1. health and fitness
2. disease
3. cancer

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ISSUE TWO
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MARCH 2008
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A P U B L I C AT I O N F R O M T H E O N C O L O G Y N U R S I N G S O C I E T Y
Funded by an unrestricted educational grant from Millennium Pharmaceuticals
AUTHOR: TIFFANY RICHARDS, MS, ANP, AOCNP®
JUST DO IT! Learn How to Recognize the Driving
Forces, Key Features, and When to Treat Multiple
Myeloma
An English physician, Dr. Samuel Solly, first described multiple myeloma as a case report in 1844, after a second patient presented
with acute onset of severe back pain and a strange sensation in her right leg. Subsequently, the patient described progressive pain
in her arm and legs, accompanied by weakness. As her disease worsened, she developed fractures, which confined her to bed.
Her disease progressed, and four years after initial onset, she was hospitalized and died. An autopsy revealed multiple
fractures and a markedly reduced thoracic cavity that compressed her right lung to one-quarter of its normal size. Furthermore,
upon examination of the patient's bones, they were found to contain a red matter and had marked destruction (Kyle, 2000).
Shortly thereafter in 1844, Dr. William McIntyre had a patient who had developed edema; he noted that the precipitated urine
protein would redissolve at high temperatures and then reprecipitate at cooler temperatures. It was not until the urine specimen
was forwarded to Dr. Henry Bence Jones that it was discovered to contain a protein called hydrated deutoxide of albumin. This event
marked the discovery of Bence Jones protein. In 1873, the term multiple myeloma was first used by Dr. von Rustizky, after
performing an autopsy in which he found eight bone marrow tumors (Clamp, 1967; Kyle, 1994). However, it was not until 1947
that Dr. Nils Alwall reported the first effective treatment for multiple myeloma with urethane (Alwall, 1947).
BACK TO THE BASICS: Understanding the Pathophysiology of Multiple Myeloma
Multiple myeloma is a B-cell malignancy, characterized by plasma cell proliferation within the bone marrow, secretion of
monoclonal immunoglobulins, lytic lesions, anemia, renal failure, and hypercalcemia. Multiple myeloma is the second most
common hematologic malignancy, and approximately 19,900 patients were diagnosed in the United States in 2007, and an
estimated 10,790 patients died from the disease (Jemal et al., 2007).
The bone marrow microenvironment comprises many types of cellular components, including erythrocytes, bone marrow
stromal cells (BMSCs), osteoclasts, osteoblasts, hematopoietic stem cells, immune cells, and bone marrow endothelial cells.
Myeloma cells adhere to the bone marrow stromal cells that increase cell proliferation and subsequently increase cytokine
signaling of interleukin (IL)-6, insulin growth factor, vascular endothelial growth factor, and tumor necrosis factor. The release
of cytokines and growth factors within the bone marrow microenvironment triggers signaling cascades that stimulate cell
proliferation. In addition, osteoclastogenesis and adhesion molecules on both myeloma cells and BMSCs are stimulated by
cytokine production. Myeloma cell growth, migration, and survival are stimulated by the interplay between the myeloma cells,
BMSCs, and cytokine release (Hideshima & Raje, 2008).
CENTER STAGE: A New System for Myeloma
Currently, two staging systems are used in myeloma: the Durie-Salmon staging system, developed first, and the International
Staging System (ISS). Multiple factors led researchers to develop a new staging system in multiple myeloma. The ISS was
developed and validated with data from more than 10,000 patients internationally (Greipp et al., 2005). The ISS utilizes albumin
and beta-2 microglobulin (B2M) and subdivides patients into three prognostic groups (see Table 1). Although the reasons for the
prognostic impact of albumin and B2M remain unclear, it may be explained in part by the reflection of tumor mass, renal
function, and possibly immune function by B2M. (Greipp et al.). The serum albumin level is an indirect measure of a patient’s
nutritional well-being, but albumin also is inversely proportional to IL-6 levels in myeloma (Jacobson, Hussein, Barlogie, Durie,
& Crowley, 2003).
1 | The Myeloma Messenger | March 2008
TABLE 1:
International
Staging System
for Myeloma
Stage Beta2 Microglobulin Albumin
Survival (Months)
I
< 3.5
≤ 3.5
62
II
< 3.5
or
3.5–5.5
< 3.5
NA
44
III
≥ 5.5
NA
29
Demographics
The average age at diagnosis of multiple myeloma is 66 years. Incidence is higher among African Americans, and the disease
affects more men than women (Jemal et al., 2007). Multiple myeloma has subtypes based upon the type of monoclonal
immunoglobulin, which is produced by the malignant clone. Approximately 20% will present with light chain disease (Bence Jones
protein), 3% will have nonsecretory disease (undetectable level of monoclonal protein in the blood and/or urine), and the
remaining will have heavy chain disease (IgA, IgG, IgD, IgE). The most common heavy chain subset is IgG or IgA, with IgD and
IgE accounting for only 1%–3% of all patients with myeloma (Rajkumar & Kyle, 2005).
To Treat or Not to Treat: That Is the Question
Patients may present with asymptomatic (smoldering) or symptomatic disease at diagnosis. Asymptomatic patients do not
require treatment and are followed on observation until they meet symptomatic criteria. The criteria for symptomatic myeloma
include the presence of a monoclonal protein in the blood and/or urine, presence of plasmacytosis in the bone marrow, and the
presence of one of the following: anemia (hemoglobin < 10), lytic lesions, impaired creatinine (> 2.0), or hypercalcemia (Durie et
al., 2006). However, in patients with anemia, elevated creatinine, and hypercalcemia, other causative etiologies should be ruled
out prior to starting treatment for myeloma. In those patients who develop progression, treatment should be initiated immediately. In a retrospective study that evaluated 695 previously untreated patients with myeloma, three risk factors for earlier time
to progression (TTP) were identified, including IgA type, Bence Jones > 0.5 g, and monoclonal peak > 3 g (Weber et al., 1997).
Magnetic resonance imaging (MRI) may provide additional prognostic information regarding TTP. In a study of 109 patients,
researchers reported that abnormal signal on MRI predicts for earlier TTP compared to patients with normal MRI (see Table 2)
(Wang, Alexanian, Delasalle, & Weber, 2003).
Conclusion
In conclusion, although multiple myeloma, has been described since 1844, major advances in treating the disease have
occurred in the past 15 years. Myeloma continues to remain complex and requires thorough diagnostic testing and staging
in order to determine observation versus treatment.
TABLE 2: Time to Progression for Asymptomatic Myeloma
Risk Factor
Time to Progression (Median Months)
Normal Magnetic
Resonance Imaging (MRI)
Abnormal MRI
Low Risk
M-protein < 3 and IgG type
79
23
Intermediate Risk
M-protein > 3 or IgA type
38
18
NA
9
High Risk
M-protein > 3 and IgA type
2 | The Myeloma Messenger | March 2008
References
Alwall, N. (1947). Urethane and stilbamidine in multiple myeloma: A report of two cases. Lancet, 2, 388–389.
Clamp, J.R. (1967). Some aspects of the first recorded case of multiple myeloma. Lancet, 2, 1354–1356.
Durie, B., Harousseau, J., Miguel, J., Blade, J., Barlogie, B., Anderson, K., et al. (2006). International uniform response criteria for multiple myeloma. Leukemia, 20, 1467–1473.
Greipp, P.R., Miguel, J.S., Durie, B.G., Crowley, J.J., Barlogie, B., Blade, J., et al. (2005). International staging system for multiple myeloma. Journal of Clinical
Oncology, 23, 3412–3420.
