The rapid evolution of novel treatment options for multiple myeloma (MM) has led to improved response rates for both transplant-eligible and -ineligible patients. To maximize efficacy and minimize toxicity in the front-line setting, it is crucial to consider patient comorbidities as well as drug safety profiles, which will affect the selection and dosing of specific therapies. In this article, R. Donald Harvey III, PharmD, BCPS, BCOP, FCCP, answers your questions related to the management of patients with renal insufficiency and hypercalcemia in the context of front-line therapies. Also discussed are recent clinical trial data on investigational drugs and combination regimens that are showing promise in the treatment of patients with newly diagnosed disease.
Given the fact that renal insufficiency is so common in newly diagnosed patients with MM, how do you approach pharmacotherapy with drugs that are cleared by the kidneys?
When a patient with MM presents with renal dysfunction, knowing the etiology of the impairment is critical for making rational treatment choices. The approach to therapy is very different for patients who have myeloma-associated renal impairment than it is for those whose renal insufficiency is caused by another disease (eg, diabetes), a contrast agent, or medication.
Myeloma is associated with renal tubular cast nephropathy, which is induced by tubular accumulation of free light chains that form obstructive casts.1 In a patient with renal insufficiency due to MM, an important goal is to reduce the disease burden as quickly as possible to improve kidney function. Therefore, whenever possible, antimyeloma therapy should be very aggressive in terms of both the specific agent(s) and the dosage. For example, a drug like lenalidomide may need to be adjusted for renal impairment, but clinicians must also try to maximize dosing in order to treat the renal insufficiency caused by the myeloma. In cases such as this, we support patients through myelosuppression and other toxicities, which may be more severe when lenalidomide dosing and exposure is kept relatively high.
Another therapeutic option that is appropriate for patients with myeloma-associated renal impairment is a bortezomibbased regimen, since this agent is hepatically cleared and requires no dose reduction in the presence of reduced creatinine clearance (CrCl).2 Results from a multicenter case analysis of 24 MM patients with advanced renal failure requiring dialysis showed a 75% response rate (including a complete response [CR]/near-complete response rate of 30%) with bortezomib-based treatment.3 Furthermore, in 4 patients, renal impairment was reversed after therapy, eliminating the need for dialysis. One patient had a rapid response to treatment and was spared from dialysis, and 3 others no longer required dialysis after achieving a CR (2 patients) or a minimal response (1 patient). Although safety data were limited by the nature of the analysis, toxicities were similar to those seen in pivotal trials of bortezomib-based therapy.3
According to International Myeloma Working Group (IMWG) guidelines on antimyeloma treatment in the setting of renal insufficiency,4 bortezomib plus high-dose dexamethasone is the treatment of choice in myeloma patients with renal dysfunction,4 and regimens containing these agents have been shown to reverse MM-associated acute renal failure in several studies.5-9 The IMWG guidelines also state that lenalidomide is effective in patients with renal failure, and can reverse renal insufficiency in a significant subset of these patients when it is given at the recommended reduced doses.4 There is limited experience with thalidomide in renally impaired patients.4
Renal insufficiency, however, may be due to other causes. For example, patients with MM often undergo a good deal of imaging, and intravenous (IV) contrast media may cause renal dysfunction, especially in those with comorbid renal insufficiency or diabetes.10,11 Medications, such as non - steroidal anti-inflammatory drugs and diuretics, can also induce renal damage. Finally, patients may present with renal impairment due to diabetes or a history of infection. In such scenarios, clinicians will often need to be less aggressive in terms of antimyeloma treatment, because therapy will not alter these types of renal impairment.
How do you adjust the dosing of lenalidomide in a newly diagnosed patient with myeloma-associated renal impairment?
Approximately two-thirds of lenalidomide is excreted by the kidney.12 The approved labeling for lenalidomide recommends dose adjustments on the basis of declining CrCl (Table 1). In a patient with CrCl between 30 and 60 mL/min, reducing lenalidomide from the normal 25-mg/day dose to a 10-mg/day dose reduces the likelihood of cytopenias secondary to excessive lenalidomide exposure.12,13 When CrCl declines to <30 mL/min but the patient is not on dialysis, dosing of 15 mg every 2 days is recommended; a patient with a CrCl <30 mL/min who also requires dialysis can receive 5 mg/day of lenalidomide.12 Obviously, very substantial dose reductions are recommended as CrCl begins to decline. It is important to remember that labeling recommendations for lenalidomide were developed from single-dose studies in patients with renal insufficiency who did not have MM.12 As a result, we are extrapolating pharmacokinetic data into a population with a different profile of risk and potential benefit.
