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Drug therapy

Treatment > 65- 70 years

Melphalan-Prednisolone-Bortezomib MPV

Melphalan-Prednisolone (MP) with the addition of bortezomib (Velcade®) is documented as better treatment than Melphalan-Prednisolone ( MP- which previously was the standard treatment). Other drug combinations have not been tested against MPV. MPV is in Norway, and also in Europe, the most established and used first-line treatment for patients not relevant for high-dose therapy with stem cell transplantation.

Lenalidomide-dexamethasone (LenDex)

Lenalidomide-dexamethasone (LenDex) is approved as first-line treatment since 2015 after being better documented than MPT (MP-thalidomid) in a clinical multisenter study. There are only indirect data on which patients who should have MPV and which ones who should have LenDex. But especially patients with renal failure, high risk cytogenetics or other signs of aggressive disease will often be prioritized for MPV (however, caution in the usage of melphalan). Elderly patients that are more fragile may be relevant to LenDex. Both MP and MPT have previously been standard first-line treatment. Currently, there are no natural situations where these will be the first choice.

Treatment of patients <65 years

Standard treatment for patients <65-70 years of biological age with adequate general condition and good organ functions is HMAS (High-dose melphalan with autologous stem cell support). Treatment-related mortality is 1-2%. 

The availability of new medications such as thalidomide, bortezomib, and lenalidomide treatment give better response before HMAS and prolonged time to progression after HMAS. The induction treatment before HMAS is 4 cycles with combinations of chemotherapy and corticosteroids. Two regimes are in use  in Norway today. One is a combination of cyclophosphamide, bortezomib (Velcade®) and dexamethasone, called VCD. The other is a combination of bortezomib, thalidomide and dexamethasone, so-called VTD.

Conditioning with melphalan alone, without total-body radiation, is recommended. The dosage is usually 200 mg/m2, but the dosage should be reduced in elderly and patients with kidney failure.

HMAS may prolong survival in younger patients and in certain cases it may be appropriate to treat with allogeneic stem cell transplantation. Allogeneic stem cell transplantation has curative potential and can provide a very long remission in those with a suitable donor.  However, the risk of fatal or troublesome side effects is so substantial that the treatment is rarely used. Allogeneic stem cell transplant with reduced pre-treatment is under evaluation in multiple studies and is so far not established in the primary treatment. The treatment is  not applicable in the first-line treatment.

Patients who cannot be offered high-dose treatment are given chemotherapy to improve quality of life and prolong survival.

Treatment of solitary tumor

A small amount of patients have a solitary tumor of monoclonal plasma cells (localized disease/plasmacytoma) either in bone or extramedullary. Some of these patients can be cured with radiation and/or surgery. However, these patients must be monitored carefully for possible development of multiple myeloma.

Treatment for patients with relapse and/or refractory illness

In younger patients where HMAS may be performed, high-dose melphalan gives the best prognosis. Replacing medication in the induction therapy increases the chance of better response, but are not better documented in clinical trials. If possible, the treatment should be included in a treatment study.

Today there are many alternative drugs and drug combinations for use in relapse of myeloma. So-called «novel drugs» include anything but alkylating agents and corticosteroids.

The drugs can be divided into the following groups :

  • Alkylating agents: Melphalan, cyclophosphamide, bendamustine
  • IMiDs (Immunomodulatory Drugs): Thalidomide, Lenalidomide, Pomalidomide
  • Protease inhibitors (PIs): Bortezomib, Carfilzomib®, Ixazomib
  • Antibodies: Daratumumab, Elotuzumab
  • HDAC inhibitors: Panobinostat.
  • Corticosteroids: Dexamethasone (Prednisolone is not used in case of relapse).

A lot of considerations must be considered when choosing a combination for the treatment of relapse, and there are many different opinions about this. If good tolerance and good bone marrow function are expected, the patient will most probably benefit from triplet therapy.  That is, Dexamethasone® plus two drugs from different groups mentioned above. The best documented regimen is carfilzomib-lenalidomide-Dexamethasone. Carfilzomib is provisionally used on registration exemption.

In most cases, a novel drug should be included. it is reasonable  to change the drug group in case of relapse. That is, if the previous treatment was based on an imide, it is reasonable to base the next one on a protease inhibitor, and vice versa. HDAC inhibitors and antibodies are currently unavailable outside clinical trials.

Side effects that have occurred must be considered when choosing medication. Both bortezomib and thalidomide may cause neuropathy, and most (with the exception of thalidomide) may cause bone marrow suppression.

Other considerations may also be relevant in the assessment, such as the patient's wishes and practical implication.

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