10.        Myeloma and Related Conditions

10.1        Multiple myeloma (MM)

10.1.1 General considerations

Multiple myeloma (MM) is a clonal B- cell tumor characterized by the neoplastic proliferation of terminally differentiated plasma cells within the bone marrow. The molecular and cytogenetic alterations in MM are still incompletely understood, but the importance of both the malignant clone and the bone marrow environment for disease evolution and progagation has been recognized.

The major clinical manifestations result from the production of monoclonal immunoglobulin (paraprotein) and its accumulation in the serum and/or urine ( anemia. Immunodeficiency, renal insufficiency) as well as from an osteolytic activity (pathological fractures, spinal cord compression, hypercalcemia, bone pain).

Staging has been based on the Durie-Salmon system which considers myeloma protein levels, hemoglobin, calcium, bone lesions and creatinine, but simplified systems are under development (based e.g. on serum B2- microglobulin and albumin values).

MM is a heterogeneous disease with variable prognosis, clinical course and response to therapeutic interventions. Treatment should not be started before a patient is symptomatic or ar risk for the occurrence of complications associated with the disease.

For those requiring treatment, melphalan plus prednisone (MP) has long been accepted as the standard therapy for previously untreated MM. It typically resulted in objective remission in 50-60% of the treated patients. This rate could be increased by the use of combinations of alkylating agents or of vincristine/doxorubicin/dexamethasone (VAD), however, without resulting in a clearcut survival benefit.

For patients younger than 65-70 years an autologous peripheral blood stem cell transplant now should be considered as the treatment of choice. Although curative only in a minority of patients, this approach led to improved CR rates, a prolongation of event-free and overall survival, and, likely, to an improved quality of life compared to conventional chemotherapy. Often stem cells are collected after three to four months of VAD administration. Stem cell collection can be followed either by early high-dose chemotherapy and stem cell infusion or by adminstration of alkylating agents until disease progression and late transplantation. Double (or tandem transplants may improve results, but the evidence is still weak).

Allogeneic bone marrow transplantation as an alternative is feasible in only 5 – 10% of patients (those < 55 years with high-risk MM: high B2- microglobulin levels and abnormalities of chromosome 13). The treatment-related mortality is high, however, and it cures only a minority of patients. Nonmyeloablative allogeneic transplantation is a less toxic novel treatment which exploits anti-myeloma immunity and carries the potential to improve treatment outcome.

Irrespective of the approach employed for remission induction , the majority of responders is at risk to relapse and efforts are being made to maintain the response e.g. with interferon alpha and/or prednisone.

The treatment of relapsed and refractory MM remains a challenge and there exists no”standard salvage therapy “. Outside of clinical studies the VAD-regimen can be tried. Thalidomide which brings about  responses in one third of patients is a promising agent for salvage treatment, even if the responses are relatively short-lived.

Combinations of thalidomide with pulse dexamethasone or other chemotherapeutic agents have shown promise in pilot studies (also for initial therapy). Arsenic trioxide is another agent that has shown activity in endstage MM and deserves further evaluation.

Bisphosphonates provide effective therapy and prevention of the skeletal complications of MM.

They block the development of and promote the apoptosis of osteoclasts and also prevent osteoclasts from moving to the bone surface. Furthermore they seem to suppress the production of cytokines involved in bone- resorbing process and to have a direct anti-myeloma effect. Adding bisphosphonates to the treatment of MM reduces pathological vertrebral fractures, hypercalcemia and bone pain, but, according to present evidence, not mortality.

Literature: for review e.g.

            ALEXANIAN and WEBER, Biomed. Pharmacother. 55(2001): 550-552

            BARLOGIE et al,  Semin. Oncol. 28 (2001): 577 –582 (thalidomide ) and

            Semin.

            Oncol. 29 (Suppl  17) (2002): 26 – 33 (high-dose therapy and

            immunomodulatory drugs)

CROWLEY et al, Semin. Hematol. 38 (2001): 203-208 (SWOG experience with conventional-dose therapy )

DJULBEGOVIC et al, Ann. Oncol. 12 (2001): 1611 – 1617 (evaluation of 136 randomized controlled trials from 1966 – 1998)

HAYASHI et al, Br. J. Haematol. 120 (2003): 10 – 17 (novel therapies)

HUFF and JONES, Curr. Opin. Oncol. 14 (2002): 147 – 151 (transplantation)

HUSSEIN et al, Curr. Opin. Oncol. 14 (2002): 31 – 35

KAUFMAN et al, Ann. Hematol. 80 (2001): 445- - 451

KYLE, Oncologist 6 (2001): 119 – 124 and Clin. Lymphoma 2 (2001): 21 – 28

PANDIT and VESOLE, Curr, Treat. Options Oncol. 2 (2001): 261 – 269 (relapsed MM)