That being said, in a newly diagnosed patient with renal impairment related only to MM, with a CrCl of 30 to 60 mL/min, we might consider an aggressive lenalidomide dose of 15 to 25 mg/day, depending on disease burden and concurrent antimyeloma therapy. The hope is that dose-intensive therapy would evoke a good response and, in so doing, improve renal function. We would be extremely vigilant in terms of monitoring and support for myelosuppression in a patient such as this.
How does renal insufficiency affect treatment planning for IV bisphosphonates, such as zoledronic acid and pamidronate?
The use of IV bisphosphonate therapy may require dose reduction for renal impairment. In rare cases, these drugs may also cause renal toxicity and impairment independent of myeloma in patients with otherwise normal renal function. 14,15 Therefore, patients who are candidates for bisphosphonate therapy should have baseline and monthly renal function assessment. Zoledronic acid must be dose-adjusted based on CrCl. Doses drop from the standard dose for MM of 4 mg IV infused over ≥15 minutes every 3 to 4 weeks in patients with CrCl >60 mL/min down to 3 mg when CrCl is 30 to 39 mL/min (Table 2).14 Zoledronic acid is not recommended for use in patients with severe renal impairment (CrCl <30 mL/min).14 We do consider using pamidronate, which is not labeled for reduced dosing in renal impairment and has an across-the-board standard monthly dose for MM patients of 90 mg IV infused over 4 hours.15 That is not to say, however, that pamidronate’s pharmacology is totally unaffected in the presence of renal insufficiency; renal clearance of this drug is closely correlated with CrCl.15 At our center, we sometimes give a lower dose (60 mg) infused over at least 4 hours, and perhaps up to 6 hours, as suggested by the 2007 American Society of Clinical Oncology (ASCO) guidelines for bisphosphonates.16 Dosing recommendations for bisphosphonate labeling were derived from single-dose studies in cancer patients with renal insufficiency,14,15 not from a cohort of MM patients exclusively, and so may not fully reflect the needs of this population.
It is important in this context to note that, in the newly diagnosed MM patient, IV bisphosphonates are indicated for more than just the prevention of skeletal-related events (SREs). These agents may also be used for immediate treatment of hypercalcemia. Therefore, the indication may determine the clinical approach. For example, in a patient with MM who presents with renal insufficiency but normal calcium levels, we may choose to hold bisphosphonate therapy until renal function stabilizes or improves after initial anti - myeloma therapy. This approach may prevent bisphosphonate- related adverse events, including hypocalcemia, in a patient who will lose little skeletal benefit in holding off on bisphosphonate therapy for a defined period. In contrast, the patient who presents with both renal insufficiency and hypercalcemia has an immediate need for bisphosphonate therapy to reduce high calcium values, which cause a host of symptoms and may contribute to renal dysfunction.
Recommended dosing of zoledronic acid for hypercalcemia is 4 mg as a single IV infusion of ≥15 minutes, with retreatment after a minimum of 7 days. For the treatment of hypercalcemia with a single dose of zoledronic acid, dose adjustments are not necessary in patients with mild-to-moderate renal impairment prior to initiation of therapy (defined as serum creatinine <4.5 mg/dL).14 Pamidronate is dosed at 60 to 90 mg as a single IV dose over 2 to 24 hours in patients with moderate hypercalcemia (defined as an albumin-corrected calcium of 12-13.5 mg/dL).15 In severe hypercalcemia (albumin-corrected calcium >13.5 mg/dL), the recommended dose of pamidronate is 90 mg given as a single IV dose over 2 to 24 hours.15 Longer infusion times, along with adequate saline hydration, may help reduce the risk for renal toxicity in patients with preexisting renal insufficiency.15 Retreatment with pamidronate, if needed, can be carried out after a minimum of 7 days.15 Whenever we initiate bisphosphonates, and especially when we are treating hypercalcemia, we make sure patients are well hydrated as comorbidities allow. Hydration itself improves hypercalcemia, while ensuring that a good fluid preload is presented to the kidneys to minimize the effect of renal insufficiency. Additionally, dexamethasone may be added for both antimyeloma and calcium-reducing effects, depending on the severity of both.
Aside from dosing for renal insufficiency, are there other notable differences between bisphosphonates?
