with kidney transplant. Those with moderate-risk disease could be considered for kidney transplant 12 months after SCT. For individuals with high-risk MM, the risk of renal transplantation and immunosuppression likely outweighs the potential benefit and kidney transplant should not be pursued (Figure 2 and Figure 3). In patients who are candidates, partial or complete remission should be obtained before proceeding with renal transplant. The published experience on the outcome of kidney transplantation in patients with MM and advanced CKD is limited to several small case series. These reports suggest that the outcome of kidney transplantation is acceptable, particularly in selected patients with newer treatment strategies which include SCT along with possible maintenance therapy after kidney transplant. However, we would advise caution in making firm conclusions based on the limited data provided by these case series which are vulnerable to the possibility of a publication bias of positive results. There does appear to be a small risk for recurrent MM in some patients treated with SCT which would warrant treatment postkidney transplant and therefore treatment options should be discussed with the hematologist before proceeding with the transplant. Although many of the newer agents pose minimal additional risks, IMIDs have been associated with severe acute rejection and allograft loss and should be used carefully. While these recommendations are from a thorough review of the current literature, we do acknowledge that there is a degree of ambiguity and that future studies are necessary to provide further guidance on maximizing outcomes in these individuals. However, with a multidisciplinary approach both before and after kidney transplant, certain individuals with MM can enjoy a survival benefit with kidney transplant compared with remaining on dialysis.

FIGURE 3
FIGURE 3:
This figure is a schematic representation of the process for individuals with MM and chronic renal failure. Transplant nephrology should be consulted for individuals with irreversible renal disease to determine their candidacy for kidney transplant. If it is felt that the patient is a candidate for kidney transplant then MM treatment should pursued which should include SCT before renal transplantation. Individuals with high-risk disease should not be considered for kidney transplant as the risk outweighs the benefit. CRF, chronic renal failure.

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