Treatment of Myeloma Bone Disease

James R. Berenson, MD

Medical & Scientific Director

Institute for Bone Cancer & Myeloma Research West Hollywood, CA

Clinical Consequences of

Myeloma Bone Disease

– Non-vertebral

– Vertebral compression

• Spinal cord compression/collapse

• Radiation therapy • Surgery to bone • Hypercalcemia • Bone pain • Use of analgesics • Quality-of-life effects • Survival

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

– Non-vertebral

– Vertebral compression

• Spinal cord compression/collapse

• Radiation therapy • Surgery to bone • Hypercalcemia • Bone pain • Use of analgesics • Quality-of-life effects • Survival

Kyphoplasty: A Minimally Invasive

Fracture Reduction Procedure

KyphX Introducer Tool Kit:

• Allows precise,

minimally invasive access to the vertebral body.

• Provides working

channel.

KyphX IBT inflation:

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

endplates.

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

• Results

– 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

Kyphoplasty

Kyphoplasty

to

to

Non

Non

-

-

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

• Oral

– 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

• Intravenous

– 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.

N N O O P P HO OH OH OH OH

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 BP – The 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

• Treatment

– 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

Benefits

Risks

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

in MGUS

(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