Diagnosis and treatment of multiple myeloma and AL amyloidosis with focus on improvement of renal lesion

In 1962, Bergsagel et al. [2] reported that l-phenylalanine mustard (melphalan) could induce remissions in approximately one third of patients with MM. In 1967, Salmon et al. [3] reported that high doses of glucocorticoids could induce remissions in patients with refractory or relapsing MM. Combination therapy with melphalan and prednisolone in 1969 by Alexanian et al. [4] showed a better result than melphalan alone.

However, the response rate with alkylators and corticosteroids was only approximately 50 %, and CR was rare. Cure was never a goal of therapy as it was assumed unattainable. Instead, the goal was to control the disease as much as possible, providing the best quality of life to patients for the longest duration by judicious, intermittent use of the 2 available classes of active chemotherapeutic agents. Also in 1986, clinical studies evaluating HDT with single ASCT (McElwain) and double ASCT (Barlogie) were conducted. In 1996, the first randomized study showed benefits with HDT with ASCT versus standard chemotherapy. Berenson et al described an efficacy of bisphosphonate pamidronate in reducing skeletal events in patients with advanced MM^.

In 1999, thalidomide was introduced and the first non-myeloablative mini-allogeneic transplants were introduced with several novel agents that target the biological pathway of the disease, as well as long-acting Adriamycin^® analogues. In the past decade, thalidomide, bortezomib, and lenalidomide have emerged as effective agents for the treatment of myeloma, producing spectacular results in combination with other known agents in terms of response rate, CR rate, progression-free survival (PFS), and, more recently, overall survival. In 2001, a new classification system introduced “CRAB” features of organ damage (Fig. 1) [5]. In 2004, the International Staging System was introduced. The results obtained from new combinations have indeed been remarkable and have created a relatively new philosophy of treating myeloma with a goal of potential cure rather than disease control.

Chemotherapy is indicated for patients with newly diagnosed symptomatic myeloma, although it is generally not recommended for patients with monoclonal gammopathy of undetermined significance (MGUS), smoldering, or asymptomatic myeloma. Age, performance status, and neurologic and co morbid conditions are critical factors in the choice of initial therapy. Melphalan and prednisone combination can no longer be considered as a standard of care in patients who are 65 years of age or older. Our findings suggest that bortezomib plus melphalan-prednisone is the standard front-line treatment for patients with myeloma who are 65 years of age or older and cannot tolerate more aggressive treatment [6].

During the past decades, high-dose therapy with autologous stem-cell transplantation (HDT-SCT) has become the standard treatment option for patients with untreated multiple myeloma (MM) who are younger than 65 years of age; however, HDT-SCT is not usually recommended for older patients and patients with clinically significant co-morbidities.

A recent study has shown that long-term survival improved significantly in younger patients while only limited improvement was achieved in elderly patients. Improved treatment for such older patients ineligible for HDT-SCT was much-awaited.

Should we treat patients with myeloma with multidrug, multitransplant combinations to pursue the goal of potentially curing a subset of patients, recognizing that the balance of adverse events and effect on quality of life will be substantial? Or should we consider myeloma as a chronic incurable disease with a goal of disease control, using the least toxic regimens, emphasizing a balance between efficacy and quality of life, and reserving more aggressive therapy for later lines?

