6 TREATMENT


6.1Front line therapy for symptomatic stage I, or stage II and III


6.1.1 Front line treatment with conventional dose chemotherapy
Systemic conventional-dose chemotherapy is standard option on a type C basis for the initial treatment of stage I patients with symptoms and for all patients stage II-III disease.
There is currently no firm evidence of the superiority of any polychemotherapy regimen over single agent chemotherapy. A meta-analysis performed on 18 prospective randomized trials confirmed that there is no overall difference in efficacy between the two approaches (6.XLVIII). However, multiagent combination chemotherapy might be superior to melphalan and prednisone for patients with a poorer prognosis.
The choice of the chemotherapy regimen should therefore be individualized. In older patients (over the age of 65) expected toxicity and its immediate impact on the patient's quality of life is an important end point. Intermittent courses of a combination of MP is standard treatment on a type 1 level of evidence (6.XLVIII) This approach induces a remission in approximately 40% (complete remissions are rare) of patients with newly diagnosed myeloma. Treatment is usually continued until a maximum response (plateau phase) is reached. The median duration of remission is approximately two years. Relapses are inevitable and survival curves show no evidence of plateau. The median survival in published series is approximately 3 years. On the contrary, in patients where a quick response is advisable (i.e. patients with highly symptomatic disease, hypercalcemia or renal failure), VAD (or VAMP) could be considered appropriate for individual clinical use on a type 3 level of evidence (6.XLVIII).

6.1.2 High dose therapy
At the present time high-dose therapy given as part of front-line therapy should be regarded as appropriate for non standard clinical use in young patients with aggressive disease (stage II-III), on a type 2 level of evidence (6.X, 6.XXXVI, 6.LII). Preliminary experience suggested that a larger reduction of the myeloma clone as compared to systemic conventional chemotherapy (complete remissions could be achieved in 30 to 50% of patients) could result in prolongation of remission duration and of survival, with 60 to 80% of patients still alive after 3 to 4 years after treatment. However, all studies published on autologous transplantation in multiple myeloma were possibly biased by the selection of patients, i.e. younger patients (under 65 years of age) with good performance status, without renal failure and usually responding to initial conventional chemotherapy. If the results of a French randomized study (6.XI) comparing high-dose versus conventional-dose therapy (CR 22% vs 5%, and 5-year survival 52% vs 12%) are confirmed by ongoing trials in the US and in Great-Britain, intensive therapy with autologous support could soon become standard option for patients under the age of 60. The use of two consecutive high dose treatments (6.XCII) remains strictly investigational.

The combination of chemotherapy and alfa interferon should still be considered as investigational.

6.1.3 Upfront spinal cord compression
Spinal cord compression should be recognized early and treated immediately with high-dose glucocorticoids and radiation therapy. Decompressive laminectomy is generally not required since plasma cell tumors are usually radiation-sensitive, but it might be appropriate for individual clinical use on a type R basis in patients requiring a rapid spinal cord decompression who cannot have immediate access to an adequate radiation therapy service or when total body irradiation followed by transplantation is planned in younger patients.

6.1.4 Maintenance therapy after remission induction treatment
The most reproducible effect of a-Interferon given as maintenance treatment after response to chemotherapy is the prolongation of remission duration in the range of none to approximately 12 months. However, the real benefit for a prolongation of survival is controversial (6.IX, 6.LXV). Moreover, a-Interferon is generally less useful in patients who obtained only a minor response to chemotherapy. Therefore, a-Interferon maintenance therapy could be considered as appropriate for individual clinical use on a type 2 level of evidence (6.LXVII, 6.LXXXIII, 6.XCIV, 6.XXV, 6.LXXVII, 6.XXII, 6.LXV) within the group of patients responding to initial conventional chemotherapy. In multiple myeloma, aIFN is generally used subcutaneously at a dose of 3 million units per square meter three times a week. With this dosage, the tolerance of a-IFN is usually good, the main side-effects being flu-like symptoms after the first injections, chronic fatigue, wasting, autoimmune disorders.

