Treatment of Myeloma Bone Disease

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James R. Berenson, MD

Medical & Scientific Director

Institute for Bone Cancer & Myeloma Research West Hollywood, CA


Clinical Consequences of

Myeloma Bone Disease

Pathological fractures


Vertebral compression

Spinal cord compression/collapse

Radiation therapySurgery to boneHypercalcemiaBone pain Use of analgesics Quality-of-life effectsSurvival


0 10 20 30 40 50 60 Spinal cord compression Surgery to bone Hypercalcemia of malignancy Radiation to bone Pathologic fracture Total

Prevalence of Skeletal Complications in

21 months among MM Patients

†9-month data.

‡Placebo arm of pamidronate randomized trial. Berenson JR et al. N Engl J Med. 1996;334:488-493. Berenson JR, et al. J Clin Oncol. 1998;16:593-602.

Patients With SREs, %‡


Clinical Consequences of

Myeloma Bone Disease

Pathological fractures


Vertebral compression

Spinal cord compression/collapse

Radiation therapySurgery to boneHypercalcemiaBone pain Use of analgesics Quality-of-life effectsSurvival


Kyphoplasty: A Minimally Invasive

Fracture Reduction Procedure

KyphX Introducer Tool Kit:

• Allows precise,

minimally invasive access to the vertebral body.

• Provides working


KyphX IBT inflation:

• Reduces the fracture. • Compacts the bone. • May elevate


KyphX IBT Removal:

• Leaves a defined cavity

and trabecular dam that can be filled with an

approved bone void filler of the physician’s


Kyphoplasty: Use in Myeloma Patients w/

Vertebral Compression Fractures

55 procedures in 18 patients

Assess safety and efficacy using the Short Form Health Survey (SFHS) scoring system at

pre, 1, 6, 12, 36, & 52 weeks

Body pain, Physical function, Vitality, Social Function


Levels: T6-L5 (majority (56%) from T11-L5)No major complications

Improvement in SFHS assessments


The CAFÉ Study

A Multicenter, Prospective,

A Multicenter, Prospective,

Randomized, Controlled Study to

Randomized, Controlled Study to

Compare Balloon

Compare Balloon









Surgical Fracture Management*

Surgical Fracture Management*

in the Treatment of Cancer Patients

in the Treatment of Cancer Patients

with Painful Vertebral Body

with Painful Vertebral Body

Compression Fractures

Compression Fractures

*Allowed to have


Bisphosphonates in the Treatment of

Myeloma Bone Disease: Randomized Studies


Etidronate* - Belch et al, J Clin Oncol 1991

Clodronate* - Lahtinen et al, Lancet 1992; McCloskey et al, Br J Haematol 1998

Pamidronate* – Brincker et al, Br J Haematol 1998


Pamidronate* – Berenson et al, N Engl J Med 1996

Ibandronate* – Menssen et al J Clin Oncol 2002

Zoledronic acid+ – Berenson et al, Cancer 2001;

Rosen et al, The Cancer J 2001


Effect of Monthly Intravenous Pamidronate (90 mg) in Reducing Skeletal Events in Patients with Advanced Multiple Myeloma: A Phase III Trial


Zoledronic acid

Zoledronic acid belongs to a new class of bisphosphonates1,2

Heterocyclic, nitrogen-containing bisphosphonate composed of:

A core bisphosphonate moiety

An imidazole-ring side chain containing 2 critically positioned

nitrogen atoms

2-3 logs more potent than pamidronate in preclinical studies1,2

1. Green J, et al. J Bone Miner Res. 1994. 2. Green J, et al. Pharmacol Toxicol. 1997.



Zoledronic Acid in Myeloma and

Breast Cancer Patients:

Protocol 010 Trial Design

24-mo dosing regimen

Pamidronate 90 mg every 3 to 4 wk/ 120-min infusion

Zoledronic acid 4 mg and 8/4 mg every 3 to 4 wk/

5-min amended to 15-min infusion

Double-blind, double-dummy

Study duration: 25 mo

Patients received oral vitamin D 400 IU

and calcium 500 mg


Breast Cancer and Multiple Myeloma

Efficacy Summary

Time to

Multiple-Proportion first SRE Mean skeletal event analysis with SRE, % (median)* morbidity rate* hazard ratio*