Two recent trials highlight some potential clinical differences between bisphosphonates. The Medical Research Council IX trial17 demonstrated that zoledronic acid, when compared with oral clodronate over 3.7 years of follow-up, significantly reduced the proportion of patients with an SRE (27.0% vs 35.3%, respectively; P=.0004). Zoledronic acid also significantly improved progression-free and overall survival independent of its favorable effect on SRE incidence (Figure). Patients also tended to stay on zoledronic acid longer than on clodronate, even if they discontinued therapy: median length of therapy for discontinued patients was 270 days with zoledronic acid and 156 days with clodronate. Deterioration in renal function was similar between the treatment groups, but incidence of osteonecrosis of the jaw (ONJ), while low, was 3.5% with zoledronic acid and 0.3% with clodronate. Although the results of this trial are encouraging, the benefit in patients without preexisting bone disease is unclear, and comparison with pamidronate (more commonly used in the United States than clodronate) may be a better marker of clinical utility.17
Zoledronic acid also produced a higher incidence of ONJ in another large comparative study. On multivariate analysis, Vahtsevanos and colleagues18 found that each dose of zoledronic acid as well as a history of zoledronic acid use were both variables associated with increased risk for this adverse event. Pamidronate or ibandronate exhibited a safer drug profile with respect to ONJ in this study. In addition, the investigators reported that patients with MM had an overall incidence of bisphosphonate-related ONJ of 8.5%, compared with 3.1% and 4.9% for bisphosphonate- treated patients with breast and prostate cancer.18 Incidence of ONJ in MM patients was actually lower in this trial than in a 2006 study by the same group, which found an 11% incidence.19 Investigators attributed the decrease to improved baseline dental evaluation and regular follow-up.18 This is a reminder that, no matter which bisphosphonate is selected, it is essential to follow best practices for the prevention of ONJ as outlined in the 2007 ASCO guidelines.16
It is important to note that choosing be tween bisphosphonates is not the only treatment decision relevant to bone support. Our team works closely with the radiation oncology service to prescribe palliative radiation therapy. This therapy must be selected judiciously; we only use it for specific lesions that are causing or contributing to pain. We also collaborate with very good orthopedic surgeons, to provide vertebroplasty or kyphoplasty and also to help patients identified by skeletal survey as having an impending fracture in weight-bearing bones. For example, it is not uncommon for a patient to have extensive lytic bone disease in the proximal femur or femoral neck. An orthopedic surgeon can place rods or pins into the femur to prevent a fracture. Obviously, fracturing a femur or hip would be a major event with potentially grave consequences, so we try to avoid that with prophylactic surgeries. It is essential to view the big picture of supportive care, which can involve radiation and surgery as well as bisphosphonates.
Which investigational drugs are showing promise in clinical trials for newly diagnosed MM?
There are a number of superb candidates for the next generation of antimyeloma therapies, which may one day be available for the newly diagnosed patient. Results of recent clinical trials highlight the abundance of research in several drug classes, including proteasome inhibitors, monoclonal antibodies, mammalian target of rapamycin inhibitors, histone deacetylase (HDAC) inhibitors, and immunomodulators. 20,21 Several emerging therapies offer potential improvements within classes we already use in MM, but there are also investigations of drugs with unique mechanisms of action, such as small-molecule WP1130 (a deubiquitinase inhibitor),22 perifosine (an AKT inhibitor),23 and MLN4924 (a Nedd8-activating enzyme inhibitor).24
Carfilzomib is an example of a promising new drug in an established class. This drug is a novel proteasome inhibitor that appears to be associated with less peripheral neuropathy than bortezomib, although direct comparative studies are yet to be completed. Our center participated in a study of single- agent carfilzomib that showed a high response rate and good tolerability in bortezomibnaïve patients with risk factors for poor prognosis.25 Another recent study showed that a regimen of carfilzomib, lenalidomide, and low-dose dexa-methasone produced at least a very good partial response (VGPR) in 70% of newly diagnosed MM patients (Table 3).26,27 Another investigational proteasome inhibitor, MLN9708, has also shown promising activity,28 and our center is getting ready to open a study evaluating a combination of this drug with lenalidomide and dexamethasone in the front-line setting.
