Plasmocytoma: Drug Therapy

Therapeutic target

Achievement of remission (remission of disease symptoms).

Therapy recommendations

SLiM-CRAB criteria of multiple myeloma requiring therapy.

Therapy requirement formally occurs when any of the following SLiM-CRAB criteria are met:

Myeloma-defining biomarkers (SLiM criteria).
  • Clonal plasma cell infiltration in the bone marrow ≥ 60 % (English ” sixty percent”)
  • Ratio of free light chains (involved/uninvolved light chains) ≥ 100 (engl. ” light chain”).
  • On MRI ≥ 2 focal lesions (at least 5 mm in diameter).
Organ damage (CRAB criteria).
  • C: Hypercalcemia: serum calcium > 0.25 mmol/l (> 1 mg/dl) above the upper norm or > 2.75 mmol/l (> 11 mg/dl)
  • R: renal function impairment (renal insufficiency): creatinine clearance < 40 ml/min or serum creatinine > 2 mg/dl (> 177 μmol/l).
  • A: Anemia: hemoglobin > 2 g/dl below the lower norm or < 10 g/dl.
  • B: Bone lesions: at least 1 osteolysis (bone tissue dissolution) on CT, PET-CT, or skeletal x-ray.

Legend: CT = computed tomography; PET-CT = positron emission tomography/computed tomography.

Therapy is based on the stage:

  • Stage I – “wait and see” (regular examinations):
    • Smouldering myeloma (“smoldering myeloma”): usually no therapy (“watch and wait”)
      • Therapy, however, in high-risk constellations (e.g., monoclonal protein ≥ 30 g/L), myeloma foci in bone marrow (MRI), quotient for free light chain test outside normal range (0.3 – 1.6))
  • Symptomatic multiple myeloma (MM; see below “SLiM-CRAB criteria of multiple myeloma requiring therapy“).
    • Stage II – Radiation therapy (radiotherapy, radiatio), because plasmacytoma is highly radiosensitive. However, radiotherapy can only be used to treat individual tumor foci (see below Radiotherapy).
    • Stage II/III – usually combined chemotherapy (see below) and radiotherapy.
  • Individuals < 70 years of age (without serious comorbidities/concomitant diseases) should receive high-dose therapy with autologous stem cell transplantation (blood stem cell transplantation) after induction therapy.
  • Substitution of immunoglobulins in antibody deficiency.
  • Bisphosphonates (concomitant therapy) to prevent osteolytic bone lesions (bone destruction due to bone resorption); in the case of dental procedures, antibiotic prophylaxis is required during bisphosphonate therapy
  • See also under “Other therapy.”

Note: Early antibiotic prophylaxis with levofloxacin (fluoroquinolone) reduces the risk of infection by 34% in newly diagnosed myeloma patients. Further notes

  • Elderly patients (> 75 LY) with multiple myeloma appear to have limited benefit from the usual -triple combination!The FIRST trial (Front-Line Investigation of REVLIMID/Dexamethasone vs. Standard Thalidomide) for first-line treatment demonstrated the superiority of the combination of lenalidomide and low-dose dexamethasone over the standard combination of melphalan/prednisone/thalidomide (MPT) in terms of progression-free survival (PFS) and overall survival (OS) for elderly patients. In the lenalidomide–dexamethasone group, the OS rate at four years was 52% versus 39% with MPT (HR 0.72). Note: Toxicity of the two-drug combination is lower than that of the three-drug combination.Continuous therapy significantly improved progression-free survival to first relapse (PFS-1), to second relapse (PFS-2), and overall survival (OS) in a pooled analysis. The extension of PFS-2 makes it likely that the benefit during the first remission phase is not negated by a shortened second remission.
  • Selinexor (XPO1 inhibitor; “Selective Inhibitor of Nuclear Export,” SINE; this prevents tumor cells from creating tumor suppressor proteins from the nucleus), in combination with dexamethasone, achieved remissions in a quarter of multiple myeloma patients in a phase 2 trial in patients who were “off therapy”; 26% of patients had a detectable decrease in plasma myeloma proteins of at least 50% (including 2 patients with a stringent complete remission).
  • Lenalidomide has been approved as monotherapy for the maintenance treatment of adults with newly diagnosed multiple myeloma who have received autologous stem cell transplantation (ASCT) (European Commission, 2017). Other indications include (see also below* ):
    • For the treatment of adults with untreated multiple myeloma who are not transplantable.
    • In combination with dexamethasone for the treatment of multiple myeloma in adults who have received at least one prior therapy
  • CAR-T cell therapy* : Phase I study result: remission was achieved in 28 of the first 33 patients (85%); it was complete in 15 patients (45%).A cure is not expected in plasmacytoma; 6 of the 15 patients with complete remission have since relapsed (recurrence of disease); remissions lasted an average of 11.8 months.
  • Red-hand letter on thalidomide: AkdÄ Drug Safety Mail | 32-2015: the initial dose of thalidomide when used in combination with melphalan should be reduced in patients older than 75 years.
  • Red-hand letter on pomalidomide: AkdÄ Drug Safety Mail | 17-2016: In rare cases (less than 1/1,000), hepatitis B reactivation occurs in patients who received pomalidomide in combination with dexamethasone and were previously infected with hepatitis B virus (HBV).
  • Red-hand letter on lenalidomide: AkdÄ Drug Safety Mail | 39-2016: new important note on reactivation of viral infections.
  • Adults with previously untreated multiple myeloma who are not eligible for transplantation should receive lenalidomide in combination with bortezomib and dexamethasone.