Hideshima, T., & Raje, N. (2008). The role of the bone marrow microenvironment in the pathogenesis of multiple myeloma. In K. Anderson & I. Ghobrial (Eds.), Multiple
myeloma: Translational and emerging therapies (pp. 23–36). New York: Informa Healthcare.
Jacobson, J.L., Hussein, M.A., Barlogie, B., Durie, B.G., & Crowley, J.J. (2003). A new staging system for multiple myeloma patients based on the Southwest Oncology Group
(SWOG) experience. British Journal of Haematology, 122, 441–450.
Jemal, A., Siegel, R., Ward, E., Murray, T., Xu, J., & Thun, M.J. (2007). Cancer statistics, 2007. CA: A Cancer Journal for Clinicians, 57, 43–66.
Kyle, R.A. (1994). Multiple myeloma: How did it begin? Mayo Clinic Proceedings, 69, 680–683.
Kyle, R.A. (2000). Multiple myeloma: An odyssey of discovery. British Journal of Haematology, 111, 1035–1044.
Rajkumar, S.V., & Kyle, R.A. (2005). Multiple myeloma: Diagnosis and treatment. Mayo Clinic Proceedings, 80, 1371–1382.
Wang, L., Alexanian, R., Delasalle, K., & Weber, D. (2003). Abnormal MRI of spine is the dominant risk factor for early progression of asymptomatic multiple myeloma [Abstract 2546]. Blood, 102.
Weber, D.M., Dimopoulos, M.A., Moulopoulos, L.A., Delasalle, K.B., Smith, T., & Alexanian, R. (1997). Prognostic features of asymptomatic multiple myeloma. British Journal of Haematology, 97, 810–814.
BAD TO THE BONE — NOT:
Learning How to Manage the Symptoms of Myeloma
The end organ damage that may occur as a result of multiple myeloma requires immediate recognition and treatment to prevent
further damage. This section will discuss each of the complications that may occur, their etiology, and treatment.
Bone lesions in multiple myeloma are osteolytic and occur when an imbalance between osteoclast destruction and osteoblast
production exists. Stromal-osteoblastic cells produce two factors: osteoprotegerin (OPG) and receptor activator of NF-kB ligand (RANKL). RANKL is expressed on the surface of osteoblasts and stimulates osteoclast formation and increased life span.
The secretion of OPG serves as a decoy receptor to RANKL by blocking the binding of RANK/RANKL (Hofbauer & Schoppet,
2004; Lentzsch, Ehrlich, & Roodman, 2007). This blockage diminishes osteoclast activity, thereby serving as an important
regulator of bone resorption (Hofbauer & Schoppet; Lentzsch et al.).
In a patient with multiple myeloma, OPG secretion is decreased and expression of RANKL is increased, which increases
osteoclast activity (Hofbauer & Schoppet, 2004). Additional factors affecting bone destruction include increased interleukin (IL)3 and macrophage inflammatory protein 1 alpha, which may increase osteoclast activity. Another factor leading to lytic
lesions is decreased osteoblast activity, which may occur because of the effects of IL-3, Dickkopf-1 (DKK-1), and IL-7.
Management of bone disease includes use of bisphosphonates, radiation therapy, kyphoplasty/vertebroplasty and initiation of
treatment. Guidelines have recently been published regarding bisphosphonate utilization in patients, including guidelines from
the American Society of Clinical Oncology and the Mayo Clinic (Berenson et al., 2002; Lacy et al., 2006). Bisphosphonates work
by inhibiting osteolysis and also may have an antimyeloma effect by inducing apoptosis, cell cycle arrest, and antiangiogenesis
(Berenson et al., 2001; Gordon et al., 2002; Shipman, Croucher, Russell, Helfrich, & Rogers, 1998; Wood et al., 2002). Bisphosphonates, including pamidronate or zoledronic acid, are indicated in all patients with bone disease; however, care should
be taken prior to initiating monthly treatments, including performing dental exams, discussing the risk of osteonecrosis of the
jaw, and evaluating kidney function (Berenson et al., 2002). If renal function is impaired, dose reduction of zoledronic acid is required for creatinine clearances less than 60 ml/min; alternatively, pamidronate may be given. Although it is not recommended
to begin bisphosphonates in asymptomatic patients with myeloma, more recently Musto et al. (2007) conducted a randomized
study in asymptomatic patients with myeloma in which 161 patients were randomized to receive zoledronic acid 4 mg IV once
monthly or to receive no zoledronic acid for one year. Although no significant differences were seen in time to progression to
symptomatic myeloma, a significant difference was demonstrated in the percentage of patients who progressed with skeletalrelated events/hypercalcemia —48.5% in the zoledronic acid group versus 81% in the nonzoledronic acid group (Musto et al.).
3 | The Myeloma Messenger | March 2008
I GOT YOUR BACK: Procedure Management of Painful Compression Fractures
Management of patients with compression fractures can be challenging because of decreased mobility and increased pain, which
may affect patients’ quality of life. Prior to the 1980s, management consisted of giving pain medication to control the pain
associated with the fractures. Since the introduction of vertebroplasty, and more recently kyphoplasty, studies have shown
improved pain scale scores, increased mobility, and improvements in quality of life (Dudeney, Lieberman, Reinhardt, &
Hussein, 2002). Vertebroplasty was first pioneered by the French in the 1980s and involved direct insertion of meythl methacrylate into the vertebral body under fluoroscopy (see Figure 1). Although this procedure reduces the pain of compression fractures,
it does not restore vertebral body height. In addition, published studies have
reported the incidence of cement leakage as ranging from 30% to 60%
(Dudeney et al.; Yeh & Berenson, 2006).
Kyphoplasty was developed in the 1990s and involves placing a balloon tamp
into the vertebral body (see Figure 2). The cavity created after balloon insertion
then is filled with meythl methacrylate (see Figure 3) (Yeh & Berenson, 2006).
Kyphoplasty is associated with reduction of pain, restoration of vertebral height,
and lowered risk of cement leakage (Dudeney et al., 2002). In both procedures,
patients may require 24 hours of observation to ensure that they do not experience focal neurologic deficits, increased pain, or fever.
GOOD TO THE LAST DROP:
Reversing Anemia
FIGURE 1: Example of Vertebroplasty
Patients may present with anemia, which is described as a normochromic
normocytic. The anemia observed in myeloma is caused by a shortened
erythrocyte survival and decreased erythrocyte production within the bone
marrow. The decreased erythrocyte production is caused by multiple factors,
including replacement of progenitor cells with myeloma cells and defective
erythropoietin production (Blade & Rosinol, 2007). Often, anemia will reverse
upon the initiation of induction therapy. Management of anemia may require
packed red blood cell transfusion, depending on the degree.
FAILURE IS NOT AN OPTION:
Managing Renal Failure
FIGURE 2: Insertion of Balloon Tamp
Into Vertebral Space
Approximately 20% of patients with untreated myeloma will present with
renal failure at the time of diagnosis (Blade et al., 1998). Normally, small
amounts of immunoglobulin light chains are present, classified as either κ
(kappa) or λ (lambda), which undergo metabolism after they are reabsorbed
in the tubuli (Chauveau & Choukroun, 1996; Goldschmidt, Lannert,
Bommer, & Ho, 2000). In patients with myeloma with light chain disease, the
light chains overload the tubules and are not reabsorbed. Subsequently, they
combine with the Tamm-Horsfall mucoprotein, which is secreted in the loop
of Henle, and cause a precipitate, which forms into obstructing casts. In
addition, dehydration, hypercalcemia, nonsteroidal anti-inflammatory drugs
(NSAIDs), and radiographic contrast may exacerbate the formation of
precipitate within the tubules (Chauveau & Choukroun; Goldschmidt et al.).
FIGURE 3: Filling of Cavity With
Often, renal failure may be reversible with immediate treatment for myeloma,
Meythl Methacrylate
as it will decrease the production of light chains (Chauveau & Choukroun).