6.1.5 Maintenance therapy after high-dose treatment
The only randomized study on a-Interferon after high dose therapy has not yet been published (6.XXXV). In this study the median progression free survival is significantly longer in the aInterferon arm, as compared to the observation arm (39 months versus 27 months). In conclusion, aInterferon maintenance after intensive therapy remains investigational.

When used as remission consolidation, hemibody radiation (mostly 750-850 rads in 150 rads fractions, with a cumulative lung dose reduced to 600 or 650 rads) proved to be inferior to maintenance chemotherapy (6.LXXXI) or to offer no survival advantage (6.LXIX). This treatment should not be recommended in this setting. Several studies have addressed the issue of the interest of prolonged maintenance therapy with cytotoxic drugs in patients responding to initial chemotherapy (6.IV, 6.XIX, 6.XXX). When compared to no maintenance, this approach shows no survival advantage and therefore should not be recommended.


6.2Indolent and smoldering myeloma, asymptomatic stage I multiple myeloma

6.2.1 Initial approach
Wait-and-see policy is standard option for patients with indolent (6.IX), smoldering myeloma (6.LXI) and asymptomatic stage I myeloma on a type 2 level of evidence (6.LIV). Chemotherapy can be withheld until there is evidence of progression or a risk of complication. Median time to progression is approximately 2 years, ranging from 5 years for good risk patients to approximately 10 months for high risk patients. Careful evaluation of initial prognostic factors and of the rate of tumor growth should help in defining patients who are most likely to have rapid disease progression and could therefore be treated earlier, such as patients with at least one lytic bone lesion (6.XL), M component in excess of 3 g/dL or presence of Bence-Jones proteinuria.


6.3 Solitary myeloma of bone and extramedullary plasmacytoma

6.3.1 Initial approach
Radiation therapy at total doses of 35 to 50 Gy is the standard treatment on a type C basis (6.IX). Spinal cord compression should be recognized early and treated immediately with high-dose glucocorticoids and radiation therapy. Decompressive laminectomy is generally not required since plasma cell tumors are usually radiation-sensitive, but it might be appropriate for individual clinical use on a type R basis in patients requiring a rapid spinal cord decompression who cannot have immediate access to an adequate radiation therapy service or when total body irradiation followed by transplantation is planned in younger patients.


6.4 Front line treatment for Waldenström's macroglobulinemia

6.4.1 Initial approach
Large controlled therapeutic trials have not yet been conducted in Waldenström's macroglobulinemia. Treatment has been adapted from programs established for chronic lymphocytic leukemias and low grade non Hodgkin's lymphomas. Combination of an alkylating agent, such as chlorambucil or cyclophosphamide, and Prednisone is standard treatment on a type C basis. Approximately 75% of patients achieve a 75% reduction of serum monoclonal IgM and of organomegaly (with less than 10% complete remissions). Treatment is usually continued until a maximum reduction is induced and patients may eventually be followed without treatment or with a 6-12 months maintenance treatment with the same drugs. In the absence of randomized studies, the use of combination chemotherapy as front-line treatment is appropriate for individual clinical use on a type 3 level of evidence (1.IV) in patients presenting with symptomatic disease when a more rapid response is desired. Fludarabine and chlorodesoxyadenosine are investigational in previously untreated patients.


6.5 Supportive therapy

6.5.1 Bone pain and bone disease in multiple myeloma
Standard treatment of bone pain on a type C basis is chemotherapy. For pain resistant to chemotherapy, localized radiation therapy is appropriate for individual clinical use on a type R basis. Orthopedic back braces may be useful but are often poorly tolerated. Surgical treatment of pathologic fractures of long bones is recommended and should be followed by local radiotherapy. The introduction of bisphosphonates represents a major advance in the control of bone disease. Bisphosphonates are powerful inhibitors of osteoclast activity. They have first been used in the control of hypercalcemia. They also appear to induce long-term control of osteolysis complications and reduce the incidence of symptoms related to bone disease. The use of bisphosphonates is appropriate for individual clinical use on a type 2 level of evidence (6.XX, 6.LXII).