Bortezomib IV is an ubiquitin-proteasome inhibitor and indicated for the treatment of MM. Bortezomib is a reversible inhibitor of the chymotrypsin-like activity of the 26S proteasome in mammalian cells. It is cytotoxic to a variety of cancer cell types in vitro and causes suppression in tumor growth in vivo in nonclinical tumor models, including MM. Specifically, bortezomib is effective in MM via its inhibition of nuclear factor-κB activation, its attenuation of interleukin-6-mediated cell growth, a direct apoptotic effect, and possibly antiangiogenic and other effects [8]. Regarding the treatment of patients who are not eligible for transplantation, MPT and MPB have shown significantly better overall survival (OS) benefit than that of MP and are the recommended treatments [6, 9]. The proteasome inhibitor bortezomib has been approved in the USA in 2005 for the treatment of MM patients with a history of at least one prior therapy, based on results from the phase III APEX study which showed superiority of bortezomib over high-dose dexamethasone in patients with relapsed MM [10]. The majority of treatment guidelines currently recommend incorporating HDT/SCT into initial therapy programs for patients who are 65 years of age or younger and to consider such a therapy for patients 60–70 years of age with good performance status and a lack of co morbid illnesses since HDT/SCT provides the highest chance of inducing a complete remission. However, even when patients achieve CR, the vast majority of patients will ultimately relapse. The standard frontline therapy for patients who are 65 years of age or older, and for patients who are not likely to proceed to HDT/SCT, consists of oral MP at doses similar to those used in this study. Combination therapies such as MP (at a dose of 0.25 mg/kg/day) are given orally at doses used for 4 consecutive days every 6 weeks, showed superior survival versus melphalan alone. With MP therapy, an OR rate of approximately 50 %, a CR rate of 2 to 5 % and a median time to response of 3–5 months have been historically reported [4].

Recently 5 year OS follow up data has been published. The data indicates that OS in MPB with 60.1 months follow-up is significantly superior to that of MP. The OS of MP-B and MP were 56.4 months (13.3 months improvement) and 43.1 months respectively. This data is very much remarkable because the OS improvement was 13.3 months although even MPT could improve only 6.6 months in its meta analysis. As a result of this VISTA study, MPB became the standard treatment for untreated transplant in-eligible patients [11].

To evaluate safety, pharmacokinetics (PK) and efficacy of bortezomib combined with melphalan and prednisolone (MPB) therapy, we conducted a phase I/II study for untreated Japanese MM patients who were ineligible for hematopoietic stem cell transplant (HSCT). This was a dose-escalation study designed to determine the recommended dose (RD) of bortezomib in combination with melphalan and prednisolone by evaluation of the maximum tolerated dose based on dose-limiting toxicity (DLT) in the phase I portion, and to investigate the overall response rate (ORR; CR + PR) and safety of MPB therapy in the phase II portion. Particularly, a continuity of treatment cycles was historically compared with a global phase III study (VISTA trial), and the incidence of interstitial lung disease was assessed. This phase I/II study in Japan suggests that the RD of bortezomib in MPB therapy is 1.3 mg/m² and the MPB therapy in newly diagnosed Japanese MM patients ineligible for HSCT is as effective as that shown in VISTA trial. Further investigation is necessary to confirm the appropriate administration schedule of this combination in Japanese patients [12].

What should be the goal of treatment in multiple myeloma? If cure is the goal, then CR is the critical first step (Fig. 3) [13]. CR is a treatment goal in many hematological malignancies, eg- AML, ALL and lymphomas. In the past, achievement of CR in MM was rare. New treatments can increase the rate of CR to the similar level with high-dose therapy followed by ASCT (Fig. 4) [14‐16]. Also, CR rate in Phase 3 trials in non-transplant patients was: MPB 30 %; MPT 2-16 %; MPR 13 %; MPR-R 18 %, and long term RD 22 %. MM may not be a single disease cytogenetically; achievement of CR seems particularly important in the 15 % of patients with high-risk MM, since survival is similar in patients without high-risk features who have and have not achieved CR [6, 17‐20].

Cyclophosphamide has been added to thalidomide and dexamethasone (CTD) with excellent response rates among newly diagnosed MM patients who received subsequent SCT, with higher response rates seen after SCT.

The combination in 3-weekly schedules of cyclophosphamide (50 mg PO or 300 mg/m² PO weekly or 150 mg/m² d1–5), thalidomide (200–800 mg daily, increasing doses or intermittent administration 400 mg d1–5 and d14–18) and dexamethasone (40 mg per day for 4 days) (CTD) results in an ORR of around 60 %, a median TTP of 10–12 months and a 2-years PFS of 57 % [21‐23].