PAJKUMAR et al, Mayo Clin. Proc. 77 (2002): 813 – 822

RICHARDSON et al, Biomed. Pharmacother. 56 (2002): 115 – 128

SONNEVELD and SEGEREN, Eur. J. Cancer 39 (2003):  9 – 18

WEBER, Curr, Treat. Options Oncol. 3 (2002): 235 – 245

ZWEEGMAN and HUIJGENS, Anti- Cancer Drugs 13 (2002): 339 – 351

10.1.2 Conventional induction and maintenance therapy

10.1.2.1                  Melphalan + prednisolone (MP)  Numerous variations ! E.g.

            To be repeated every 4 weeks

• Daily dosage can be increased in following cycles, if leucocytes > 3000/mm³ and trombocytes >

100000/mm³

            Literature:

            ALEXANIAN et al, J. Am. Med. Ass. 208 (1969): 1680 – 1685

BLADE et al. Hematol. J. 2 (2001): 272-278 (long-term results of two randomized PETHEMA trials comparing MP with combination chemotherapy at standard and higher doses and no differences in response duration and survival) CAVO et al, Haematologica 87 (2002): 934 – 942 (randomized study of MP vs alternating combination VAD/MP or VND/MP with no improvement of outcome for alternating therapy)

MYELOMA TRIALISTS’S COLLABORATIVE GROUP, J. Clin. Oncol. 16 (1998): 3832 – 3842

RICCARDI et al, Eur. J. Cancer 39 (2003): 31 – 37 (MM87 prospective randomized protocol of the Italian Cooperative Group of Study Treatment of Multiple Myeloma which compared MP with more aggressive first-line induction)

ZERVAS et al, Eur. J. Haematol. 66 (2001): 18 – 23 (randomized study of the Greek Myeloma Study Group which showed that combination chemotherapy alternating interferon with alpha has no advantage over MP plus interferon alpha with regard to response rate, response duration and overall survival in patients with good prognosis)

10.1.2.2  VBMCP (M-2 protocol) Numerous variations! E.g.

            To be repeated every 5 weeks

            Literature:

                        CASE et al, Am. J. Med. 63 (1977): 897 – 903

                        OKEN et al. Cancer 79 (1997): 1561 – 1567 and Cancer 86 (1999): 957 –

                        968

                        (VBMPC + interferon alpha)

ZERVAS et al, Eur. J. Haematol. 66 (2001): 18 – 23 (VBMCP + interferon alpha vs MP+ interferon alpha)

10.1.2.3 Thalidomide + dexamethasone

Candidates for high-dose treatment may persue stem cell collection and transplantation after 4 cycles, but treatment may continue beyond 4 cycles.

*   Dose escalation above 200 mg /d was stopped because of unexpected skin toxicity

**  Given only in odd cycles

      Literature:

                  RAJKUMAR et al, J. Clin. Oncol. 20 (2002): 4319 – 4323

10.1.2.4Interferon alpha

Interferon alpha as part of induction therapy or as maintenance therapy following induction chemotherapy prolongs the duration of response and (possibly) of survival, but the benefit needs balancing against cost and toxicity.

Literature:

                        ALEXANIAN et al, Am. J. Hematol. 65 (2000): 204 – 209

                        BLADE and ESTEVE , Med. Oncol. 17 (2000): 77 – 84

MYELOMA TRIALISTS’S COLLABORATIVE GROUP, Br. J. Haematol 113 (2001): 1020 – 1034 (individual patient data overview of 24 randomized trials  and 4012 patients)

10.1.2.5                    Prednisone maintenance therapy

              Until disease progression

               Literature:

                        BERENSON et al, Blood 99 (2002): 3163 – 3168 (randomized study

                        SWOG 9210 maintenance with prednisone improves PFS and OS after

                   response to conventional therapy)

10.1.3   Myeloablative and nonmyeloablative therapy with hematopoitic stem cell support

MM is highly responsive to high-dose chemotherapy based on melphalan or cyclophosphamide (± total body irradiation) or busulfan/melphalan followed by autologous (in younger patients possibly also allogeneic) bone marrow or peripheral blood stem cell transplantation. Nonmyeloablative therapy often based on melphalan and / or fludarabine can establish stable engraftment after allogeneic transplantation and maintain the antitumor effect with less toxicity than standard allogeneic transplantation.

Literature: for review and representative studies, e.g.