In a study that evaluated the impact of high-dose dexamethasone-containing
regimens in patients with acute renal failure, 73% of patients had reversal of
renal failure in a median of 1.9 months (Kastritis et al., 2007). Twenty-four percent of patients did not meet the requirement
of reversal of renal failure; however, most of those patients had improvement in their creatinine level (Kastritis et al.).
Nursing management of renal failure should focus on educating patients on adequate fluid intake, avoiding NSAIDs, and
avoiding radiographic contrast.
4 | The Myeloma Messenger | March 2008
TABLE 1: Objective and Subjective Findings of Hypercalcemia
Objective
Subjective
Hypertension and bradycardia
Hyperreflexia
Anorexia
Lethargy
Shortened QT interval
Nausea/vomiting
Altered mental status
Constipation
Weakness
Polyuria
Headache
TOO MUCH OF A GOOD THING: How to Manage Hypercalcemia
Hypercalcemia occurs in approximately 15% of untreated patients and may aggravate renal failure (Kyle, 2001).
Hypercalcemia may be related to increased bone resorption, which increases serum calcium levels (Oyajobi, 2007). Symptoms
consist of both objective and subjective findings, including hyperreflexia, altered mental status, and lethargy (see Table 1).
Hydration and antimyeloma therapy often are initiated to reverse the hypercalcemia; however, bisphosphonates can be used
to bring the calcium to a normal level. In the presence of renal failure, pamidronate should be instituted at a reduced dose (Kyle).
CONCLUSION
Although patients with multiple myeloma may present with a variety of complications, proper management and prompt
treatment can minimize the effects. In those patients who present with multiple complications, initiating the aforementioned
interventions can improve renal function, decrease pain, improve quality of life, and ultimately improve performance status.
Advanced practice nurses play a critical role in recognizing symptoms, initiating interventions to relieve the symptoms, and
educating patients about their disease.
References
Berenson, J.R., Rosen, L.S., Howell, A., Porter, L., Coleman, R., Morley, W., et al. (2001). Zoledronic acid reduces skeletal-related events in patients with osteolytic metastases.
Cancer, 91, 1191–1200.
Berenson, J.R., Hillner, B.E., Kyle, R.A., Anderson, K.,Lipton, A., Yee, G.C., et al. (2002). American Society of Clinical Oncology clinical practice guidelines: The role of bisphosphonates in multiple myeloma. Journal of Clinical Oncology, 20, 3719–3736.
Blade, J., Fernandez-Llama, P., Bosch, F., Montoliu, J., Lens, X.M., Montoto, S., et al. (1998). Renal failure in multiple myeloma: Presenting features and predictors of outcome
in 94 patients from a single institution. Archives of Internal Medicine, 158, 1889–1893.
Blade, J., & Rosinol, L. (2007). Complications of multiple myeloma. Hematology/Oncology Clinics of North America, 21, 1231–1246.
Chauveau, D., & Choukroun, G. (1996). Bence Jones proteinuria and myeloma kidney. Nephrology, Dialysis, Transplantation, 11, 413–415.
Dudeney, S., Lieberman, I.H., Reinhardt, M.K., & Hussein, M. (2002). Kyphoplasty in the treatment of osteolytic vertebral compression fractures as a result of multiple myeloma.
Journal of Clinical Oncology, 20, 2382–2387.
Goldschmidt, H., Lannert, H., Bommer, J., & Ho, A.D. (2000). Multiple myeloma and renal failure. Nephrology, Dialysis, Transplantation, 15, 301–304.
Gordon, S., Helfrich, M.H., Sati, H.I.A., Greaves, M., Ralston, S.H., Culligan, D.J., et al. (2002). Pamidronate causes apoptosis of plasma cells in vivo in patients with multiple
myeloma. British Journal of Haematology, 119, 475–483.
Hofbauer, L.C., & Schoppet, M. (2004). Clinical implications of the osteoprotegerin/RANKL/RANK system for bone and vascular diseases. JAMA, 292, 490–495.
Kastritis, E., Anagnostopoulos, A., Roussou, M., Gika, D., Matsouka, C., Barmparousi, D., et al. (2007). Reversibility of renal failure in newly diagnosed multiple myeloma patients treated with high dose dexamethasone-containing regimens and the impact of novel agents. Haematologica, 92, 546–549.
Kyle, R.A. (2001). Update on the treatment of multiple myeloma. Oncologist, 6, 119–124.
Lacy, M.Q., Dispenzieri, A.Q., Gertz, M.A., Greipp, P.R., Gollbach, K.L., Hayman, S.R., et al. (2006). Mayo Clinic consensus statement for the use of bisphosphonates
in multiple myeloma. Mayo Clinic Proceedings, 81, 1047–1053.
Lentzsch, S., Ehrlich, L., & Roodman, D. (2007). Pathophysiology of multiple myeloma bone disease. Hematology/Oncology Clinics of North America, 21, 1035–1049.
Musto, P., Petrucci, M.T., Bringhen, S., Guglielmelli, T., Caravita, T., Balleari, E., et al. (2007). Final analysis of a multicenter, randomised study comparing zoledronate vs observation in patients with asymptomatic myeloma [Abstract 534]. Blood, 110.
Oyajobi, B.O. (2007). Multiple myeloma/hypercalcemia. Arthritis Research and Therapy, 9 (Suppl. 1), S4.
Shipman, C.M., Croucher, P.I., Russell, R.G., Helfrich, M.H., & Rogers, M.J. (1998). The bisphosphonate incadronate (YM175) causes apoptosis of human myeloma cells in vitro
by inhibiting the mevalonate pathway. Cancer Research, 58, 5294–5297.
Wood, J., Bonjean, K., Ruetz, S., Bellahcene, A., Devy, L., Foidart, J.M., et al. (2002). Novel antiangiogenic effects of the bisphosphonate compound zoledronic acid. Journal of
Pharmacology and Experimental Therapeutics, 302, 1055–1061.
Yeh, H.S., & Berenson, J.R. (2006). Treatment for myeloma bone disease. Clinical Cancer Research, 12(20, Pt. 2), 6279s–6284s.
5 | The Myeloma Messenger | March 2008
TRICK OR TREAT: No Trick Here: Novel Agents and
Transplant Offer New Promise for Untreated Patients
Up until the early 1940s, treatment for myeloma focused on symptom management. Then in 1947, Dr. N. Alwall reported the
first case reports of the use of urethane in multiple myeloma. Subsequently, melphalan was found to have efficacy in myeloma, with
a response rate of 33% (Bergsagel, Sprague, Austin, & Griffith, 1962). When prednisone was combined with melphalan, response
rates increased to 55%–60% (Alexanian, Bergsagel, Migliore, Vaughn, & Howe, 1968). In addition, dexamethasone given at doses
of 20 mg/m2 on days 1–4, 9–12, and 17–20 was found to produce partial response (PR) rates of 45% and a complete response
(CR)rate of 5% (Alexanian, Dimopoulos, Delasalle, & Barlogie, 1992). The combination of vincristine, doxorubicin, and dexamethasone (VAD) invoked PR rates of 45%–65% with 10% achieving CR. Grade 3/4 toxicities reported included infection, myelosuppression, and neuropathy (Alexanian, Barlogie, & Tucker, 1990).
Thalidomide
Thalidomide was first used as a
sedative and antiemetic in the 1950s.
