Recent Advances in the Treatment of Patients with Multiple Myeloma

Regarding reviewer 1, comment 1: As you mention DOR for CART treatment you should also add the DOR to Belantamab mafodotin for comparison.

This has been added and updated with the latest data available along to the text as it has been suggested.  (Page 13, Paragraph 1, Reference [95]).

The median DoR estimate was 11 months (95% CI, 4.2–NR) in the 2.5 mg/kg group and 6.2 months (95% CI, 4.8–NR) in the 3.4 mg/kg group. With these results, the recommended dose for belantamab was 2.5 mg/kg. The most common ≥G3 AE observed in the 2.5 mg/kg cohort of patients were keratopathy (27%), thrombocytopenia (20%), anemia (20%), and pneumonia (4%)[94, 95].

Regarding reviewer 1, comment 2: You may add a paragraph to discuss treatment of high-risk disease and that, despite all improvements, we have not identified successful treatment yet to overcome high risk disease.

Since it is a cross-cutting problem that has an impact at each moment of treatment and persists as an unresolved need within the treatment of MM, it has been addressed within the conclusions:

Likewise, there are still unmet medical needs in distinct patients subgroups. Renal impairment (RI) is one of the most common complications of symptomatic MM, affecting 20–30% of patients at the time of diagnosis [107] and around 10% of them require haemodialysis, with a negative impact on prognosis [108]. Most trials performed in MM excluded patients with RI and though the use of novel anti myeloma agents have resulted in a substantial increase in the survival of patients with MM with RI, RI remains one of the most challenging situations in clinical practice. [109; 110]. Besides, the management of MM patients presenting with high-risk cytogenetic negatively affect both PFS and OS both in patients with NDMM and RRMM. Recent treatment strategies combing PI with lenalidomide/pomalidomide and double autologous stem cell transplant have shown promise for HR cytogenetic diseases. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed. (Page 14, Paragraph 3, References [107-110])

Regarding reviewer 1, comment 3: You may also mention that, in contrast to CART treatment in lymphoma, we do not see a plateau (yet?) in the survival of patients after CART.

This has been added along to the text as it has been suggested.  (Page 14, Paragraph 2).

There are other CAR-Ts in clinical and preclinical research targeting BCMA and many other antigens [105-106], so we may expect encouraging results in the near future, however there is still no plateau in survival in contrast to that seen with CAR-T cells treatment in other hematologic malignancies.

Regarding reviewer 1, comment 4 Also you may add a paragraph discussing the implication of Daratumumab in the first line for the choice of second line treatment

This has been added along to the text as it has been suggested.

(Page 7, Paragraph 3).

Finally, as it has been previously mentioned, the approval of daratumumab as combination therapy in patients with newly diagnosed transplant-ineligible (Dara-VMP, DRd) and transplant eligible (D-VTd, D-VRd) patients will expand the range of MM treatment settings in which daratumumab is an option. This highlights a new and important challenge in MM therapy in the next future for finding strategies that improve the survival of CD38 monoclonal antibody-refractory patients.

Regarding reviewer 2, comment 1: In Figure 1, an arrow form VTD/VRD/VCD to ASCT is missing and VTD/VRD/VCD should be changed to VTd/VRd/VCd.

Thanks for your suggestion, the figure has been corrected.

Regarding reviewer 2, comment 2: VMP-Rd regimen is not a standard treatment. The authors therefore should mention the efficacy of this regimen if it is noted in Figure 1.

The efficacy of this regimen was mentioned already in the text, however we have added a more information to explain it better. (Page 5, paragraph 4, Reference [37])

The GEM2010 trial phase 2 trial evaluated a sequential vs alternating administration of nine cycles of VMP and nine cycles of Rd as front-line treatment in elderly patients (N= 233). Both arms yielded similar anti myeloma efficacy bothe in terms of CR (42% vs. 40%), median PFS (32 months vs 34 months; p = 0.65), and 3-year OS (72% vs 74%; p = 0.63).[37]. Notably, MRD-negative status surpasses the prognostic value of CR achievement for PFS and OS across the disease spectrum, regardless of the type of treatment or patient risk group[38]

Regarding reviewer 2, comment 3: The authors noted that the objective of the induction is to achieve high response and rates of minimal residual disease (MRD) with minimal toxicity to preserve stem cell harvesting. Further, it was reported that low level MRD detected by NGS in the autograft product or BM cells had significant prognostic value [Takamatsu H, et al. Ann Hematol 2017].MRD assessment using flow cytometry and next generation sequence (NGS) is one of recent advances. Thus, it would be preferable to note recent assessment of MRD to obtain a deep response..

