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Drug therapy

Treatment in patients ineligible for ASCT

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, an established first-line treatment for patients not eligible for high-dose therapy with stem cell transplantation.

Lenalidomide-Dexamethasone (LenDex)

Lenalidomide-dexamethasone (LenDex) is approved as first-line treatment since 2015 after being superior to MPT (MP-thalidomid) in a clinical multicenter 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.  Elderly patients that are more fragile may be eligible to LenDex. Both MP and MPT have previously been standard first-line treatment.

Bortezomib-Lenalidomid-Dexamehtasone (VRD)

Bortezomib-lenalidomide-dexamethasone (VRD), is since 2017 documented as a better treatment than LenDex in patients where high-dose treatment was not planned. However, the average age in the study was low, and a lot of these patients would be offered ASCT at Oslo University Hospital. This is probably the most potent regimen, and should be considered for patients who are believed to tolerate it. VRD is probably the best choice for fit patients not eligible for ASCT.

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 <70 years

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

The availability of new drugs such as thalidomide, bortezomib, and lenalidomide treatment give better response before ASCT and prolonged time to progression after ASCT. The induction treatment before ASCT is 4 cycles with combinations of  myeloma directed drugs. Three 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 and the third is VRD (bortezomib, lenalidomide and dexamethasone). VRD is by many considered as the best regime.

Conditioning with melphalan alone, without total-body radiation, is recommended. The dosage is usually 200 mg/m2, but the dosage could be reduced in elderly and in patients with renal failure. Tandem ASCT is currently carried out in selected patients with high-risk disease on FISH and suboptimal response of the first ASCT.

ASCT prolongs survival in younger patients. Allogeneic stem cell transplantation has curative potential. However, the risk of fatal or troublesome side effects is so substantial that the treatment is rarely used. The treatment is not used in the routine treatment.

Patients who cannot be offered high-dose treatment are given myeloma directe drugs 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 ASCT may be performed, high-dose melphalan gives the best prognosis. Replacing medication in the induction therapy increases the chance of better response and is recommended if possible.

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
  • Proteasome 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.

  1. 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. Currently, several regimes of this type are marketed in Norway, but no one are approved by the decision-making forum.
  2. 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 proteasome inhibitor, and vice versa. If using av proteasom inhibitor in relapse, carfilzomib should be preferred unless there is severe heart disease. If bortezomib, carfilzomib and lenalidomide have been tried, pomalidomide is the next natural agent and then panobinostat. Ixazomid, elotuzumab and daratumumab are all available in Norway, but are not approved by the decision-making forum. These should be prioritized as early as possible in the course of treatment, if they can be reimbursed.
  3. Side effects that have occurred must be considered when choosing drugs.  Both bortezomib and thalidomide may cause neuropathy, and most drugs (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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