Comprehensive reviews on the use of thalidomide have been published and include efficacy and safety in relapsed MM. The rationale for using thalidomide was based on its antiangiogenic properties because, in MM, increased microvessel density has been inversely correlated to survival. However, thalidomide has multiple modes of action, including immunomodulatory effects. This initial experience generated a great enthusiasm, and a large number of phase II trials were rapidly conducted. A systematic review of such 42 trials on >1600 patients confirm that the response rate is 29 % with an estimated 1-year overall survival (OS) of 60 %. The well-known teratogenicity of thalidomide is not a major concern in patients with MM because of patients age, but justifies careful informing of patients and programs to avoid drug exposure in women with childbearing potential. The major toxicities of thalidomide are fatigue, somnolence, constipation, and mostly peripheral neuropathy, which are related to the daily dosage and to treatment duration. The overall incidence of peripheral neuropathy is 30 % but may be higher if treatment is prolonged for >1 year. Because this complication may be disabling and sometimes irreversible, patients should decrease the dose or stop the treatment if significant numbness occurs.

After induction treatment, two to four cycles of combination therapies is followed by the maintenance therapy, which is continuous therapy with a single agent, with reasonable balance between maximum benefits and minimum toxicities [24] until the time of disease progression.

Another important issue in MM is risk of developing SPMs due to living longer from diagnosis. Population studies show MM patients have increased risk of specific SPMs following initial diagnosis, notably acute myeloid leukemia (AML). Some MM therapeutic agents are particularly associated with elevated risk of SPMs. Melphalan is associated with increased risk of secondary acute leukemia. There were imbalances in SPM incidence, including myeloid and lymphoid leukemias, with post-transplant lenalidomide maintenance therapy and with MP-lenalidomide. Persistent significant OS benefit with VMP versus MP; 13.3-months increase in median, and MPT versus MP increase 6.6 months [9].

Secondary malignancies and lenalidomide: by summarizing the data to-date, the incidence of all/invasive SPM is significantly increased in Lenalidomide arms, driven by hematologic SPM (P < 0.001). B-ALL, Hodgkin lymphoma is reported in post high-dose melphalan and ASCT setting. Sensitivity analysis (including SPM as an event) demonstrates negligible PFS differences. The overall benefit–risk profile of lenalidomide in NDMM remains positive [31, 32]. Risk Factors for Secondary Malignancies Treatment with lenalidomide may be treatment duration >24 months, male, age >55 years, ISS stage III, previous DCEP (role of concomittant or previous exposure to alkylators?) induction by univariate and multivariate analysis in IFM 2005.

In Japanese SPM Report by JRCMC, retrospective analysis for 325 MM patients from 1998 to 2010 (13 years) showed t-MDS/AML developed 17 (5.2 %) patients. Median time to onset: 52 months in t-AML and months in t-MDS. All the patients with t-AML died in a short time, suspected to be treated with Melphalan, and no patients had been given Lenalidomide. We have to select chemo regimen taking into account the risk of t-MDS/AML [33].