Another antimyeloma agent of note is the HDAC in - hibitor vorinostat. In conjunction with M D Anderson Cancer Center and Dana-Farber Cancer Institute, our center has led phase 1 research evaluating a 4-drug regimen of bortezomib/ lenalidomide/dexamethasone (VRD) plus this agent in newly diagnosed MM,29 and patient accrual continues for this study. So far, we have been impressed with outcomes of adding vorinostat to an VRD “backbone,” which has resulted in a 50% rate of ≥VGPR in early efficacy data.29 In addition to investigational agents to treat the disease itself, novel therapeutic approaches to support bone health in MM have also emerged. These novel agents have a different mechanism of action than bisphosphonates, which bind the mineral component of bone and interfere with the action of osteoclasts, the bone-resorbing cells in the metabolic process of bone remodeling.30,31 For example, the monoclonal anti-body denosumab, which is approved for osteoporosis and bone metastases of solid tumors, reduces osteoclast activity by binding to and suppressing receptor activator of nuclear factor B ligand (RANKL).30 Up-regulation of RANKL on the surface of marrow stromal cells and immature osteoclast precursors is critical in the formation of osteoclasts.31 A phase 2 trial in MM suggested that denosumab effectively inhibited the RANKL pathway regardless of previous exposure to bisphosphonates, as evidenced by suppressed levels of the bone turnover marker, serum C-terminal telopeptide of type 1 collagen. 32 However, due to higher mortality in a licensing trial, this agent is not indicated for the prevention of SREs in patients with myeloma.33
Another promising target is the Wnt signaling pathway and its endogenous antagonism by the Dickkopf 1 (DKK1) protein produced by myeloma cells. Wnt signaling plays a critical role in the production of osteoblasts, the cells that build new bone.34 When myeloma cells produce DKK1, they may thereby interfere Wnt mediated with bone formation, so that inhibition of DKK1 is a potential target of bone supportive therapy.34 Interestingly, recent data have shown that treatment with bortezomib can increase 2 markers of osteoblast ac tivity/bone formation; specifically, alkaline phosphatase and osteocalcin. In animal models, this agent has also been shown to induce the differentiation of mesenchymal stem/progenitor cells into osteoblasts.35 Ongoing studies are investigating the potential effect of bortezomib on bone, and it will be intriguing to learn whether this agent can support bone health, alone or as an enhancement to bisphosphonates or other therapies.
- Goldschmidt H, Lannert H, Bommer K, Ho AD. Multiple myeloma and renal failure. Nephrol Dialysis Transplant. 2000;15:301-304.
- Velcade® [package insert]. Cambridge, MA: Millennium Pharma - ceuticals, Inc. December 2009.
- Chanan-Khan AA, Kaufman JL, Mehta J, et al. Activity and safety of bortezomib in multiple myeloma patients with advanced renal failure: a multicenter retrospective study. Blood. 2007;109:2604-2606.
- Dimopoulos MA, Terpos E, Chanan-Khan A, et al. Renal impairment in patients with multiple myeloma: a consensus statement on behalf of the International Myeloma Working Group. J Clin Oncol. 2010;28: 4976-4984.
- Dimopoulos MA, Richardson PG, Schlag R, et al. VMP (bortezomib, melphalan, and prednisone) is active and well tolerated in newly diagnosed patients with multiple myeloma with moderately impaired renal function, and results in reversal of renal impairment: cohort analysis of the phase III VISTA study. J Clin Oncol. 2009;27:6086-6093.
- Qayum A, Aleem A, Rehman A, et al. Rapid improvement in renal function in patients with multiple myeloma and renal failure treated with bortezomib. Saudi J Kidney Dis Transpl. 2010;21:63-68.
- Malani AL, Gupta V, Rangineni R. Bortezomib and dexamethasone in previously untreated multiple myeloma associated with renal failure and reversal of renal failure. Acta Haematol. 2006;116:255-258.
- Ludwig H, Drach J, Graf H, et al. Reversal of acute renal failure by bortezomib-based chemotherapy in patients with multiple myeloma. Haematologica. 2007;92:1411-1414.
- Kastritis E, Anagnostopoulos A, Roussou M, et al. Reversibility of renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone-containing regimens and the impact of novel agents. Haematologica. 2009;92:546-549.
- Palfrey PS, Griffiths SM, Barrett BJ, et al. Contrast material-induced renal failure in patients with diabetes mellitus, renal insufficiency, or both. N Engl J Med. 1989;320:143-149.
- Ledneva E, Karie S, Launay-Vacher V, et al. Renal safety of gadolinium- based contrast media in patients with chronic renal insufficiency. Radiology. 2009;250:618-628.
- Revlimid® [package insert]. Summit, NJ: Celgene Corporation. October 2010.