Unfortunately, it was found to have
teratogenic effects andwas pulled from
the market. Thalidomide reemerged as
a treatment for Behçet syndrome,
leprosy, and graft-versus-host disease
and in the 1990s was approved by the
U.S. Food and Drug Administration
(FDA) for the treatment of erythema
nodosum leprosy (Nightingale, 1998;
Pearson & Vedagiri, 1969; Saylan &
Saltik, 1982). When thalidomide was
found to have antiangiogenic properties, a phase II study at the University
of Arkansas evaluated its clinical
efficacy and confirmed thalidomide’s
activity in relapsed/refractory myeloma
with a PR rate of 25% (Singhal et al.,
1999). Since then, numerous studies
have shown thalidomide’s activity both
as a single agent as well as in combination with other agents. These studies
have led to clinical trials of thalidomide
combinations in previously untreated
patients.
FIGURE 1: Mechanism of Action for Thalidomide/Lenalidomide
bFGF—basic fibroblast growth factor; FLIP-FLICE—inhibitory protein; ICAM—intercellular adhesion
molecule; IFN—interferon; IGF—insulin-like growth factor; IL—interleukin; NK—natural killer; NFKB—nuclear factor κB; TNF—tumor necrosis factor; TRAIL—TNF-related apoptosis-inducing ligand;
VCAM—vascular cell adhesion molecule; VEGF—vascular endothelial growth factor
Note. Figure courtesy of Donna Weber, MD. Used with permission. Based on information from Anderson, 2005; Hideshima
et al., 2000; Mitsiades et al., 2002a, 2002b; Raje et al., 2006.
Thalidomide: Mechanism of Action
Thalidomide is thought to act directly on myeloma cells as well as indirectly within the bone marrow microenvironment
(see Figure 1). Degradation of tumor necrosis factor alpha (TNF-α ) mRNA is enhanced by thalidomide, thereby decreasing
secretion of interleukin (IL)-6 (promoter of cell proliferation) and IL-8 (regulator of angiogenesis) (Hideshima, Chauhan, Podar,
et al., 2001; Kumar & Rajkumar, 2006). In addition, it suppresses inhibitor of kappa B (IκB) activity through inhibition of
nuclear factor-κB (NFκB) binding (Keifer, Guttridge, Ashburner, & Baldwin, 2001). Thalidomide also acts directly on myeloma
cells through G1 growth arrest, activation of caspase-8, and stimulation of T cells (Davies et al., 2001; Kumar & Rajkumar;
Mitsiades et al., 2002a).
Thalidomide: Clinical Trials
Thalidomide’s activity in combination with thalidomide-dexamethasone (TD) in the untreated setting was evaluated in two
phase II clinical trials (Rajkumar et al., 2002; Weber, Rankin, Gavino, Delasalle, & Alexanian, 2003). The PR rates in both
6 | The Myeloma Messenger | March 2008
trials were 64% and 72% with a CR rate of 16% in one of the trials (Rajkumar et al., 2002; Weber et al., 2003). Subsequently, a
phase III trial of 207 previously untreated patients was conducted comparing TD to dexamethasone alone (Rajkumar, Blood,
Vesole, Fonseca, & Greipp, 2006). A PR rate of 63% in the TD arm compared to 41% in the dexamethasone arm was observed.
Similarly, a phase III placebo-controlled, double-blind trial of 470 patients randomized to receive either TD or placebo-dexamethasone was conducted (Rajkumar, Hussein, et al., 2006). Response rates observed included a superior overall response rate of 59%
in the TD arm compared to 42% in the placebo-dexamethasone arm. In addition, progression-free survival (PFS) improved,
which had not been reached in the TD arm compared to placebo-dexamethasone with 8.1 months. Subsequently, the trial was
halted early and unblinded, which led to FDA approval of TD for first-line therapy of multiple myeloma (Rajkumar, Hussein,
et al.).
Although TD showed a clear benefit in terms of overall response and PFS when compared to dexamethasone alone, its role as
first-line therapy had not been compared to dexamethasone combined with an alkylating agent combination. Therefore, a
randomized study comparing TD to VAD with autologous stem cell transplant (ASCT) evaluated 204 previously untreated patients (Macro et al., 2006). The TD arm revealed a very good partial response (VGPR) (34.7% compared to 12.6% with VAD)
prior to ASCT. When response rates were evaluated six months after ASCT, the VGPR rate was similar, with 44.4% in the TD
arm compared with 41.7% in the VAD group. Toxicities observed were similar to previous TD and VAD trials; however, thromboembolic events were higher in the TD arm at 22%, and symptomatic peripheral neuropathy was present in both arms (17.4%
versus 12.9%) (Macro et al.).
Additional studies have evaluated thalidomide in combination with alkylating agents and novel agents with response rates of 50%–
90% with low CR rates (Chanan-Khan et al., 2004; Hassoun et al., 2006; Hussein et al., 2006; Offidani et al., 2006; Zervas et al., 2004)
(see Table 1). In a future edition of Myeloma Messenger, combination therapies in older adults will be discussed in detail.
TABLE 1: Selected Thalidomide-Based Combination Therapy for Previously
Untreated Multiple Myeloma
Study
(Study Acronym)
Regimen
Number of
Patients
Partial
Response
(%)
Complete
Response
(%)
Weber et al. (2003)
(Thal-dex)
T
D
40
56
16
Rajkumar et al. (2006a)
(Thal-dex vs. Dex)
T
D
235
59
0
D
235
42
0
T
D
99
68
4
D
Rajkumar et al. (2006b)
(Thal-Dex vs. Dex)
100
50
0
Chanan-Khan et al. (2004) V
(VAD-T)
A
D
T
11
63
27
Hussein et al. (2006)
(DVd-T)
T
Do
V
T
53
47
36
Zervas et al. (2004)
(T-VAD doxil)
T
V
Do
39
64
10
Offidani et al. (2006)
(ThaDD)
T
D
50
54
34
Hassoun et al. (2006)
(AD-TD)
A
42
D
Patients with ≥ SD received 3
cycles then received 2 cycles
TD as below
T
D
69
16
A—doxorubicin; D—dexamethasone; Do—pegylated liposomal doxorubicin; M—melphalan; P—prednisone;
T—thalidomide; V—vincristine
7 | The Myeloma Messenger | March 2008
Lenalidomide: Mechanism of Action
Lenalidomide is a structural analog to thalidomide that is 50,000 times more potent in inhibiting TNF-α (Muller et al., 1999).
Similar to thalidomide, it has direct antitumor activities via activation of caspase-8, which may stimulate G0/G1 growth arrest
(Raje, Hideshima, & Anderson, 2006). Immunomodulatory drugs like lenalidomide may disrupt cytokine secretion and cellular
adhesion through downregulation of NFκB (regulates cell cycle, apoptosis, and cytokine production), which also may play a
role in restoring sensitivity to chemotherapeutics (Mitsiades et al., 2002a). Lenalidomide decreases release of IL-6 (regulator of
myeloma cell growth), vascular endothelial growth factor (VEGF) (promotes angiogenesis), and blast growth factor (bFGF),
which is further augmented by dexamethasone (Anderson, 2005). Lenalidomide stimulates cytotoxic T-cell proliferation
50–20,000 times more than thalidomide through increased secretion of IL-2 (promotes natural killer cells) and interferon-γ
(Anderson).
Lenalidomide: Clinical Trials
In previously treated patients, lenalidomide as a single agent provided response rates of 20%–25% (Richardson et al., 2002).
Based on in vitro studies that showed synergy between lenalidomide and dexamethasone, a phase II trial was designed to add
dexamethasone to single-agent lenalidomide in patients unresponsive to lenalidomide alone, with an additional 29% of
patientsresponding (Hideshima et al., 2000; Richardson, Blood, et al., 2006). These results led to two phase III double-blind,
placebo-controlled trials conducted in North America (MM-009) as well as in Europe, Australia, and Israel (MM-010), which
combined dexamethasone with lenalidomide. In both trials, lenalidomide/dexamethasone (LD) was compared to dexamethasone/placebo with response rates of 61% (MM-009) and 57% (MM-010), with CR rates of 14.1% and 15.9% (Dimopoulos et al.,
2007; Weber et al., 2007).