* CAR T-cell therapy (“chimeric antigen receptor T cells”): patient’s own T cells are genetically engineered outside the body (ex vivo) with chimeric antigen receptors (“CAR”) to specifically target the cancer. These cells are then reinfused into the body. They then bind to the corresponding tumor characteristics (in this case: “B-cell maturation antigen” (BCMA)) on the lymphoma cells, leading to a sustained immune response through the release of chemokines, cytokines and lytic molecules. Side effects: The release of the previously mentioned endogenous messengers (cytokine storm) may result in high fever and life-threatening organ damage; other possible side effects include tumor lysis syndrome (TLS; life-threatening metabolic derailment that can occur when a large number of tumor cells are suddenly destroyed) and neurotoxicity (property of a substance to have a damaging effect on nerve tissue).

Agents (main indication)

Cytostatics

  • Fit patients: Therapy with melphalan (high dose); followed by autologous stem cell transplantation.
  • Unfit patients: limited duration of therapy VMP (bortezomib/melphalan/prednisone) regimen or the continuous Rd(lenalidomide/dexamethasone) regimen (median progression-free survival of approximately two years).
  • Caveat: Melphalan is stem cell toxic (do not use before stem cell mobilization).
  • No information on dosages is given here, as changes in the respective regimens often occur during chemotherapy.

Therapy combinations for first-line treatment of multiple myeloma.

Scheme Active ingredients/dosage Cycle duration Cycle count Approval
VCd Bortezomib (V)
Cyclophosphamide (C)
Dexamethasone (d) 		3 TE: usually 3-4 (or until HDT). EU
VRd Bortezomib (V)
Lenalidomide (R)
Dexamethasone (d) 		3 TE: usually 3-4 (or until HDT).
NTE: 5 max.8 cycles, Rd until progression or toxicity. 		EU, CH
RVD lite Lenalidomide (R) bortezomib (V)
Dexamethasone (d) 		5 RVd for 9 cycles, then RV for 6 more cycles.
Lenalidomide maintenance optional until progression or toxicity 		EU
(D-)VMP Daratumumab (D)
Bortezomib (V) (from cycle 2)
Melphalan (M)
Prednisone (P) 		6 D: weekly cycle 1, 3-weekly cycles 2-9, then 4-weekly until progression or toxicity VMP max. 9 cycles EU, CH
(D-)Rd Daratumumab (D)
Lenalidomide (R)
Dexamethasone (d) 		4 D: weekly cycles 1-2, 2-weekly cycles 3-6, then 4-weekly.
Rd until progression or toxicity All therapies until progression or toxicity. 		EU

Legend

  • TE = patients eligible for transplantation.
  • NTE = patients for whom transplantation is not an option.
  • HDT = high-dose chemotherapy

The following agents can be used for treatment failure (selected regimens):

