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Quadruple Therapy for Newly Diagnosed Patients With MM Shows PFS Benefit Over Triple Therapy

Allison Inserro
Quadruple therapy for newly diagnosed patients with multiple myeloma (MM) led to significantly longer progression-free survival (PFS), according to an abstract presented at the 17th International Myeloma Workshop 2019 in Boston, Massachusetts, last month.
Quadruple therapy for newly diagnosed patients with multiple myeloma (MM) led to significantly longer progression-free survival (PFS), according to an abstract presented at the 17th International Myeloma Workshop 2019 in Boston, Massachusetts, last month.

Compared with triple therapy, quadruple therapy was associated with deep responses before and after autologous stem cell transplantation (ASCT), with a significant PFS gain across all risk groups.  

Given MM’s significant spatial and temporal clonal heterogeneity, researchers believe that therapeutic agents with different mechanisms of action are required to improve both response and outcomes. These agents may be administered in combination or sequentially.

The UK NCRI Myeloma XI phase 3 trial compared a standard chemotherapy regimen of cyclophosphamide, dexamethasone plus thalidomide with a newer regimen of cyclophosphamide, dexamethasone plus lenalidomide with or without carfilzomib. Patients who did not have the best response might be randomized to receive a combination of cyclophosphamide, dexamethasone plus bortezomib. Patients may have also received more intensive chemotherapy, along with ASCT.

After maximal response was achieved, patients were treated with either long-term lenalidomide, lenalidomide with vorinostat, or receive no further treatment.

The intensive induction phase—carfilzomib, lenalidomide, cyclophosphamide, and dexamethasone (KCRD)—was compared with a response-adapted approach of sequential triplet therapies in newly diagnosed transplant-eligible patients.

Carfilzomib, a selective proteasome inhibitor (PI), is approved for the treatment of patients with relapsed or refractory MM; combination regimens incorporating a PI and immunomodulatory drug (IMiD) have been associated with deep responses and extended survival in patients with newly diagnosed MM. 

In the study, 1056 patients were randomized between KCRD (28 day cycles of carfilzomib 36 mg/m2 given intravenously days 1-2, 8-9, and 15-16; cyclophosphamide 500 mg PO day 1 and 8; lenalidomide 25 mg days 1-21; dexamethasone 40 mg days 1-4, 8-9, and 15-16), and IMiD triplet cyclophosphamide, thalidomide, and dexamethasone (CTD)/cyclophosphamide, lenalidomide, and dexamethasone (CRD) prior to ASCT.

Patients with a suboptimal response to CTD/CRD underwent response-adapted intensification randomization to a different PI (bortezomib, plus cyclophosphamide and dexamethasone, a combination known as CVD) containing triplet or no CVD. A maintenance randomization at 3 months post-ASCT compared lenalidomide with observation.

Molecular high-risk (HiR) was classified by t(4;14), t(14;16), t(14;20), del(17p) or gain(1q) with ultrahigh risk (UHiR) the presence of >1 lesions.

KCRD treatment was linked with a significantly longer PFS than IMiD triplet therapy (hazard ratio [HR] 0.63; 95% CI 0.51-0.76; 3 year PFS KCRD 64.5% vs CTD/CRD 50.3%; P <.0001). There was no significant toxicity due to the quadruplet regimen.

In addition, a higher proportion of patients receiving KCRD induction were able to undergo ASCT than those who received response-adapted induction. In an analysis restricted to those who had completed ASCT, KCRD induction was still associated with a significantly longer PFS.

There was no significant difference in PFS outcome between molecular risk groups, with a benefit for quadruple therapy over triplet therapy.

In patients receiving KCRD there was no difference in response rate at the end of initial induction by risk group, but UHiR disease was associated with significantly shorter PFS than both patients with standard risk (SR) and HiR. There was no difference in outcome between patients with HiR (1 adverse lesion only) and SR.

An exploratory analysis compared the patients receiving KCRD to patients in the CTD/CRD arm who had received the optimum response-adapted approach (ie excluding those with a suboptimal response randomized to no CVD).

KCRD was associated with significantly longer PFS than using a response adapted sequential triplet approach (HR 0.64; 95% CI 0.52-0.78; P .0001).

Reference

Pawlyn C, Davies F, Cairns D, et al. Quadruplet KCRD (carfilzomib, cyclophosphamide, lenalidomide and dexamethasone) induction for newly diagnosed myeloma patients. Presented at: 17th International Myeloma Workshop; Boston, Massachusetts September 12-15, 2019. Abstract OAB-002.

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