In a phase II trial, 34 previously untreated patients were enrolled to receive lenalidomide (25 mg on days 1–21) plus dexamethasone (40 mg on days 1–4, 9–12, and 17–20) for at least four cycles (Rajkumar et al., 2005). After the fourth cycle, patients
proceeded onto stem cell transplant or continued on the regimen with dexamethasone on days 1–4 only. The overall
combined response rate was 91%, with 18% achieving CR. Median time to progression (TTP) was 32.4 months for those patients
who did not receive transplant, and in those patients who went on to receive transplant, the median TTP had not been reached.
The two-year overall survival rates for the nontransplant group and transplant group were 90% and 92%, respectively. Grade
3/4 toxicities (55%) included fatigue (21%), neutropenia (21%), anxiety (6%), pneumonitis (6%), muscle weakness (6%), and rash (6%)
(Lacy et al., 2007; Rajkumar et al., 2005).
Based on data suggesting that clarTABLE 2: Lenalidomide-Based Combination Therapy for Previously
ithromycin may increase the bioavailUntreated Multiple Myeloma
ability of dexamethasone in patients
Study
Regimen Number of Partial
Complete
receiving thalidomide and dexametha(Study Acronym)
Patients
Response (%) Response (%)
sone, Niesvizky et al. (2006) reported the
Rajkumar et al. (2005)
L
34
79
6
Lacy et al. (2007)
D
73
18
results of the combination of onceNiesvizky
et
al.
(2006)
Bi
40
70
25
weekly dexamethasone, lenalidomide (25
(BiRd)
L
mg on days 1–21), and clarithromycin
D
in a trial of 50 patients. Response rates
Zonder et al. (2007)
LD
61
63.2
22
versus
were high, with 70% achieving PR and
D
72
47.5
3.8
25% obtaining CR (Niesvizky et al.,
Kumar et al. (2007)
L
33
68
2006). Similar to the findings in the
C
11 (VGPR)
(RCd)
d
phase III study of lenalidomide/dexamRichardson (2007)
L
28
54
35
ethasone, patients with a creatinine
B
(CR/nCR/VGPR)
(R/V/D)
D
clearance less than 40 ml/min required
dose reductions related to myelosupBi—clarithromycin; C—cyclophosphamide; CR—complete response; D—dexamethasone; d—once-weekly
pression (Niesvizky et al., 2007). Subsedexamethasone; L—lenalidomide; LD—lenalidomide/dexamethasone; nCR—near complete response; V—
bortezomib; VGPR—very good partial response
quently, the Eastern Cooperative
Oncology Group conducted a randomized phase III trial of 445 patients evaluating lenalidomide 25 mg/day for 21 days with either “high-dose” dexamethasone (40 mg/day on days 1–4, 9–12, and 17–20)
or “low-dose” dexamethasone (40 mg/day once weekly) (Rajkumar et al., 2007). This trial was halted early because of the increased
one-year survival rate observed in the low-dose dexamethasone arm (96%) compared to the high-dose dexamethasone arm (87%).
At the time of publication, response rates were unavailable; however, grade 3/4 toxicity data included neutropenia (10% versus
19%), deep venous thrombosis/pulmonary emboli (25% versus 9%), and based on in vitro studies, which showed synergy
8 | The Myeloma Messenger | March 2008
between lenalidomide and alkylating agents as well as other novel agents such as bortezomib (see Table 2) (Hideshima, Richardson, et al., 2001; Kumar et al., 2007; Richardson, Jagannath, Raje, Jakubowiak, Lonial, Avigan, et al., 2007).
Interestingly, Zonder et al. (2007) reported the results of a phase III double-blind, placebo-controlled study of LD versus highdose dexamethasone that was conducted among 198 patients. Of the 133 patients that were evaluable for response, the CR was
higher in the LD arm (22.1%) compared to the dexamethasone-alone arm (3.8%). Although both arms had high one-year survival rates, the LD arm was superior when compared to dexamethasone alone (93% versus 91%) (Zonder et al.).
In vitro, lenalidomide has been found to act synergistically with bortezomib and dexamethasone. Therefore, a phase I study in
27 relapsed/refractory patients was conducted (Hideshima, Richardson, et al., 2001; Richardson, Jagannath, Raje, Jakubowiak,
Lonial, Ghobrial, et al., 2007). Patients were treated with the combination of lenalidomide, bortezomib, and dexamethasone. The
CR/near
complete
response
(nCR)/VGPR rate was 33%, which led FIGURE 2: Mechanism of Action of Bortezomib
to a phase II trial in previously untreated patients (Richardson, Jagannath, Raje, Jakubowiak, Lonial,
Ghobrial, et al.). Among untreated patients, less toxicity, improved response
rates, and less neuropathy were observed, with 54% obtaining PR and 35%
achieving CR/nCR/VGPR (Richardson
Jagannath, Raje, Jakubowiak, Lonial,
Avigan, et al., 2007). The maximum tolerated dose was defined for bortezomib (1.3 mg/m2), lenalidomide (25
mg d1-21), and dexamethasone (20 mg),
and phase II trials are ongoing
(Richardson
Jagannath,
Raje,
Jakubowiak, Lonial, Avigan, et al.).
Additional studies have been conducted
with lenalidomide in combination with
alkylating agents of multiubiquinated
proteins that are involved in cell prolifer- bFGF—basic fibroblast growth factor; ICAM—intercellular adhesion molecule; IL—interleukin;
ation, thereby disrupting the pathways NFκB—nuclear factor-κB; TNFα—tumor necrosis factor alpha; VCAM—vascular cell adhesion molecule;
involved in signaling molecules that VEGF—vascular endothelial growth factor;
occur between the bone marrow mi- Note. Figure courtesy of Donna Weber, MD. Used with permission. Based on information from Hideshima et al., 2002;
Hideshima, Richardson, et al., 2001; Richardson, Mitsiades, et al., 2006; Roccaro et al., 2006.
croenvironment and the myeloma cells
(Richardson, Mitsiades, et al., 2006;
Roccaro et al., 2006).
Bortezomib: Clinical Trials
Bortezomib is a boronic dipeptide that blocks proteasome inhibition of the 26S proteasome (Richardson, Mitsiades, Hideshima,
& Anderson, 2006). The 26S proteasome is responsible for degradation of protein through catalytic activities. Bortezomib inhibits
the degradation of protein through catalytic activities. Bortezomib inhibits the degradation of multi- ubiquinated proteins that
are involved in cell proliferation, thereby disrupting the pathways involved in signaling molecules that occur between the bone
marrow microenvironment and the myeloma cells (Richardson et al., 2006b; Roccaro et al., 2006).
Bortezomib: Mechanism of Action
While bortezomib inhibits the proteasome, it exerts many of its effects via the NFκB signaling pathway (see Figure 2) (Hideshima
et al., 2002). In myeloma cells, immune response and growth are thought to be mediated by NFκB, and bortezomib’s blockade
of this signaling cascade leads to apoptosis (Hideshima, Richardson, et al., 2001; Roccaro et al., 2006). The blockade of NFκB signaling increases the susceptibility of myeloma cells to therapeutic agents through the downregulation of adhesion molecules
such as vascular cell adhesion molecule-1 (VCAM) (Roccaro et al.). In addition, bortezomib demonstrates activity on IL-6 production, VEGF, and growth factors, as well as direct apoptotic effects via caspase-8 and/or caspase-9 activation (Adams, 2004;
Hideshima et al., 2002; Hideshima, Richardson, et al., 2001; Mitsiades et al., 2002b; Roccaro et al.).
