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Multiple Myeloma

Severe pain is a common and continuous problem with multiple myeloma; pathologic fractures may occur; bacterial infections recur with distressing frequency; and anemia, renal disease, and other manifestations may be multiple myeloma, miloma, multiple myloma. In addition, the disease is almost invariably fatal. To ease the patient's lot, it is important to call attention to the improving prognosis with therapy, and it is necessary to alleviate exaggerated fears of pathologic fractures and to stress the dangers of immobilization with the consequent further skeletal demineralization with hypercalcemia. Above all, the physician must show a sincere and continuing interest in the patients and their inevitably recurring complaints and multiple myeloma, miloma, multiple myloma.

Mobilization is of prime importance, but it often is made difficult by pain, fractures, and fear. The milder forms of pain frequently respond to salicylates or NSAIDs, but sometimes more potent analgesics such as codeine, morphine or hydromorphone are

Corticosteroids are often helpful in the treatment of pain caused by lytic lesions, soft tissue infiltration, and acute nerve or spinal cord compression; dexamethasone in doses of 4 to 20 mg daily or equivalent doses of other steroids may be used. Neuropathic pain often responds to tricyclic antidepressants such as amitriptyline, 50-150 mg at

When pain originates from a readily identifiable bone lesion, local radiotherapy usually is effective (see below). Orthopedic supports for the spine, the rib cage, or the extremities often are helpful, but these devices must be 

Anemia is a common complication of MM and causes disabling symptoms, often requiring blood transfusions. Recombinant human erythropoietin has been shown to correct the anemia in most patients without producing

Irradiation Therapy

Radiotherapy is the treatment of choice for individual painful bone lesions that do not respond to chemotherapy, for pathologic fractures, and for lesions that impair the function of vital structures. Relief of pain is prompt, pathologic fractures may heal, and impending compression of the spinal cord is prevented. Unfortunately, patients frequently return in a short time with trouble in another area and, although radiation may be given again, its use is ultimately limited by the development of bone marrow suppression, which also interferes with effective chemotherapy. Thus, it is important to restrict the field of therapy and the total administered dose, especially when the aim is relief of pain, rather than the treatment or prevention of a pathologic fracture. For the management of pain, single fractions are preferred increasingly to fractionated treatment. There was no difference in rapidity of onset or duration of pain relief between a single fraction of 8 Gy and a fractionated 2-week course of 30 Gy in a randomized study of 288 patients who had widespread bony metastases, including 23 patients with myeloma. In myeloma, tumor doses of 5 Gy frequently are effective and seldom is it necessary to exceed 15 Gy. Tumor doses in excess of 30 Gy given over a period of 3 weeks may be necessary to treat paraspinal lesions or large lytic lesions of  

Solitary Plasmacytomas

Solitary plasmacytomas of bone of extra-medullary sites should receive potentially curative local radiotherapy, using wider fields in doses of 35 to 50 Gy over 5 to 6 weeks. Unfortunately, despite adequate curative surgery and radiotherapy, up to 12% of solitary plasmacytomas will relapse locally within 10 years and 15% of patients will

Before initiating local radiotherapy for a presumed solitary plasmacytoma, the diagnostic criteria for this rare plasma cell neoplasm must be satisfied: Bone marrow aspirated at a distance must be free of monoclonal plasma


General Considerations

Because MM is a generalized disease, systemic chemotherapy is the treatment of choice. However, treatment is not indicated for asymptomatic patients (usually stage I) until previously stable disease has entered the progressive phase as indicated by clinical and laboratory changes. Ominous clinical signs of disease progression include the appearance of lytic bone lesions; most patients develop symptoms or disease progression within a year of their

Primary Chemotherapy, Conventional Dose

Intermittent courses of melphalan and prednisone represent standard chemotherapy for newly diagnosed, symptomatic myeloma. Melphalan is administered at a dose of 9 mg/m2 daily by mouth for 4 consecutive days, together with prednisone 60 mg/m2 /day or 100 mg by mouth for four days. Because the absorption of melphalan is decreased by as much as 40% with food intake, the drug should be taken on an empty stomach, perhaps 30-60

TABLE 99-9 -- Dosage Schedules
1.Melphalan and prednisone (MP)
  M--9 mg/m2 per day for 4 days (or 0.25 mg/kg dayŚ4) orally, on an empty stomach, e.g., 1 hour before breakfast
   P--100 mg/day with breakfast for 4 days
2.Cyclophosphamide and prednisone
  (A)High-dose cyclophosphamide and prednisone (HiD CP)
    C--1.0 g/m2 IV on one day only, or 0.25 g/m2 orally in the morning for 4 days, every 3 weeks
    P--100 mg/day with breakfast for 4 days, orally, every 3 weeks
  (B)Low-dose, weekly cyclophosphamide and prednisone (LoD CP)
    C--300 mg/m2 IV, or orally, once a week
    P--100 mg orally, with breakfast, every other day
  (C)Low-dose, daily cyclophosphamide
    C--60 to 150 mg/m2 /day
1, 2A and 2B reprinted with permission of Bailliere's Clinical Hematology 1995; 8(4):783-794.