Timing of treatment initiation in multiple myeloma is depending on existence of organ dysfunction. Usually when any symptom such as bone symptoms, renal dysfunction, anemia, or hypercalcemia is observed, it is diagnosed as symptomatic multiple myeloma and treatment should be started. Renal dysfunction in multiple myeloma is one of the complications that require the most careful attention and occurs via various mechanisms. Of these, the most frequent case is cast nephropathy, also known as myeloma kidney, in which excessive light chains of M protein (BJP) secreted by proliferated plasma cells form cast by depositing themselves in renal tubules. In addition, hypercalcemia associated with osteolysis by myeloma cells, deposition of amyloid in glomeruli, hyperviscosity syndrome, hyperphosphatemia, renal infiltration of myeloma cells are also the causes of renal dysfunction. Other than those, care must be given to recurring urinary tract infection, drugs, dehydration that may act as exacerbation factor. According to the statistics of Japanese Society of Myeloma [34], approximately 15 % of newly diagnosed multiple myeloma patients have complication of renal dysfunction and the rate increases as the disease progresses. Bence Jones protein (BJP) type and IgD type of myeloma that excrete high amount of Bence Jones protein into urine show high frequency of renal dysfunction. In 197 patients diagnosed as multiple myeloma during 12 years (1995–2006) in our facility, 3.6 % of IgG type and 8.9 % of IgA type showed higher than 2 mg/dL of creatinine on the first visit, were whereas BJP type accounted for 36.8 % (Fig. 8). Because renal dysfunction becomes irreversible if timing of treatment is missed, immediate treatment is necessary. It is reported that renal dysfunction remains reversible when serum creatinine is below 4 mg/dL, Ca is below 11.5 mg/dL and urine protein is 1 g/day or lower [35]. Although these are the data before introduction of novel agents, in the 423 patients with newly diagnosed multiple myeloma, patients with renal dysfunction (22 %) showed significantly shorter survival time compared to the patients with normal renal function (8.6 vs. 34.5 months). In addition, Blade et al. reported that in the same patients with reduced renal function, those who recovered their renal function by subsequent chemotherapy showed significantly extended survival time compared to those without recovery of renal function (28.3 vs. 3.8 months). Therefore, although renal dysfunction in multiple myeloma is a poor prognostic factor, good prognosis can be expected if the treatment restores renal function. For this, it is important to restore renal function by implementing effective treatment in patients with renal dysfunction before it becomes irreversible and requires hemodialysis. In the multiple myeloma patents in our facility mentioned above, hemodialysis was introduced to eight out of 197 cases.

Improvement of the primary disease is the basic remedy of renal dysfunction that complicates with multiple myeloma. Since 2005, treatment strategy for multiple myeloma has significantly changed due to the successive introduction of novel agents. The three drugs including a proteasome inhibitor bortezomib, and two immunomodulatory drugs (IMiDs), lenalidomide and thalidomide, are referred to as novel agents, and each drug has characteristic profiles of efficacy and safety. While all those agents can be expected to restore renal function due to improvement of the primary disease, bortezomib, with strong antitumor effect, is reported to rapidly improve renal function (Fig. 9). Roussou et al. retrospectively compared improvement of renal function among traditional chemotherapy group, IMiDs (lenalidomide or thalidomide)-based treatment group, and bortezomib-based treatment group with 96 cases of newly diagnosed multiple myeloma. It showed that the best and the most rapid improvement of renal function were observed in the bortezomib-based treatment group. Renal response rate (minor response and better) based on creatine clearance improvement and time to response as 59 % and 1.8 months in chemotherapy group, 79 % and 1.6 months in IMiDs-based group, and 94 % and 0.69 month in bortezomib-based group, respectively [36]. In addition, some cases with withdrawal from dialysis are also reported. Thus, administration of bortezomib should be considered in patients with acute or severe renal dysfunction if it is possible.

Lenalidomide is an anti-myeloma drug possessing dual functions of antitumor effect and immunomodulating activity. Because lenalidomide is urinary excreted, its blood concentration increases in patients with renal dysfunction which leads to high incidence risk of adverse reactions [37]. However, lenalidomide itself has no renal toxicity and clinical studies showed improvement of renal function in the patients treated with lenalidomide. Lenalidomide can be administrated by proper adjustment of its dose corresponding to renal function according to the package description [38]. In fact, it is reported that adjusted dosing of lenalidomide to patients with renal dysfunction resulted with similar anti-myeloma efficacy to those with normal renal function [39, 40], and recovery of renal function was also observed [41]. Similar to bortezomib, cases that withdrew from dialysis are reported [42]. Stratified analysis of lenalidomide/dexamethasone therapy by age showed similar efficacy and tolerability in elderly (over 65 years of age) to those of youth [43]. Hence this therapy is considered to be useful especially for elderly patients with renal dysfunction if the dose is properly adjusted corresponding to the renal function. Thalidomide does not require dose control depending on renal dysfunction, but it has not been reported in large studies that thalidomide is effective on the improvement of renal function. In any case, early diagnosis and timing of initiation of treatment are important. In addition, full understanding of efficacy and safety profiles of novel agents and using them in combination with existing drugs appropriate for individual patients are the basis of treatment strategy.