6.5.2 Hypercalcemia
Approximately 25% of patients with multiple myeloma have hypercalcemia. Prompt therapy with glucocorticoids and vigorous hydration given concomitantly with institution of systemic chemotherapy was considered the best approach to a rapid control of hypercalcemia. However, the use of bisphosphonates (particularly clodronate and pamidronate) is currently recommended to obtain a rapid reversal of hypercalcemia. Other treatments such as mithramycin, calcitonin or phosphates are not currently used.

6.5.3 Hyperviscosity
Hyperviscosity syndrome is rare in multiple myeloma (fewer than 5% of patients) but very frequent in Waldenström's macroglobulinemia (up to 50% of patients). The standard therapy of hyperviscosity syndrome is to perform plasmapheresis daily until control. Although plasmapheresis relieves hyperviscosity syndrome, systemic chemotherapy should be initiated rapidly to reduce M-component production.

6.5.4 Anemia
Anemia is the most common complication in multiple myeloma. Since the degree of anemia correlates with tumor burden, it usually improves in association with response to chemotherapy. However anemia can be multifactorial and be caused not only by marrow infiltration but also by renal failure, shortened red-cell survival, dilution due to hypervolemia. Severe anemia requires transfusion of packed red blood cells. Recombinant human erythropoietin has also been used in non-controlled studies and has proved useful not only in patients with renal failure but also in patients with low serum levels of erythropoietin (under 100 units/L) (6.XVII, 6.LXIV). At an initial dose of 150 units/K by subcutaneous injections three times a week, the treatment is well tolerated and no stimulation of myeloma cell growth has been reported. These findings have been confirmed by a recently published randomized controlled study (6.XXVIII). Erythropoietin treatment is appropriate for individual clinical use in patients with defective endogenous erythropoietin production on a type 2 level of evidence (6.XXVIII).

6.5.5Infections
Bacterial infections frequently complicate the course of multiple myeloma and infection is the direct cause of death in over 50% of patients. The introduction of aggressive therapeutic regimens also associated with prolonged hospitalization and the use of central lines modified the spectrum of responsible organisms. Whereas encapsulated organisms, particularly S. pneumoniae and hemophilus influenzae, were considered in the past as the principal causes of infection in multiple myeloma, enteric gram- negative bacilli are currently the most frequent isolates. The incidence of viral and fungal infections increases with the indications of intensive treatments. Prompt initiation of empiric broad-spectrum antibiotics is critical in multiple myeloma. The use of prophylactic antibodies is controversial and can only be appropriate for individual non standard clinical use in patients at high risk of infections. Prophylactic administration of gammaglobulins did not reduce the frequency of bacterial infections and, therefore, is not recommended. Pneumococcal vaccination often fails to produce protective antibody levels and can be considered investigational or appropriate for individual non standard clinical use.


6.6 Restaging and response criteria

6.6.1 Response criteria after conventional therapy
As M-component production usually has a quantitative relationship with tumor burden, its serial assessment is considered as a simple and useful indication of the response to treatment or of disease progression. Among the three elements used for the diagnosis of multiple myeloma (bone marrow plasmacytosis, M-component and bone lytic lesions), the evaluation of serum and urine M-component was considered as the most useful one to assess and quantify response after initial chemotherapy. Two different systems are currently used for defining response to treatment with objective criteria: the Leukemia-Myeloma Task Force of the NCI (6.XXIX) and the SWOG criteria (6.III). These criteria are listed as follows:

Chronic leukemia/myeloma Task Force

SWOG


Serum M protein
50% reduction in serum M protein on 2 measurements at least 4 wks apart		 A Responsive patients
a sustained decrease in the synthesis index of the m protein to 25% or less of the pre-treatment value on 2 measurements at least 4 wks apart
Urine M protein at least 90% reduction in 24-hr excretion on 2 measurements at least 4 wks apart a sustained decrease in 24-hr urine globulin to 10% or less of the pre-treatment values and to less than 0.2 g/24 hr on 2 measurements at least 4 wks apart
Other parameters No evidence of progression No increase in size and number of bone lesions of the skull and serum calcium must remain normal. Correction of anemia and low serum albumin level if secondary to myeloma

B Improved patients
a decrease in the synthesis index of the M protein between 50% and 25% of the pre-treatment value on 2 measurements at least 4 wks apart

C Unresponsive patients

When conventional chemotherapy is used, bone pains usually disappear but recalcification of lytic lesions is extremely uncommon.

6.6.2 Response criteria after high-dose therapy
The introduction of intensive therapy has changed the restaging strategy, because complete remissions have been obtained in up to 50% of patients.
The criteria for complete remission have been recently redefined (6.XLVI). They include:

The absence of marrow plasmacytosis on aspiration should be confirmed by bone marrow biopsy. For other investigators, more strict criteria including the absence of M-component on immunofixation are required to ascertain complete remission. However the clinical impact of a negative immunofixation is not yet known.

6.6.3 Response evaluation at the molecular level
In the context of autologous transplantation, defining more stringent criteria for complete remission could be useful. It is now possible to define a molecular level of complete remission using very sensitive PCR techniques. For instance allele-specific oligonucleotide PCR is specific of each patient's malignant clone and is sensitive enough to detect one malignant cell out of 100,000 normal cells. This PCR evaluation of minimal residual disease is useful not only for complete remission assessment but also for evaluation of contamination of autologous stem cells to be transplanted (bone marrow or peripheral blood) by the malignant clone. However the prognostic significance of a molecular remission is still unknown.

6.6.4 Relapse criteria
Relapse is assessed according to the following criteria (6.LXVII): or reappearance of the M-component in serum or urine or increase of the size or number of lytic bone lesions.


6.7 Treatment of relapsed or refractory myeloma

6.7.1 Treatment of relapsed myeloma
Optimal retreatment of patients who relapse after having achieved initial response depends on age, type of first treatment and duration of first remission. For relapses occurring after unmaintained remission, regimens similar to those used initially can induce a second remission. VAD chemotherapy is appropriate for individual clinical use, on a type 3 level of evidence, for patients who do not respond to primary treatment with an alkylating agent combined with a glucocorticoid or who relapse despite continued therapy, inducing a remission in 40% of patients (6.IX). High-dose glucocorticoids represent a valuable alternative when anthracyclines are contra-indicated. High dose chemotherapy with stem cell transplantation is appropriate for individual clinical use in younger patients (up to the age of 65) responding to second-line conventional dose chemotherapy (sensitive relapses) on a type 3 level of evidence (6.XIV, 6.XV). The probability of complete remission after autologous transplantation in patients with sensitive relapses is in the range of 30 to 40%. On the opposite, autologous transplantation is not recommended for patients with refractory relapses.

6.7.2 Treatment of relapsed myeloma
Another approach for patients with multiple myeloma resistant to both alkylating agents and VAD, is the combination of high dose cyclophosphamide (3 g/m2) and etoposide (200 mg/m2) followed by GM-CSF (6.XXXIX). Since this regimen has been evaluated in only one trial, it is should still be considered as investigational.
The use of drugs reversing in vitro the expression of the multidrug resistance gene, like verapamil or cyclosporine has been advocated in multiple myeloma resistant to VAD. The expression of the protein encoded by this gene (P-gp) is related to prior administration of chemotherapeutic agents (6.XLIX). High dose infusion verapamil in combination with VAD has reversed multidrug resistance in patients with myeloma progressing on VAD alone (6.XXXVIII, 6.LXXXII). Promising results have also been obtained with high-dose infusion cyclosporine (6.LXXXVII). However, these results are preliminary and the toxicity of these treatments is noteworthy. They remain investigational.