ALYEA and ANDERSON, Cancer J, 7 (2001): 166-174 )review of allotransplantation)

BADROS et al, Br. J. haematol, 114 (2001):600 – 607 (autotransplantation in patients > 70 years) and J, Clin. Oncol, 20 (2002): 1295 – 1303 (nonmyeloablative conditioning with “ mini” – transplantation)

BENSINGER, biomed. Pharmacother. 56 (2002): 133 – 138 (review of allotransplantation )

BJÖRKSTRAND, Semin, Hematol. 38 (2001): 219- 225 (overview of European

Group for Blood and Marrow Transplantation Registry Studies in MM)

BJÖRKSTRAND et al, Bone Marrow Transplant. 27 (2001): 511- 515 (interferon alpha maintenance treatment after autotransplantation)

FASSAS and TRICOT, Semin, Hematol. 38 (2001): 231 – 242 (review of auto-transplantation)

HUFF and JONES, Curr, Opin, Oncol. 14 (2000): 147-151 (general review of all types of transplantation)

HUIJGENS et al, Bone Marrow Transplant. 27 (2001): 925 – 931 (tandem transplantation)

KRÖGER et al, Blood 100 (2002): 755 – 760 (autotransplantation followed by “mini”- allotransplantation)

LAHUERTA et al, leuk. Lymphoma 43 (2002): 67 – 74 (comparison of conditioning regimens)

MOREAU et al, Blood 99 (2002): 731 – 735 (IFM 9502 trial comparing 8 Gy TBI+ HDM 140 vs HDM 200)

PANDIT and VESOLE, Oncology 16 (2002): 1268-1274 (review of allotransplantation )

10.1.4   Salvage therapy

10.1.4.1 High-dose dexamethasone

To be repeated every 4 – 5 weeks

Literature:

            ALEXANIAN et al, Ann. Intern. Med. 105 (1986): 8 – 11

10.1.4.2 VAD Many variations! E.g.   

            To be repeated every 4 – 5 weeks

* Cycle 1 only

Literature:

            BARLOGIE et al, N. Engl. J. Med. 310 (1984): 1353-1356

            EGERER et al, Support. Care Cancer 9 (2001): 380 – 385 (outpatient treatment)

            MINEUR et al, Br. J. Haematol. 103 (1998): 512- 517

10.1.4.3 VBMCP see 10.1.2.2

            Literature:

                        MINEUR et al, Br. J. Haematol. 103 (1998): 512 – 517

10.1.4.4Low-dose cyclophosphamide + prednisone

Treatment was maintained until development of signs of progression or of any WHO side effect grade 3 and 4

* Reduced to 50 mg/d when neutrophils and/or platelets dropped below 1 x 10⁹/1 and/or platelets dropped below 0.5 x 10⁹/1  and/or 30 x 10⁹/1, respectively

**  Tapered to 10 mg/d within 8 weeks

Literature:

            DeWEERDT et al, Neth. J. Med. 59 (2001): 50 – 56

10.1.4.5thalidomide

* Median dose generally in the range of 400 mg

Literature:

            BARLOGIE et al, Blood 98 (2001): 492 – 494

            CAVENAGH et al, Br. J. haematol. 120 (2003): 18 – 26 (review and guidelines)

            KYLE and RAJKUMAR, Semin. Oncol. 28 (2001): 583 – 587 (review)

            RIBAS and COLLEONI, leuk. Lymphoma 44 (2003): 291 – 298 (review)

            SINGHAL et al, N. Engl. J. Med. 341 (1999): 1565 – 1571

            TOSI et al, Haematologica 87 (2002): 408 – 414

            YAKOUB-AGHA et al, Hematol. 3 (2002): 185 – 192

or

Thalidomide + dexamethasone

• During first course sometimes repeated on d  9 – 12 and d 17 – 20

Literature:

                        DIMOPOULOS et al, Ann. Oncol. 12 (2001): 991-995

                        PALUMBO et al, Haematologica 86 (2001): 399 – 403

10.1.5       Bisphosphonates, e.g.

Pamidronate

or

Zoledronic acid

or

Clodronate

Literature:

            BERENSON, Semin. Oncol. 19 (Suppl 17) (2002): 11 – 16 (review)

BERENSON et al, j. Clin. Oncol. 20 (2002): 3719 – 3736 (ASCO Clinical practice Guidelines)

            JANTUNEN, Eur. J. haematol, 69 (2002): 257 – 264 (review)

McCLOSKEY et al, br. J. haematol. 113 (2001): 1035 – 1043 (long-term follow-up of a prospective, double-blind, placebo-controlled randomized trial of clodronate)

            TERPOS et al, Eur. J. Haematol. 70 (2003): 34 – 42 (pamidronate vs  

            ibandronate)