Scheme Admission requirements Comments
Lenalidomide-based
Carfilzomib/lenalidomide/dexamethasone From 2nd line
Ixazomib/lenalidomide/dexamethasone From 2nd line
Elotuzumab/lenalidomide/dexamethasone From 2nd line
Daratumumab/lenalidomide/dexamethasone (DRd). From 2nd line Daratumumab prolonged progression-free survival in a phase III trial-when added to melphalan, prednisone, and bortezomib (from 50.2% to 71.6%; 90.9% of patients achieved remission, which was complete in 42.6%)
Bortezomib-based
Daratumumab/bortezomib/dexamethasone From 2nd line
Panobinostat/bortezomib/dexamethasone From 3rd line (after bortezomib & lenalidomide pre-therapy).
More
Carfilzomib/dexamethasone From 2nd line
Daratumumab monotherapy After proteasome inhibitor and immunomodulator pre-therapy and progression during last line
Pomalidomide/dexamethasone From 3rd line (after bortezomib and lenalidomide pre-therapy) and progression during last line
Bendamustine/prednisone From primary therapy
Isatuximab in combination with pomalidomide and dexamethasone (POM-DEX). Have shown disease progression after two therapies, including lenalidomide and a proteasome inhibitor (PI), and on the last therapy. Therapy for relapsed and refractory multiple myeloma (MM) in adults.
Carfilzomib in combination with dexamethasone the CD38 antibody isatuximab. Patients with relapsed or refractory (r/r) multiple myeloma (MM) IKEMA study: longer progression-free, with comparable toxicity.
Antibody-drug conjugate belantamab-mafodotin, in which the antibody belantamab induces targeted uptake of the cytostatic drug mafodotin. Approval is limited to adult patients who have received at least 4 prior therapies. These must have included at least one proteasome inhibitor, one immunomodulatory agent, and one anti-CD38 monoclonal antibody Approval is based on is based on the results of the DREAMM-2 study.
  • Thalidomide/lenalidomide* – inhibits monoclonal immunoglobulins; in combination with dexamethasone* ; approved for primary and relapse therapy.
  • Bortezomib (proteasome inhibitor) – in combination with dexamethasone; approved for primary and relapse therapy.
  • Carfilzomib (irreversible proteasome inhibitor) – in combination with dexamethasone; since 2015, the European Commission has approved carfilzomib in combination with lenalidomide and dexamethasone; used in relapse.
  • Elotuzumab – monoclonal lgG1 (immunoglobulin G1) antibody directed against the glycoprotein SLAMF7. This glycoprotein is expressed on the surface of myeloma cells and natural killer cells.The dual mechanism of action of elotuzumab is based on activation of natural killer cells (NK cells) and antibody-mediated cellular cytotoxicity (ADCC). By stimulating natural killer cells, elotuzumab can thus influence the immune response and the body’s own tumor defense as an immuno-oncological substance. The phase III study “Eloquent-2” concluded that elotuzumab can reduce the risk of further disease progression and mortality risk by 30 percent.
  • Isatuximab (monoclonal antibody; binds to a specific epitope of the CD38 receptor): In ICARIA-MM (phase III study), isatuximab/POM-DEX resulted in a statistically significant improvement in progression-free survival (PFS) (median PFS 11.53 months vs. 6.47 months after POM-DEX alone).
  • Ixazomib (proteasome inhibitor): used in relapse; in combination with lenalidomide plus dexamethasone prolonged progression-free survival from 17.6 to 26.3 months
  • Daratumumab (the monoclonal antibody recognizes the CD 38 antigen on the cell surface, this leads to plasma cell destruction); approved for primary and relapse therapy; 2nd line indications: at least three prior treatment failures
  • Pomalidomide (immunomodulator); related to thalidomide and lenalidomide; used in relapse.
    • A particularly good response was observed in patients refractory to newer agents (including pomalidomide and carfilzomib).
    • It improved patient outcomes when the agent was used in combination with bortezomib and dexamethasone.

    Side effects: Progressive multifocal leukoencephalopathy (PML): consider differential diagnosis for new or worsening neuropsychiatric symptoms.

  • First-line: daratumumab in combination with bortezomib, melphalan, and prednisone (D-VMP): treatment of adults with newly diagnosed multiple myeloma who are not eligible for autologous stem cell transplantation. Note: Daratumumab can cause fatal hepatitis B virus (HBV) reactivation.

All agents are usually given with chemotherapy. * The addition of lenalidomide to melphalan-prednisone induction therapy in elderly patients (> 65 years) significantly prolongs progression-free survival. February 2015 Lenalidomide received European Commission approval for the treatment of adult patients with untreated multiple myeloma who are not transplantable. Further notes

  • Patients with relapsed or refractory multiple myeloma (relapsed or treatment-naïve multiple myeloma):
    • Venetoclax (inhibitor of the protein BCL-2, which protects multiple myeloma cells from programmed cell death) in combination with bortezumab and dexamethasone prolonged progression-free survival (22.4 vs. 11.5 months); increased mortality (death rate) was seen in the venetoclax group due to an increased infection rate.

Supportive/supportive measures

  • Pain management
  • Osteoprotective therapy with bisphosphate in combination with vitamin D and calcium.
  • If necessary, local radiatio (radiotherapy) of fracture-prone (bone fracture-prone) or fractured skeletal sections; if necessary, surgical skeletal stabilization (e.g., spondylodesis/surgical stiffening of spinal sections, kyphoplasty/minimally invasive procedure for the treatment of vertebral fractures of the middle and lower thoracic spine and lumbar spine)
  • Blood transfusions for anemia (anemia) or thrombocytopenia (decreased number (<150,000/µl) of platelets (thrombocytes) in the blood)
  • Immunoglobulin administration in recurrent (recurring) bacterial infections.

Hypercalcemic crisis

Therapy recommendations

  • Forced diuresis, i.e., greatly increased urine production with the aid of diuretics (dehydrating agents) with simultaneous fluid replacement.
  • Bisphosphonates (drug of choice for tumor-induced hypercalcemia (calcium excess)).
  • Glucocorticoids (inhibition of plasmacytoma cells, thereby lowering elevated serum calcium levels).