a trial that compare two treatments in newly diagnosed myeloma patients not eligible for transplant

Conditions: Multiple Myeloma; New Diagnosis Tumor

Summary: the combination of lenalidomide plus low-dose dexamethasone (rd) is considered the new standard for elderly newly diagnosed multiple myeloma (ndmm) patients. the combination carfilzomib plus lenalidomide-dexamethasone (krd) in relapsed-refractory mm patients improved the progression-free survival (pfs) of approximately 1 year compared to standard rd treatment. in a small phase 2 trial (23 pts) the krd combination in elderly ndmm pts showed a complete response (cr) rate of 79% and a pfs at 3 years of 80%. cardiovascular adverse events are the most limiting toxicities, especially in elderly patients.

this protocol is a randomized, multicenter study designed to determine the mrd negativity and the pfs of krd treatment regimen. patients will be randomized in a 1:1 ratio to receive carfilzomib-lenalidomide-dexamethasone (krd - arm a) or lenalidomide-dexamethasone (rd - arm b). patients will be stratified basing on international staging system (iss) and fitness status using a web-based procedure completely concealed to study participants. all consecutive patients ≥ 65 years with newly diagnosed mm will be enrolled in a large randomized study during a period of 24 months. patients will be treated until disease progression or intolerance to the therapy. the only exception is for patients enrolled in krd arm who achieve at least a vgpr during the first year of treatment and in sustained mrd negativity (mrd negative at least at 10-5 after one and two years of therapy): these patients will stop carfilzomib administration after 2 years, whereas treatment with lenalidomide and dexamethasone will be continued.

Eligibility criteria:
inclusion criteria: * newly diagnosed symptomatic mm based on either standard crab criteria (at least 10% of clonal bone marrow plasma cells plus crab defined as the onset of any of the following clinical symptoms: hypercalcemia, renal failure, anemia and bone lesions) or at least 10% of bone marrow plasma cells plus the presence of at least one of the following biomarkers of malignancy: * 60% or greater clonal plasma cells on bone marrow examination; * serum involved/uninvolved free light chain (flc) ratio of 100 or greater; * more than one focal lesion on magnetic resonance imaging (mri) that is at least 5 mm or greater in size. * patient not eligible for asct (age ≥ 65 years or abnormal cardiac, pulmonary and liver function). * patient defined as fit or intermediate according to the imwg (international myeloma working group) frailty score * patient has given voluntary written informed consent. * patient is able to be compliant with hospital visits and procedures required per protocol. * patient agrees to use acceptable methods for contraception. * patient has measurable disease according to imwg criteria. * patient has ecog (eastern cooperative oncology group) performance status \< 3. * pre-treatment clinical laboratory values within 30 days before randomization: * platelet count ≥50 x 109/l (≥30 x 109 /l if myeloma involvement in the bone marrow is \> 50%) * absolute neutrophil count (anc) ≥ 1 x 109/l without the use of growth factors * corrected serum calcium ≤14 mg/dl (3.5 mmol/l) * alanine transaminase (alt): ≤ 3 x the uln * total bilirubin: ≤ 2 x the uln * calculated or measured creatinine clearance: ≥ 30 ml/minute. * lvef≥ 40%: 2-d transthoracic echocardiogram (echo) is the preferred method of evaluation; multigated acquisition scan (muga) is acceptable if echo is not available * pre-treatment blood pressure value \< 140/90 mmhg even with adequate therapy: 24 hours blood pressure monitoring is the preferred method of evaluation; blood pressure diary at home for 2 weeks is acceptable. * females of childbearing potential (fbcp) comply with the conditions of the pregnancy prevention plan, including confirmation that she has an adequate level of understanding. * fbcp must follow the pregnancy prevention plan and use a highly effective and an additional barrier contraception method simultaneously for 4 weeks before starting therapy, during treatment and dose interruptions and for at least 30 days after the last dose of study drugs\* * males must use an effective barrier method of contraception if sexually active with fcbp during the treatment and for at least 90 days after the last administration of study drug/s. male subjects must agree to refrain from sperm donation for at least 90 days after the last dose of carfilzomib. exclusion criteria: * serious medical condition, laboratory abnormality or psychiatric illness that prevented the subject from the screening or place the subject at unacceptable risk. * patient defined as frail according to the imwg frailty score. * previous treatment with anti-myeloma therapy (does not include radiotherapy, bisphosphonates, or a single short course of steroid \< to the equivalent of dexamethasone 40 mg/day for 4 days). * pregnant or lactating females. * presence of: * clinical active infectious hepatitis type a, b, c or hiv * acute active infection requiring antibiotics or infiltrative pulmonary disease * pulmonary hypertension and interstitial lung disease * uncontrolled arrhythmias or history of qt prolongation * myocardial infarction or unstable angina ≤ 6 months or other clinically significant heart disease * peripheral neuropathy or neuropathic pain grade 2 or higher, as defined by national cancer institute common toxicity criteria (nci ctc) 5.0 (appendix a) * uncontrolled hypertension defined as persistent hypertension (\>140/90 mmhg) regardless treatment with 3 drugs, including a diuretic. * contraindication to any of the required drugs or supportive treatments and hypersensitivity to any excipient of the study drugs. * known history of allergy to captisol (a cyclodextrin derivative used to solubilize carfilzomib). * invasive malignancy within the past 3 years. * administration of any experimental drug within 4 weeks prior the baseline or within 5 drug half-lives.

Keywords: multiple myeloma autologous stem cell transplantation ineligible proteasome inhibitor immunomodulating agents