9 | The Myeloma Messenger | March 2008
Bortezomib: Clinical Trials
In phase I, II, and III trials, bortezomib was found to have response rates as a single agent of 25%–30% (Jagannath et al., 2004;
Orlowski et al., 2002; Richardson et al., 2003, 2005). The synergistic effect of bortezomib and dexamethasone in vitro led to further investigations of this combination in untreated patients (Hideshima, Richardson, et al., 2001).
Jagannath et al. (2005) initially reported the use of single-agent bortezomib as induction therapy. In this study, patients who had
not achieved PR after two cycles were given oral dexamethasone. Among 48 evaluable patients, an overall response rate of 90%
was observed, with 19% achieving CR/nCR. Dexamethasone was added in 75% of patients, which improved the response in
64% of those treated with the bortezomib-dexamethasone combination. The one-year survival rate for all patients was 90%.
Interestingly, in those patients who did not proceed on to stem cell transplant, the one-year survival rate was 80%, whereas those
who underwent ASCT had a one-year
survival rate of 90%. Toxicities inTABLE 3: Bortezomib-Based Combination Therapy for Previously
cluded neuropathy, thrombocytopeUntreated Multiple Myeloma
nia, fatigue, and constipation
(Jagannath et al., 2005)
Study
Regimen Number of Partial
Complete
Anderson et al. (2006) reported bortezomib’s activity as a single agent in
previously untreated patients with an
overall response of 38%, with 10%
achieving CR. These results are similar to Jagannath et al.’s (2005) response
rate before the addition of dexamethasone increased the overall response rate.
(Study Acronym)
Jagannath et al. (2005)
Anderson et al. (2006)
Oakervee et al. (2005)
Popat et al. (2005)
Jakubowiak et al. (2006)
Bortezomib
Combinations
Based on preclinical studies by
Hideshima, Richardson, et al. (2001),
bortezomib was combined with other
novel agents and/or conventional
chemotherapy in the relapsed/refractory settings. Response rates of 55%–
75% observed in the relapsed/
refractory setting provided the rationale to investigate these drugs in the
previously untreated population (see
Table 3) (Borrello et al., 2006; Cavo et
al., 2007; Chanan-Khan et al., 2007;
Corso et al., 2007; Jagannath et al.,
2007; Jakubowiak Friedman, Kendall,
Al-Zoubi, & Kaminski, 2006; Kropff
et al., 2007; Oakervee et al., 2005; Orlowski et al., 2006; Popat et al., 2005;
Reeder et al., 2007; Rosinol et al., 2007;
Terpos et al., 2007). Although bortezomib-based combination therapies
have shown excellent response rates,
randomized studies comparing them
to conventional chemotherapies and
even thalidomide/dexamethasone had
not been evaluated until recently.
Zangari et al. (2003) reported overall
response rates of 57% when borte-
10 | The Myeloma Messenger | March 2008
Borrello et al. (2006)
Orlowski et al. (2006)
Harousseau et al. (2007)
Terpos et al. (2007)
Cavo et al. (2007)
Jagannath et al. (2007)
Kropff et al. (2007)
Reeder et al. (2007)
Rosinol et al. (2007)
Patients
Response (%) Response (%)
B
D
B
48
71*
19 CR/nCR
60
28
10
B
A
D
B
A
D
B
Do
D
B
T
B
Do
BD
versus
VAD
21
71
24
18
78
11
10
18
57
32
CR/nCR
27
51
31
57
58
108
87
(post ASCT)
16
CR/nCR
38
CR/nCR
28
CR/nCR
B
Dox
D
BTD
versus
TD
23
69%
26
92
38
B
C
T
D
B
C
D
C
B
D
25
60
VGPR
25
VGPR
46
27
74
11
17
34
66
CR/nCR
B
40
33
33
38
71
21
(post ASCT)
88
95
7
31
CR/nCR
alternating
Kaufman et al. (2007)
D
B
T
D
A—doxorubicin; B—bortezomib; C—cyclophosphamide; CR—complete response; D—dexamethasone;
Dox-doxorubicin; DCEP—dexamethasone, cyclophosphamide, etoposide, platinum; Do—pegylated
liposomal doxorubicin; nCR—near complete response; P—prednisone; T—thalidomide; V—vincristine;
VGPR—very good partial response
zomib was combined with thalidomide and dexamethasone (VTD) in relapsed/refractory patients. This prompted Alexanian
et al. (2004) to conduct a retrospective review of patients who received bortezomib, thalidomide, and dexamethasone as induction
therapy prior to ASCT, demonstrating a PR rate of 84% with CR rates unconfirmed. Subsequently, other studies have investigated
this regimen with a PR rate of 71% and CR rate of 21% (Kaufman, Gleason, Heffner, & Lonial, 2007). These studies led to a phase
III study in which patients were randomized to receive either VTD (n = 92) or TD (n = 95) (Cavo et al., 2007). The results revealed
that VTD was superior to TD, with 38% achieving a CR/nCR compared to 7% with TD. In addition, the VGPR rate was superior in the VTD arm (60%) when compared to the TD arm (25%). Toxicities were similar in both groups, although neuropathy was slightly higher in the VTD arm (8%) than in the TD arm (2%) (Cavo et al.)
In a phase II randomized trial of 482 patients comparing bortezomib (1.3 mg/m2 on days 1, 4, 8, and 11) and dexamethasone (VD)
(40 mg on days 1–4 and 9–12) with VAD found superior response rates in the VD arm compared to VAD (Harousseau et al.,
2007). In this trial, patients were randomized to one of four arms in order to determine the impact of two cycles of dexamethasone, cyclophosphamide, etoposide, and platinum (DCEP) as consolidation treatment prior to ASCT. At the time of publication,
208 patients were evaluable, with a higher CR/nCR rate following ASCT in the VD arm compared to those patients receiving
VAD. In addition, DCEP did not increase CR rates before ASCT. The toxicities were similar in all arms; however, an increase
in neurologic grade 3/4 toxicities occurred in the VD arm (36%) compared to those who received VAD (11%). However, it was
not reported whether patients had improvement in their neurologic symptoms with dose reduction or cessation of the drug
(Harousseau et al.).
Conclusion
In conclusion, treatment options for patients have evolved significantly over the past 10 years, with increased response rates, including high CR rates for induction therapy. However, it remains unclear which induction program will best improve overall survival rates in the future. Therefore, treatment recommendations need to take into account renal function, cytogenetic
abnormalities, comorbidities, preexisting neuropathy, and the patient’s life circumstances in order to design an individualized optimal induction program.
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12 | The Myeloma Messenger | March 2008
newly diagnosed myeloma. Blood, 106, 4050–4053.
Rajkumar, S.V., Hussein, M., Catalano, J., Jedrzejcak, W., Sirkovich, S., Olesnyckyj, M., et al. (2006b). A randomized, double-blind, placebo-controlled trial of thalidomide
plus dexamethasone versus dexamethasone alone as primary therapy for newly diagnosed multiple myeloma [Abstract 795]. Blood, 108.
Rajkumar, S.V., Jacobus, S., Callander, N., Fonseca, R., Vesole, D., Williams, M., et al. (2007). A randomized trial of lenalidomide plus high-dose dexamethasone (RD) versus lenalidomide plus low-dose dexamethasone (Rd) in newly diagnosed multiple myeloma (E4A03): A trial coordinated by the Eastern Cooperative Oncology Group
[Abstract 74]. Blood, 110.
Reeder, C.B., Reece, D.E., Fonseca, R., Bergsagel, P.L., Hentz, J., Pirooz, N.A., et al. (2007). A phase II trial of myeloma induction therapy with cyclophosphamide, bortezomib, and dexamethasone (Cybor-D): Improved response over historical lenalidomide-dexamethasone controls [Abstract 3601]. Blood, 110.