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6.L
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6.LXXIX
Salmon SE, Durie BG, Yung L et al. Effects of cloned leucocyte interferon in the human tumor stem cell assay. J Clin Oncol, 1983;1:217-25.

6.LXXX
Salmon SE, Haut A, Bonnet J et al. Alternating combination chemotherapy improves survival in multiple myeloma. A Southwest Oncology Group Study. J Clin Oncol 1983;1:453-61.

6.LXXXI
Salmon SE, Tesh D, Crowley J et al. Chemotherapy is superior to sequential hemibody irradiation for remission consolidation in multiple myeloma: a Southwest Oncology Group Study. J Clin Oncol 1990;8:1575-84.

6.LXXXII
Salmon SE, Dalton WS, Grogan TM et al. Multidrug-resistant myeloma: laboratory and clinical effects of verapamil as chemosensitizer. Blood 1991;78:44-50.

6.LXXXIII
Salmon SE, Crowley JJ, Grogan TM, Finley P, Pugh RP, Barlogie B. Combination chemotherapy, glucocorticoids, and interferon alpha in the treatment of multiple myeloma: a Southwest Oncology Group study. J Clin Oncol 1994;12:2405-14.

6.LXXXIV
Samson D, Newland A, Kearney J et al. Infusion of vincristine and doxorubicin with oral dexamethasone as first-line therapy for multiple myeloma. Lancet 1989;2:882-5.

6.LXXXV
Selby PJ, McElwain TJ, Nandi AC et al. Multiple myeloma treated with high dose intravenous melphalan. Br J Haematol 1987;66:55-62.

6.LXXXVI
Sidell N, Taga T, Hirano T, Kishimoto T, Saxon A. Retinoic acid-induced growth inhibition of a human myeloma cell line via down-regulation of IL-6 receptors. J Immunol 1991;146:3809-3814.

6.LXXXVII
Sonneveld P, Durie BGM, Lockhorst HM et al. Modulation of multidrug-resistant multiple myeloma by cyclosporin. Lancet 1992;340:255-9.

6.LXXXVIII
Tanaka M, Tanabe O, Iwato K et al. Sensitive inhibitory effect of interferon alpha on M protein secretion of human myeloma cells. Blood 1989;74:1718-22.

6.LXXXIX
Tobias JS, Richards JDM, Blackman GM et al. Hemibody irradiation in multiple myeloma. Radiother Oncol 1985;3:11-6.

6.XC
Tobler A, Meyer R, Seitz M, Dewald B, Baggiolioni M, Fay MF. Glucocorticoids down regulate gene expression of GM-CSF in human fibroblasts. Blood 1992;79:45-51.

6.XCI
Vesole D, Kornbluth S, Jagannath et al. Biological response modifiers in refractory multiple myeloma: lack of clinical efficacy of recombinant human interleukin 4 and all trans retinoic acid. Blood 1993;82, suppl1:p. 263a, abst.1037.

6.XCII
Vesole DH, Barlogie B, Jagannath S et al. High-dose therapy for refractory multiple myeloma: improved prognosis with better supportive care and double transplant. Blood 1994;84:950-6.

6.XCIII
Welander CE, Morgan TM, Homesley HD et al. Combined recombinant human Interferon alpha 2 and cytotoxic agents studied in the clonogenic assay. Int J Cancer 1985;35:721-9.

6.XCIV
Westin J, Rödjer S, Turesson I, Cortelezzi A, Hjorth M, Zador G. Interferon alpha-2b versus no maintenance therapy during the plateau phase in multiple myeloma: a randomized study. Br J Haematol 1995;89:561-8.

6.XCV
Westin J. Interferon alpha-2b in addition to melphalan prednisone for initial and maintenance treatment in multiple myeloma. Blood 1995;86(suppl 1):441a (abstract).




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