ZA** 4 mg 47 376 1.04 0.841

Pam 90 mg 51 356 1.39

P value .243 .151 .084 .030

*Hypercalcemia of malignancy is included as a skeletal-related event ** ZA- zoledronic acid


Multiple Myeloma

Time to First Serum Creatinine Increase*

0 20 40 60 80 100 0 120 240 360 480 600 720 Time, days‡ P a ti en ts w it h o u t i n crease, %

n Hazard ratio† P value

ZOMETA® 4 mg–15 min 91 0.764 .502

Pamidronate 90 mg-2 hr 84

*Post–15-minute infusion amendment. †Versus pamidronate infused over 2 hours ‡After start of study drug.

ZOMETA 4 mg 91 76 71 57 32 30 18 Pamidronate 84 71 62 50 23 17 8


How to Approach the Patient w/ Rises in

Creatinine While on a Bisphosphonate (BP)

Look for possible causes besides the BPThe Cancer (myeloma, etc)

Other co-morbid diseases (diabetes, hypertension, etc)Medications (NSAIDS, COX-2 inhibitors, statins, etc)Consider a kidney biopsy

If the BP still may be the cause, hold the dose until the

creatinine returns to baseline, & since the rate of infusion relates to kidney toxicity, SLOW the infusion down

To 60 min for Zometa

To > 4 hours for Aredia

If problems persists, consider switching to the other IV BP

If does not improve the problem, discontinue intravenously administered BPs and consider Fosamax orally


Osteonecrosis of the Jaw (ONJ) &

Bisphosphonate (BP) Use

Observed among CA patients receiving IV BPs (both pamidronate & zoledronic acid)

Less frequent among pts receiving oral BPs

Relationship to BPs unproven


Good oral hygiene

Peridex (chlorhexidine gluconate) rinse or Arestin (minocycline hydrochloride) periodontal pockets

Intermittent antibiotics, antifungals or antivirals

Keep surgery to a minimum

No evidence that discontinuation of BP changes course of jaw problem


ONJ in Myeloma

Patients-The IMBCR Experience

6 cases of ONJ

Range of severity

3 patients required intermittent antibiotics (Aredia + Zometa, Zometa only in 2) - remain on bisphosphonate treatment

1 patient recently diagnosed with minor temporary discomfort (Aredia only) - remains on treatment

Largely resolved with clarithromycin PO

2 patients (Aredia + Zometa, Zometa only) discontinued

bisphosphonate secondary to significant effect on mastication

Status of myeloma

3 in long-term complete remission (auto-PSCT, VAD, thalidomide)

1 in near complete remission (on steroids)

2 with long-term indolent myeloma requiring no other therapy


IV Bisphosphonates for

Patients With Myeloma Bone

Disease—Benefits vs Risks



Fractures Radiotherapy Bone pain ONJ ? Renal (infrequent) Humeral fracture in a myeloma patient


Monoclonal Gammopathy of

Undetermined Significance (MGUS)

Pts w/ monoclonal immunoglobulin

3% of individuals over 70 years

None of the clinical manifestations of myeloma, however

Bone effects

Increased osteoclastic activity

High rate of bone loss

Enhanced risk of fracture especially vertebral compression fracture*


Phase I/II Study of ZOMETA



Patients with MGUS and osteopenia/osteoporosis (n=80)

(t-score < –1)

ZOMETA 4 mg via 15-minute infusion at 0, 6 and 12 months

Primary endpoint:

Posterior-anterior spine BMD (0 & 13 mo)

Secondary endpoints:

Nondominant proximal femur BMD Skeletal radiographs

in M-protein Progression


Myeloma Bone Disease

Conclusions (I)

Major clinical manifestation of MM

High risk of pathological fractures

Many patients receive radiotherapy

Keep radiotherapy to a minimum

Side effects

Compromises bone marrow function

Increasing recognition of the role of

kyphoplasty to treat vertebral

compression fractures


Myeloma Bone Disease

Conclusions (II)

IV zoledronic acid and pamidronate

Reduce skeletal complications

Pathologic fractures

Radiation therapy

Monitoring of kidney function

(assess monthly serum creatinine) necessary although other causes more likely to cause renal dysfunction

Osteonecrosis of the jaw may be associated with bisphosphonate use

Good oral hygiene important to emphasize

Avoid invasive dental procedures