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ABSTRACT
Introduction
Gain/amplification of 1q (+1q) represents one of the most prevalent cytogenetic abnormalities (CAs) observed in multiple myeloma (MM). Historical studies predating the advent of anti-CD38 monoclonal antibodies (moAbs) implicated + 1q in poor prognoses, prompting its integration into novel staging systems. However, with the emergence of daratumumab and isatuximab, two pivotal anti-CD38 moAbs, the landscape of MM therapy has undergone a profound transformation.
Areas covered
This review encompasses a comprehensive analysis of diverse study methodologies, including observational investigations, clinical trials, meta-analyses, and real-world database analyses. By synthesizing these data sources, we aim to provide an overview of the current understanding of + 1q in the context of anti-CD38 moAbs therapies.
Expert opinion
Despite the paucity of available data, evidence suggests a potential mitigating effect of daratumumab on the adverse prognostic implications of + 1q. However, this benefit seems to diminish in patients harboring ≥ 4 copies or with concurrent high-risk CAs. On the other hand, isatuximab demonstrated promising outcomes in the relapsed-refractory setting for + 1q MM patients. Nevertheless, direct comparison between the two compounds is currently challenging. The current evidence firmly supports the integration of anti-CD38 moAb-based therapies as the standard of care for + 1q patients, pending further elucidation.
Article highlights
Current evidence supports the use of anti-CD38 moAb-based therapies as standard-of-care therapies for + 1q patients.
No consensus on a standard definition of 1q abnormalities has been reached and studies so far have lacked uniformity in reporting data for + 1q patients.
Available data on + 1q patients treated with daratumumab are still scarce. While acknowledging this limitation, daratumumab seems able to mitigate the negative prognostic impact of + 1q, although this benefit seems diminished, if not abolished, in patients with ≥ 4 copies or with additional high-risk CAs, and has been questioned by real-world studies.
More data have been reported for + 1q patients by RCTs that investigated isatuximab-based regimens, with subgroup analyses from two phase III trials demonstrating that isatuximab can ease the negative impact conferred by + 1q in RRMM patients.
Speculations have been made on the possibility that + 1q may confer selective resistance to daratumumab and not to isatuximab. However, this hypothesis has yet to be proved.
Abbreviation
| aCGH | = | Array comparative genomic hybridization |
| Amp1q | = | Amplification of chromosome arm 1q |
| ASCT | = | Autologous stem cell transplant |
| ASH | = | American Society of Hematology |
| BsAb | = | Bispecific antibody |
| CA | = | Cytogenetic abnormality |
| CAR | = | Chimeric antigen receptor |
| CELMoD | = | Cereblon E3 ligase modulatory drug |
| CI | = | Confidence interval |
| Cilta-cel | = | Ciltacabtagene autoleucel |
| CNA | = | Chromosomal copy number abnormality |
| CR | = | Complete response |
| DaraKd | = | Daratumumab, carfilzomib and dexamethasone |
| DaraKRd | = | Daratumumab, carfilzomib, lenalidomide and dexamethasone |
| DaraPd | = | Daratumumab, pomalidomide and dexamethasone |
| DaraRd | = | Daratumumab, lenalidomide and dexamethasone |
| DaraVCRd | = | Daratumumab, bortezomib, cyclophosphamide, lenalidomide and dexamethasone |
| DaraVd | = | Daratumumab, bortezomib and dexametashone |
| DaraVMP | = | Daratumumab, bortezomib, melphalan and prednisone |
| DaraVRd | = | Daratumumab, bortezomib, lenalidomide and dexamethasone |
| Dara-mono | = | Daratumumab monotherapy |
| EloPd | = | Elotuzumab, pomalidomide and dexamethasone |
| EloRd | = | Elotuzumab, lenalidomide and dexamethasone |
| EloVRd | = | Elotuzumab, bortezomib, lenalidomide and dexamethasone |
| EMN | = | European Myeloma Network |
| FDA | = | Food and Drug Administration |
| FISH | = | Fluorescence in situ hybridization |
| FU | = | Follow-up |
| Gain1q | = | Gain of chromosome arm 1q |
| GEP | = | Gene expression profiling |
| HiR | = | High-risk |
| HiRCA | = | High-risk cytogenetic abnormality |
| HR | = | Hazard ratio |
| Ide-cel | = | Idecabtagene vicleucel |
| IFM | = | Intergroupe Francophone du Myelome |
| IGH | = | Immunoglobulin heavy chain |
| IMiD | = | Immunomodulatory drug |
| IMWG | = | International Myeloma Working Group |
| IsaKd | = | Isatuximab, carfilzomib and dexamethasone |
| IsaKRd | = | Isatuximab, carfilzomib, lenalidomide and dexamethasone |
| IsaPd | = | Isatuximab, pomalidomide and dexamethasone |
| IsaVRd | = | Isatuximab, bortezomib, lenalidomide and dexamethasone |
| ISS | = | International Staging System |
| IxaRd | = | Ixazomib, lenalidomide and dexamethasone |
| ITT | = | Intention-to-treat |
| KCd | = | Carfilzomib, cyclophosphamide and dexamethasone |
| Kd | = | Carfilzomib and dexamethasone |
| KRd | = | Carfilzomib, lenalidomide and dexamethasone |
| LDH | = | Lactate dehydrogenase |
| LOT | = | Line of therapy |
| MGP | = | Myeloma Genome Project |
| MGUS | = | Monoclonal gammopathy of undetermined significance |
| MM | = | Multiple Myeloma |
| moAb | = | Monoclonal antibody |
| mOS | = | Median overall survival |
| mPFS | = | Median progression-free survival |
| mTTNT | = | Median time to next treatment |
| MRD | = | Minimal residual disease |
| ND | = | Newly-diagnosed |
| NDMM | = | Newly-diagnosed Multiple Myeloma |
| N/D | = | Not defined |
| NOS | = | Not otherwise specified |
| NR | = | Not-reached |
| OR | = | Odds ratio |
| ORR | = | Overall response rate |
| OS | = | Overall survival |
| PC | = | Plasma cell |
| PCL | = | Plasma cell leukemia |
| Pd | = | Pomalidomide and dexamethasone |
| PFS | = | Progression-free survival |
| PI | = | Proteasome inhibitor |
| RCT | = | Pandomized controlled clinical trial |
| Rd | = | Lenalidomide and dexamethasone |
| RR | = | Pelapsed/refractory |
| RRMM | = | Relapsed/refractory Multiple Myeloma |
| R-ISS | = | Revised International Staging System |
| R2-ISS | = | Second Revision of the International Staging System |
| sCR | = | Stringent complete response |
| SR | = | Standard-risk |
| SRCA | = | Standard-risk cytogenetic abnormality |
| SVd | = | Selinexor, bortezomib and dexamethasone |
| TE | = | Transplant-eligible |
| TI | = | Transplant-ineligible |
| TTNT | = | Time to next treatment |
| UHiR | = | Ultra-high-risk |
| Vd | = | Bortezomib and dexametashone |
| VMP | = | Bortezomib, melphalan and prednisone |
| VRd | = | Bortezomib, lenalidomide and dexamethasone |
| +1q | = | Gain/amplification of chromosome arm 1q |
Declaration of interest
The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.
Reviewer disclosures
Peer reviewers on this manuscript have no relevant financial or other relationships to disclose.
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/14712598.2024.2357382.