Richardson, P., Jagannath, S., Raje, N., Jakubowiak, A., Lonial, S., Avigan, D., et al. (2007). Lenalidomide, bortezomib, and dexamethasone (Rev/Vel/Dex) as front-line therapy for patients with multiple myeloma (MM): Preliminary results of a phase 1/2 Study [Abstract 187]. Blood, 110.
Richardson, P., Jagannath, S., Raje, N., Jakubowiak, A., Lonial, S., Ghobrial, I., et al. (2007). Lenalidomide, bortezomib, and dexamethasone (Rev/Vel/Dex) in patients with
relapsed or relapsed/refractory multiple myeloma (MM): Preliminary results of a phase II study [Abstract 2714]. Blood, 110.
Richardson, P.G., Barlogie, B., Berenson, J., Singhal, S., Jagannath, S., Irwin, D., et al. (2003). A phase 2 study of bortezomib in relapsed, refractory myeloma. New England
Journal of Medicine, 348, 2609–2617.
Richardson, P.G., Blood, E., Mitsiades, C.S., Jagannath, S., Zeldenrust, S.R., Alsina, M., et al. (2006). A randomized phase 2 study of lenalidomide therapy for patients with
relapsed or relapsed and refractory multiple myeloma. Blood, 108, 3458–3464.
Richardson, P.G., Mitsiades, C., Hideshima, T., & Anderson, K.C. (2006). Bortezomib: Proteasome inhibition as an effective anticancer therapy. Annual Review of Medicine,
57, 33–47.
Richardson, P.G., Schlossman, R.L., Weller, E., Hideshima, T., Mitsiades, C., Davies, F., et al. (2002). Immunomodulatory drug CC-5013 overcomes drug resistance and is
well tolerated in patients with relapsed multiple myeloma. Blood, 100, 3063–3067.
Richardson, P.G., Sonneveld, P., Schuster, M.W., Irwin, D., Stadtmauer, E.A., Facon, T., et al. (2005). Bortezomib or high-dose dexamethasone for relapsed multiple
myeloma. New England Journal of Medicine, 352, 2487–2498.
Roccaro, A.M., Hideshima, T., Richardson, P.G., Russo, D., Ribatti, D., Vacca, A., et al. (2006). Bortezomib as an antitumor agent. Current Pharmaceutical Biotechnology, 7,
441–448.
Rosinol, L., Oriol, A., Mateos, M.V., Sureda, A., Garcia-Sanchez, P., Gutierrez, N., et al. (2007). Phase II PETHEMA trial of alternating bortezomib and dexamethasone as
induction regimen before autologous stem-cell transplantation in younger patients with multiple myeloma: Efficacy and clinical implications of tumor response kinetics. Journal of Clinical Oncology, 25, 4452–4458.
Saylan, T., & Saltik, I. (1982). Thalidomide in the treatment of Behçet’s syndrome. Archives of Dermatology, 118, 536.
Singhal, S., Mehta, J., Desikan, R., Ayers, D., Roberson, P., Eddlemon, P., et al. (1999). Antitumor activity of thalidomide in refractory multiple myeloma. New England
Journal of Medicine, 341, 1565–1571.
Terpos, E., Delimpasi, S., Anargyrou, K., Baltathakis, I., Kastritis, E., Christoforidou, A., et al. (2007). The combination of bortezomib, doxorubicin, and dexamethasone
(PAD) is an effective regimen for high risk, newly diagnosed, patients with multiple myeloma, reduces bone resorption and normalizes angiopoietin-1 to angiopoietin-2 ratio [Abstract 3596]. Blood, 110.
Weber, D., Rankin, K., Gavino, M., Delasalle, K., & Alexanian, R. (2003). Thalidomide alone or with dexamethasone for previously untreated multiple myeloma. Journal of
Clinical Oncology, 21, 16–19.
Weber, D.M., Chen, C., Niesvizky, R., Wang, M., Belch, A., Stadtmauer, E.A., et al. (2007). Lenalidomide plus dexamethasone for relapsed multiple myeloma in North
America. New England Journal of Medicine, 357, 2133–2142.
Zangari, M., Barlogie, B., Jacobson, J., Rasmussen, E., Burns, M., Kordsmeier, B., et al. (2003). VTD regimen comprising Velcade (V) + thalidomide (T) and added dexamethasone (D) for non-responders to V + T effects a 57% PR rate among 56 patients with myeloma (M) relapsing after autologous transplant [Abstract 830]. Blood, 102.
Zervas, K., Dimopoulos, M.A., Hatzicharissi, E., Anagnostopoulos, A., Papaioannou, M., Mitsouli, C., et al. (2004). Primary treatment of multiple myeloma with thalidomide, vincristine, liposomal doxorubicin and dexamethasone (T-VAD doxil): A phase II multicenter study. Annals of Oncology, 15, 134–138.
Zonder, J.A., Crowley, J., Hussein, M.A., Bolejack, V., Moore, D.F., Whittenberger, B.F., et al. (2007). Superiority of lenalidomide (Len) plus high-dose dexamethasone (HD)
compared to HD alone as treatment of newly-diagnosed multiple myeloma (NDMM): Results of the randomized, double-blinded, placebo-controlled SWOG Trial
S0232 [Abstract 77]. Blood, 110.
13 | The Myeloma Messenger | March 2008
IT ALL STEMS FROM HERE: Transplant Options for
Patients With Myeloma
Myeloablative Therapy With Autologous Stem Cell Support
Frontline treatment for multiple myeloma has incorporated the use of high-dose melphalan followed by autologous stem cell
transplant (ASCT) since initial studies showed improved complete response (CR) rates and longer overall survival (OS) compared
with conventional chemotherapy (Attal et al., 1996; Child et al., 2003). Traditionally, the conditioning regimen for ASCT is melphalan 200 mg/m2, although studies are ongoing incorporating bortezomib into conditioning regimens (Attal, Moreau, AvetLoiseau, & Harousseau, 2007). In addition, older patients and those with renal failure require dose adjustments because the standard
dose may cause increased toxicity and mortality (Bjorkstrand & Gahrton, 2007). The timing of ASCT continues to be debated, particularly with regard to its role as first remission consolidation of induction therapy or as a rescue therapy after first relapse, especially since the introduction of novel agents. A randomized study of 202 patients that compared early ASCT with ASCT after
failure of conventional chemotherapy demonstrated a longer event-free survival (EFS) in the early ASCT arm; however, OS was
not affected (Fermand et al., 1998), indicating that ASCT is appropriate either as first remission consolidation or for the treatment of first relapse of multiple myeloma. At this point, similar studies have not been conducted comparing early ASCT to
ASCT after failure of novel agent combinations.
Although single ASCT is standard treatment, studies have shown that a subgroup of patients may benefit from a double ASCT.
In a trial conducted by Barlogie et al. (1999), patients underwent a double ASCT (total therapy program), which showed an increase in CR and OS. However, the increase in OS occurred in those patients who received the second ASCT within 13 months
(Barlogie et al.). The first study to compare a single versus a double ASCT was conducted among 399 previously untreated patients who received vincristine, doxorubicin, and dexamethasone and then were randomized to receive either single ASCT or
double ASCT with melphalan 140 mg/m2 and total body irradiation (Attal et al., 2003). At a median follow-up time of 72 months,
the double ASCT arm’s median OS was twice that of the single ASCT (42% versus 21%). Further subgroup analysis identified
that those patients who had at least a 90% reduction (i.e., very good partial response [VGPR]) of their monoclonal protein three
months after single ASCT had a similar OS and EFS as counterparts that had double ASCT. In addition, those patients who
did not obtain a 90% reduction had increased OS and EFS after a double ASCT (Attal et al., 2003). Additional randomized
studies have been conducted, and three of the five additional studies did not show a benefit in OS with double ASCT compared
to a single ASCT. Therefore, in those patients who achieve at least a VGPR after a single ASCT, a double ASCT may not be
necessary (Bjorkstrand & Gahrton, 2007).