- Niesvizky R, Narib T, Christos PJ, et al. Lenalidomide-induced myelosuppression is associated with renal dysfunction: adverse events evaluation of treatment-naïve patients undergoing front-line lenalidomide and dexamethasone therapy. Br J Haematol. 2007;138:640-643.
- Zometa® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. February 2011.
- Aredia® [package insert]. East Hanover, NJ: Novartis Pharmaceuticals Corporation. November 2008.
- Kyle RA, Yee GC, Somerfield MR, et al. American Society of Clinical Oncology 2007 clinical practice guideline update on the role of bisphos - phonates in multiple myeloma. J Clin Oncol. 2007;25:2464-2472.
- Rajkumar SV. Zoledronic acid in myeloma: MRC Myeloma IX. Lancet. 2010;376:1965-1966.
- Vahtsevanos K, Kyrgidis A, Verrou E, et al. Longitudinal cohort study of risk factors in cancer patients of bisphosphonate-related osteonecrosis of the jaw. J Clin Oncol. 2009;27:5356-5362.
- Zervas K, Verrou E, Teleioudis Z, et al. Incidence, risk factors and management of osteonecrosis of the jaw in patients with multiple myeloma: a single-centre experience in 303 patients. Br J Haematol. 2006;134: 620-623.
- Lonial S. Relapsed multiple myeloma. Hematology Am Soc Hematol Educ Program. 2010:303-309.
- Ghobrial IM, Weller E, Vij R, et al. Weekly bortezomib in combination with temsirolimus in relapsed or relapsed and refractory multiple myeloma: a multicentre, phase 1/2, open-label, dose-escalation study. Lancet Oncol. 2011 [epub ahead of print].
- Kapurnia V, Petersomn LF, Fang D, et al. Deubiquitinase inhibition by small-molecule WP1130 triggers aggresome formation and tumor cell apoptosis. Cancer Res. 2010;70:9265-9276.
- Jakubowiak AJ, Richardson PG, Zimmermann TM, et al. Final phase I results of perifosine in combination with lenalidomide and dexamethasone in patients with relapsed or refractory multiple myeloma (MM). Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 3064.
- Shah JJ, Harvey RD, O’Connor OA, et al. Phase 1 dose-escalation study of multiple dosing schedules of the investigational drug MLN4924, a Nedd8-activating enzyme inhibitor, in patients with relapsed and/or refractory multiple myeloma or lymphoma. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 2801.
- Vij R, Kaufman JL, Jakubowiak AJ, et al. Carfilzomib: high single agent response rate with minimal neuropathy even in high-risk patients. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 1938.
- Jakubowiak AJ, Dytfeld D, Jagannath S, et al. Carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma: initial results of phase I/II MMRC trial. Blood (ASH Annual Meeting Abstracts). 2010;116:Abstract 862.
- Jakubowiak AJ, Dytfeld D, Jagannath S, et al. Carfilzomib, lenalidomide, and dexamethasone in newly diagnosed multiple myeloma: initial results of phase I/II MMRC trial, presentation. Presented at the 52nd American Society of Hematology Annual Meeting. Orlando, FL, December 4-7, 2010.
- Masood A, Chitta K, Miles KM, et al. An investigational proteasome inhibitor MLN9708 (MLN2238) induces apoptosis in human multiple myeloma cells. Blood (ASH Annual Meeting Abstracts). 2010;116: Abstract 3066.
- Kaufman JL, Shah JJ, Laubach JP, et al. Lenalidomide, bortezomib, and dexamethasone (RVD) in combination with vorinostat as front-line therapy for patients with multiple myeloma (MM): initial results of a phase I study. Blood (ASH Annual Meeting Abstracts). 2010;116: Abstract 3034.
- Baron R, Ferrari S, Russell RGG. Denosumab and bisphosphonates: different mechanisms of action and effects. Bone. 2010 [epub ahead of print].
- Roodman GD. Mechanisms of bone metastasis. N Engl J Med. 2004;350:1655-1664.
- Vij R, Horvath N, Spencer A, et al. An open-label, phase 2 trial of denosumab in the treatment of relapsed or plateau-phase multiple myeloma. Am J Hematol. 2009;84:650-656.
- Xgeva® [package insert]. Thousand Oaks, CA: Amgen, Inc. November 2010.
- Reddy GK, Mughal TI, Roodman GD. Novel approaches in the management of myeloma-related skeletal conditions. Support Cancer Ther. 2006;4:15-18. 35. Roodman GD. Bone building with bortezomib. J Clin Invest. 2008; 118:462-464.