(16 mg/m2 every 2 weeks for four treatments, then reducing the frequency of therapy to once every 4 weeks), but the response to therapy and survival are no better than with conventional oral therapy.

The renal clearance of melphalan has been thought to play an important role in limiting hematologic toxicity. The incidence of severe leukopenia following intravenous melphalan has been shown to be much greater in myeloma patients with renal insufficiency than in those with normal renal function, but a similar relationship has not been

Cyclophosphamide, another alkylating agent, is as effective as melphalan in the therapy of myeloma. Unlike other alkylating agents, which are equally toxic for resting and proliferating cells, cyclophosphamide is more toxic for rapidly proliferating than for resting populations. In addition, cyclophosphamide is schedule dependent, producing more effective tumor cell kill and yielding a better therapeutic ratio when given in large doses intermittently as

Although both melphalan and cyclophosphamide are alkylating agents, their respective mechanisms of action probably differ to some degree--patients resistant to one may still respond to the other. Prolonged remissions have been obtained with the second agent after the patient developed resistance to the first.

A simple treatment method, consisting of cyclophosphamide given weekly at a dose of 200 to 300 mg/m2 and

Ifosfamide, another alkylating agent, has produced good responses as a single agent in two patients with plasma cell leukemia, including one complete remission, and deserves further study. Its contribution to the effectiveness of

Carmustine (BCNU), like melphalan, is not schedule-dependent, but the intermittent administration of this agent permits the patient to be followed at less frequent intervals. The most common dosage is 150 mg/m2 intravenously

Many other drug combinations have been studied, including regimens using multiple alkylating agents, vincristine, nitrosurea and anthracyclines. Most have failed to show significantly better response rates or median survivals when


The VAD regimen combines vincristine 0.4 mg/day and doxorubicin 9 mg/m2 /day administered by continuous infusion for 4 days with oral dexamethasone, 20 mg/m2 /day for days 1-4, 9-12, and 17-20. In newly diagnosed patients, the response rate is in excess of 50%, with a median survival comparable to that of standard regimens. A similar combination using methyl-prednisone (VAMP) is equally effective, but neither has prolonged survival. The.

Interferon Alfa

Interferon-alpha-2b (IFN-alpha) is known to inhibit plasma cell growth and to produce responses in 15% of previously untreated patients. Whether superior results are obtained when IFN-alpha is added to

TABLE 99-10 -- First-Line Chemotherapy Regimen
Acronym Agents Dose Route Schedule Cycle
MP Melphalan 9mg/m2 PO days 1-4 q 4-6 wk

Prednisone 100mg PO days 1-4
CP Cyclophosphamide 1,000mg/m2 IV day 1 q 3 wk

Prednisone 100mg PO days 1-4
CP Cyclophosphamide 300mg/m2 PO day 1 q 7 d

Prednisone 100mg PO days 1-2
ABCM Doxorubicin 30mg/m2 IV day 1 q 6 wk

Carmustine 30mg/m2 IV day 1

Cyclophosphamide 100mg/m2 PO days 22-25

Melphalan 6mg/m2 PO days 22-25
VMCP Vincristine 1mg/m2 IV day 1 q 3 wk

Melphalan 6mg/m2 PO days 1-4

Cyclophosphamide 125mg/m2 PO days 1-4

Prednisone 60mg/m2 PO days 1-4
VBAP Vincristine 1mg/m2 IV day 1 q 3 wk

Carmustine 30mg/m2 IV day 1

Doxorubicin 30mg/m2 IV day 1

Prednisone 60mg/m2 PO days 1-4
VAD Vincristine 0.4mg/day IV continuous days 1-4 q 4 wk

Doxorubicin 9mg/m2 /day IV continuous days 1-4

Dexamethasone 40mg/day * IV or PO days 1-4, 9-12, 17-20
VAMP Vincristine 0.4mg/day IV continuous days 1-4 q 3-4 wk

