Induction Therapy in Multiple Myeloma

Background: Current definition of multi-hit multiple myeloma (MM) is based upon the number of high-risk cytogenetic abnormalities (CA). But we may overlook the influence of standard-risk CA and different concurrent patterns. In fact, standard-risk t(11;14) and del(13q) may bring extra danger when concurrent with other CA. And the concurrency of two secondary CA may do more harm to patients than that of one secondary CA with one primary CA. This study is to answer whether CA number or pattern exert an impact on outcomes of MM patients. Methods: This study was carried out based on the prospective, non-randomized clinical trial BDH 2008/02. 537 MM patients with complete cytogenetic data were enrolled, of whom 64% (341/537) patients were treated with bortezomib-based three-drug induction therapy, and the remaining patients with thalidomide-based therapy. Autologous stem cell transplantation (ASCT) was recommended post induction therapy in transplant-eligible patients, and all patients received maintenance therapy for two years. CA were divided into primary CA [pCA: any type of IgH breakage], and secondary CA [sCA: del(17p), del(13q), gain(1q) (≥3 copies)] Results: In the era of novel agents, patients with pCA only did not have outcomes different from those patients without any FISH abnormality. Patients with s1 CA or s1+p CA had hazard ratio for PFS or OS of 1.5-2.0. Patients with s2 CA or s2+p CA had hazard ratio for PFS or OS of 2.0-3.0. Patients with concurrent del(13q), del(17p) and gain(1q) (s3 CA) had hazard ratio for PFS of 3.11 and for OS of 3.00. Patients with s3+p CA had hazard ratio for PFS of 4.65 and for OS of 6.16. Based on these results, we divided patients into four subgroups: no CA or only pCA, s1 CA in the presence or absence of pCA, s2 CA in the presence or absence of pCA, and s3 CA in the presence or absence of pCA. Both the PFS and OS decreased in a stepwise fashion with the accumulation of CA (Figure 1). Therefore, we defined double-hit MM as any one sCA in the presence or absence of pCA. Triple-hit MM referred to two sCA plus pCA or not, and quadra-hit MM referred to three sCA plus pCA or not. Furthermore, we confirmed the prognostic independence of CA pattern in the multivariant analysis with International Staging System (ISS) and LDH (Table 1). Conclusion: In this study, we found that the primary CA as a whole lost its adverse effect when treated by bortezomib-based regimens. CA subtype conferred a prognostic value. In details, secondary CA imposed an accumulative risk to patients. For the first time, we indicated that double-hit or triple-hit MM should be defined upon the number of secondary CA. This definition coincides with the "Two-Hit" theory of cancer causation and fits well with MM evolution model. The prognostic significance of CA pattern needs validation in further prospective trials. Disclosures No relevant conflicts of interest to declare.

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ECOG-ACRIN EAA181: Effective quadruplet utilization after treatment evaluation (EQUATE)—a randomized phase 3 trial for newly diagnosed multiple myeloma (NDMM) not intended for early autologous transplantation.

Journal of Clinical Oncology ◽

10.1200/jco.2021.39.15_suppl.tps8052 ◽

2021 ◽

Vol 39 (15_suppl) ◽

pp. TPS8052-TPS8052

Author(s):

Shaji Kumar ◽

Zihan Wei ◽

Michael A. Thompson ◽

Bradley Snyder ◽

Matthias Weiss ◽

...

Keyword(s):