Allogeneic Stem Cell Transplant
Allogeneic stem cell transplantation (ALSCT) in myeloma remains controversial because of the increased mortality risk. More recently, the concept of “mini-allo,” or reduced-intensity conditioning (RIC-AlloSCT), has been studied in myeloma. In a randomized study, 284 high-risk patients (deletion 13 and high B2M) were randomized to either a double ASCT (n = 219) or to a single
ASCT followed by RIC-AlloSCT from a matched sibling (Garban et al., 2006). After a median follow-up of 24 months,
no significant difference was seen in progression-free survival or OS between the two treatment groups. Treatment-related mortality was low at 7%–10%. In a more recent study, patients were randomized to either a double ASCT (n = 59) or a single ASCT
followed by RIC-AlloSCT (n = 60) (Bruno et al., 2007). In this study, patients of all risk categories were included, and at a median
follow-up of 45 months, OS had not been reached in the single autologous followed by RIC-AlloSCT group but was 58 months
in the double ASCT group (Bruno et al.). However, concerns have been raised about this trial including a lower-dose conditioning regimen in the double ASCT arm and lower rates of response than have been previously noted with double ASCT (van Rhee
et al., 2007). Therefore, current recommendations stress that autologous followed by RIC-AlloSCT should be reserved for clinical
trials until additional studies confirm a clear benefit for RIC-AlloSCT.
Conclusion
The role of ASCT remains controversial, especially in the era of novel agents. Although randomized studies comparing induction
regimens are ongoing, recent randomized studies have not been done to compare ASCT to standard therapy with novel agents,
particularly utilizing similar induction regimens in both arms. In addition, while survival data is important in any study; as
patients live longer, studies which incorporate quality of life data is needed. Nurses manage toxicities and complications in order to allow
patients to receive treatment while minimizing the impact on their daily lives. Therefore, nurses can play an instrumental role in developing a quality-of-life design to incorporate into the new randomized studies.
14 | The Myeloma Messenger | March 2008
References
Attal, M., Harousseau, J.-L., Facon, T., Guilhot, F., Doyen, C., Fuzibet, J.-G., et al. (2003). Single versus double autologous stem-cell transplantation for multiple myeloma. New
England Journal of Medicine, 349, 2495–2502.
Attal, M., Harousseau, J.-L., Stoppa, A.M., Sotto, J.J., Fuzibet, J.G., Rossi, J.F., et al. (1996). A prospective, randomized trial of autologous bone marrow transplantation and
chemotherapy in multiple myeloma. Intergroupe Francais du Myelome. New England Journal of Medicine, 335, 91–97.
Attal, M., Moreau, P., Avet-Loiseau, H., & Harousseau, J.-L. (2007). Stem cell transplantation in multiple myeloma. Hematology: The Education Program of the American
Society of Hematology, 2007, 311–316.
Barlogie, B., Jagannath, S., Desikan, K.R., Mattox, S., Vesole, D., Siegel, D., et al. (1999). Total therapy with tandem transplants for newly diagnosed multiple myeloma. Blood,
93, 55–65.
Bjorkstrand, B., & Gahrton, G. (2007). High dose treatment with autologous stem cell transplantation in multiple myeloma: Past, present, and future. Seminars in Hematology,
44, 227–233.
Bruno, B., Rotta, M., Patriarca, F., Mordini, N., Allione, B., Carnevale-Schianca, F., et al. (2007). A comparison of allografting with autografting for newly diagnosed myeloma.
New England Journal of Medicine, 356, 1110–1120.
Child, J.A., Morgan, G.J., Davies, F.E., Owen, R.G., Bell, S.E., Hawkins, K., et al. (2003). High-dose chemotherapy with hematopoietic stem-cell rescue for multiple myeloma.
New England Journal of Medicine, 348, 1875–1883.
Fermand, J.-P., Ravaud, P., Chevret, S., Divine, M., Leblond, V., Belanger, C., et al. (1998). High-dose therapy and autologous peripheral blood stem cell transplantation in multiple myeloma: Up-front or rescue treatment? Results of a multicenter sequential randomized clinical trial. Blood, 92, 3131–3136.
Garban, F., Attal, M., Michallet, M., Hulin, C., Bourhis, J.H., Yakoub-Agha, I., et al. (2006). Prospective comparison of autologous stem cell transplantation followed by dosereduced allograft (IFM99-03 trial) with tandem autologous stem cell transplantation (IFM99-04 trial) in high-risk de novo multiple myeloma. Blood, 107, 3474–3480.
van Rhee, F., Crowley, J., Barlogie, B., Rajkumar, S.V., Kyle, R.A., Moreau, P., et al. (2007). Allografting or autografting for myeloma. New England Journal of Medicine, 356,
2646–2648.
15 | The Myeloma Messenger | March 2008
Goal
The goal of this continuing education activity is to examine the pathophysiology,
treatment, side effect management, and education needs of patients with multiple myeloma who are newly diagnosed.
Objectives
At the completion of the continuing education activity, the participant will be
able to
1.Understand the mechanism of action of the novel agents used in the treatment
of newly diagnosed patients with multiple myeloma.
Ms. Tiffany Richards, MS, ANP,
AOCNP®, is an advanced nurse
practitioner in the Department of
Lymphoma and Myeloma at M.D.
Anderson Cancer Center in Houston,
Texas. She earned both her bachelor’s
degree in nursing and master’s degree
in science from the University of
Wisconsin–Madison. As an advanced
oncology certified nurse practitioner, Ms.
Richards speaks to professional audiences
on the nurse’s role in the treatment and
management of patients with multiple
myeloma and Waldenström’s macroglobulinemia. Ms. Richards is on the speaker
bureau for Celgene Corporation and
Millenium Pharmaceuticals and recently
collaborated on two book chapters and
a review article on therapy in multiple
myeloma, which are soon to be
published.
2.Discuss the newest combinations of treatment agents being used in previously
untreated patients with multiple myeloma.
3.Discuss the response rates of combination therapies in the treatment of multiple myeloma.
4.Discuss complications of myeloma and their appropriate management.
5.Discuss the role of stem cell transplant in multiple myeloma.
Participants will receive 1.48 contact hours of continuing nursing education upon
review of the newspaper, listening to the podcast, and successful completion of
the associated post-test and evaluation.
ONS is accredited as a provider of continuing nursing education by the American Nurses Credentialing Center’s (ANCC’s) Commission on Accreditation.
ONS is approved as a provider of continuing education by the California
Board of Registered Nursing, Provider #2850.
Accreditation as an American Nurses Credentialing
Center’s Commission provider refers only to its continuing nursing education activities and does not imply
ANCC Commission on Accreditation endorsement of
any commercial products.
The contact hours earned from this educational opportunity qualify for initial oncology nursing certification and renewal via ONC-PRO. Visit
www.oncc.org for complete details on oncology nursing certification.
Directions for viewing podcast
and accessing post-test and evaluation
Once you have reviewed the content of this edition of ONS’s Myeloma Messenger, direct your browser to:
http://www.ons.org/ceCentral/types/hematological/myeloma.shtml
to download and listen to the accompanying podcast for this edition. You
may also access the post-test and evaluation at this URL location. A printable CNE certificate is available to participants who successfully complete
the post-test with a score of 80% or better, and who complete the evaluation.
16 | The Myeloma Messenger | March 2008