Doxorubicin 9mg/m2 /day IV continuous days 1-4

Methylprednisolone 1,000mg IV or PO days 1-5
C-VAMP Cyclophosphamide 500mg IV days 1, 8, 15 q 3 wk

Vincristine 0.4mg/day IV continuous days 1-4

Doxorubicin 9mg/m2 /day IV continuous days 1-4

Methylprednisolone 1,000mg IV or PO days 1-5
Abbreviations: PO, orally; IV,intravenously; q, every.
* or 20 mg/m2 /day

unclear. In newly diagnosed patients, the addition of IFN-alpha to high-dose dexamethasone therapy yielded no benefits in terms of remission induction or survival. When IFN-alpha is added to melphalan/prednisone regimens, a variety of outcomes have been recorded in controlled trials:no improvement in response rate or survival time; in addition, the patients receiving IFN-alpha reported significantly more fever, chills, fatigue, pain, nausea and vomiting and loss of appetite than the control patients, and recorded a moderate reduction in global quality of life scores

High-Dose Therapy

The lack of significant progress over the past 30 years has led to the development of highly aggressive treatment regimens. Melphalan in doses of 140 mg/m2 , given intravenously without stem cell support, can induce complete remissions (CR) in 20-30% of patients, where CR is defined as a sustained absence of M-protein, and fewer than 5% plasma cells on bone marrow biopsies. The mortality rate is about 10%, however, in newly treated patients and twice that in previously treated patients. The addition of GM-CSF or G-CSF reduces the duration of neutropenia, but does not reduce significantly morbidity or mortality caused by infection, which ranges between 8 and 20%; neither does it eliminate the risk of protracted morrow aplasia, which is sometimes irreversible.

High-dose therapy supported by autologous stem cell transplantation allows for the administration of even higher doses of melphalan (200 mg/m2 ) or a combination of intensive chemotherapy and additional modalities such as total body irradiation. Complete remission rates of 30%-50% have been reported in uncontrolled studies involving newly

Maintenance Therapy

Following successful therapy at diagnosis, patients enter a plateau phase of their disease, defined as a state of tumor quiescence during which the malignant plasma cell is dormant. The achievement of a plateau phase and its duration determines the duration of survival, hence the preoccupation with prolonging its duration by therapeutic

TABLE 99-11 -- Results of Intergroupe Francaise du Myelome Trial

High Dose Therapy Standard Therapy
CR and VGPR 38% 14%
EFS (Median) 27 months 18 months
  (5 year probability) 28% 10%
O.S. (Median) Not Reached 37 months
  (5 year probability) 52% 12%
CR,complete remission; VGPR,very good partial remission; EFS,event-free survival; OS,overall survival.

means. A sine qua non of the plateau phase is a low labeling index; other characteristics include low levels of proliferation markers such as serum thymidine kinase, normal levels of oncoproteins, normal nucleoside transporters, and sIL-6 receptors. Escape from the plateau phase is associated with a bewildering array of biologic abnormalities discussed previously, including nucleoside transporter dysfunction, the emergence of the multidrug

Therapy of Multiple Myeloma in Relapse

The approach to the therapy of patients in relapse will be guided by the patient's response to therapy to date: If a relapse occurs while the patient is receiving no therapy, especially if the duration of remission has been greater than 3 months, there is a 50% probability that the patient will again respond to the original chemotherapy, usually melphalan/prednisone, but the duration of the second remission is usually shorter than the first. Second remissions

Treatment-Resistant Myeloma

When patients progress on initial therapy or no longer respond to repeat courses of first-line therapy, they require a change to other combinations of drugs or other treatment modalities.

VAD therapy is the treatment of choice for disease relapsing despite therapy with melphalan/prednisone, achieving a remission in approximately 40% of patients. In primary resistant disease, VAD or

Myeloablative Therapy in Chemo-resistant and Relapsing MM

Randomized trials, similar to those conducted for recently diagnosed MM are not available for chemo-resistant or relapsing disease. Nevertheless, encouraging studies have been reported. In one study 63 consecutive patients, two thirds of whom had resistant disease and a similar number of whom had received more than 6 months of previous chemotherapy, received either autologous bone marrow, peripheral blood stem cells (PBSC), or both following therapy with busulfan, cyclophosphamide, and TBI, or busulfan, melphalan and thiotepa. Sixteen of 63 patients

More than 500 myeloma patients have been treated with allogeneic marrow or PBSC transplants to date, but not all of these transplants involved patients in relapse. Generally, allogeneic transplants are limited to patients aged 59 or younger, who have a matched sibling or a matched unrelated donor. The treatment-related mortality has been as