Multiple Myeloma ◽

Induction Therapy ◽

Residual Disease ◽

Intensive Therapy ◽

Autologous Transplantation ◽

Chronic Obstructive ◽

Newly Diagnosed ◽

Operating Characteristics ◽

Obstructive Pulmonary Disease ◽

Depth Of Response

TPS8052 Background: The monoclonal antibody (MoAb) daratumumab (dara) has been approved for treatment of newly diagnosed Multiple Myeloma (NDMM) in combination with lenalidomide (len) and dexamethasone (DRd) in patients who are not eligible to undergo stem cell transplantation (SCT). Ongoing trials are examining the role of adding bortezomib (Btz) to DRd, but it remains unclear if all patients benefit from a quadruplet regimen. Availability of sensitive assays to detect measurable/minimal residual disease (MRD) in MM and emerging data demonstrating significant prognostic value for attaining MRD negativity, offers an unprecedented opportunity to develop individualized treatment approaches. An important question is to identify who benefits from adding a fourth drug to the MoAb-IMiD triplet, thus individualizing therapy based on depth of response. We hypothesize that prolonged intensive therapy with the addition of Btz for consolidation and maintenance after DRd induction therapy for NDMM will improve survival outcomes with a more pronounced effect when used in MRD positive patients. Methods: Patients with NDMM, R-ISS Stage I or II, who are not eligible to undergo SCT or those willing to defer SCT to first relapse and have not received more than 1 cycle of any NDMM therapy will be enrolled, provided they have measurable disease, adequate organ and marrow function, have received no more than once cycle of therapy for MM and significant peripheral neuropathy or chronic obstructive pulmonary disease. Importantly, a dominant clone should be identified by lymphotrack assay for future MRD monitoring. Once enrolled, induction therapy will be in 28 day cycles consisting of daraSC (1800 mg) weekly for 2 cycles, every other week for cycles 3-6 and then every 4 weeks for 9 cycles, along with len 25 mg days 1-21 of each cycle and dex 40 mg (20 mg for those > 75 years) weekly. At end of 9 cycles (induction), patients will undergo MRD testing by next generation sequencing and will be classified into MRD positive or negative subgroups. Using MRD as an integral biomarker, the trial employs a randomized biomarker-stratified design as proposed by Freidlin et al. to determine efficacy for each MRD subgroup. Patients will be stratified by MRD status and R-ISS stage and randomized to receive 9 cycles of consolidation with DRd, without (control arm) or with (experimental arm) Btz (1.3 mg/m2 weekly for 3 of 4 weeks), followed by DR maintenance until progression The primary endpoint is consolidation OS. Sample size considerations rest on estimates of MRD subgroup prevalence at the end of induction and operating characteristics establishing the treatment effect within the MRD positive subgroup as primary and MRD negative subgroup as key secondary. The total accrual goal is 1450 patients. Clinical trial information: NCT04566328.

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Maintenance Therapy With Bortezomib and Dexamethasone for Transplant-ineligible Patients With Multiple Myeloma

Cancer Diagnosis & Prognosis ◽

10.21873/cdp.10006 ◽

2021 ◽

Vol 1 (2) ◽

pp. 35-42

Author(s):

YURIKA NOGUCHI ◽

NORIYOSHI IRIYAMA ◽

HIROMICHI TAKAHASHI ◽

YOSHIHITO UCHINO ◽

MASARU NAKAGAWA ◽

...

Keyword(s):

Multiple Myeloma ◽

Overall Survival ◽

Maintenance Therapy ◽

Induction Therapy ◽

Survival Rates ◽

Patient Characteristics ◽

Newly Diagnosed ◽

Estimated Glomerular Filtration Rates ◽

Overall Survival Rates ◽

Maintenance Group

Background/Aim: Here, we investigated whether bortezomib as a maintenance therapy affected outcomes in transplant-ineligible patients with multiple myeloma (MM). Patients and Methods: Following induction therapy with bortezomib, maintenance therapy with bortezomib (1.3 mg/m2) and dexamethasone (20 mg) was administered once or twice every 4 weeks until disease progression. The endpoints of this study were time to next treatment and overall survival. Results: Seventy-six newly diagnosed, transplant-ineligible patients were treated with a bortezomib-based regimen; 28 discontinued induction therapy, 27 did not receive maintenance therapy after induction therapy (the non-maintenance group), and 21 did (the maintenance group). In the three groups, the median times to the next required treatment were 3, 14, and 37 months, respectively. The 3-year overall survival rates were 55%, 69%, and 85%, respectively. There were no significant differences in patient characteristics between the non-maintenance and maintenance groups, except for poorer estimated glomerular filtration rates in the maintenance group. Conclusion: Bortezomib maintenance therapy may be a useful option for transplant-ineligible patients with MM.

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