This has been added along to the text as it has been suggested.  (Page 2, Paragraph 2). Reference [6].

The objective of the induction is to achieve high response and rates of minimal residual disease (MRD) with minimal toxicity to preserve stem cell harvesting. In fact, some authors have shown that MRD negative (<10^-6) results measured by next-generation sequencing (NGS) either in the autograft product or in the bone marrow post-ASCT are associated to a significantly better PFS (96% at 4 years; p< 0.001) and OS (100% at 4 years; p = 0.04) than in MRD-positive patient [6].

Regarding reviewer 2, comment 4: The initial treatment for transplant-ineligible patients is a crucial for a better prognosis. Thus, the authors should describe the result of meta-analysis of initial treatment such as the data presented by Facon T in the ASH Annual Meeting 2019 (#2144).

This has been added along to the text as it has been suggested. 

(Page 6, Paragraph 2, Reference [43]).

The selection of treatment in elderly patients should also consider the risk of toxicity and the capability to tolerate treatment, since advanced age and the occurrence of severe adverse events may negatively affect survival. In this regard, a recent meta-analysis showed favorable efficacy outcomes for daratumumab-based regimens vs other relevant frontline options in most of the subgroups analyzed [43].

Regarding reviewer 2, comment 5: The treatment strategy for newly-diagnosed patients with renal failure or high-risk chromosomal abnormalities is still important. Most clinical trials did not included patients with renal failure that is a major complication in MM. The author therefore should be mentioned which regimen would be reasonable for those patients.

This has been addressed on the text (Page 14, Paragraph 3, References [107-110]).

Since it is a cross-cutting problem that has an impact at each moment of treatment and persists as an unresolved need within the treatment of MM, it has been addressed within the conclusions:

Likewise, there are still unmet medical needs in distinct patients subgroups. Renal impairment (RI) is one of the most common complications of symptomatic MM, affecting 20–30% of patients at the time of diagnosis [107] and around 10% of them require haemodialysis, with a negative impact on prognosis [108]. Most trials performed in MM excluded patients with RI and though the use of novel anti myeloma agents have resulted in a substantial increase in the survival of patients with MM with RI, RI remains one of the most challenging situations in clinical practice. [109; 110]. Besides, the management of MM patients presenting with high-risk cytogenetic negatively affect both PFS and OS both in patients with NDMM and RRMM. Recent treatment strategies combing PI with lenalidomide/pomalidomide and double autologous stem cell transplant have shown promise for HR cytogenetic diseases. Careful analysis of cytogenetic subgroups in trials comparing different treatments remains an important goal. Cross-trial comparisons may provide insight into the effect of new drugs in patients with cytogenetic abnormalities. However, to achieve this, consensus on definitions of analytical techniques, proportion of abnormal cells, and treatment regimens is needed.

Regarding reviewer 2, comment 6: The definition of early relapse should be noted in the text. Because patients with 3 prior lines of treatment are included in this group and Table 5 shows clinical trials in patients with ≧3 prior lines of treatment. Table 3 should be revised and no citation of Table 5 in the text.

The definition of early relapse was added to text (Page 6, Paragraph 3)., table 3 was revised and table 5 cited.  (Page 9, Paragraph 2).

Regarding reviewer 3, comments: Some centers, however, will stratify relapsed patients based on their previous response to lenalidomide into lenalidomide refractory and non-refractory but will also split patients based on their previous response to Velcade into Velcade resistant and non-resistant.

In this section,  the authors should allude to the different agents used to overcome lenalidomide and Velcade resistance.

In our approach to RRMM treatment, we do not refer to patients refractory to bortezomib because they are a smaller group due to the fact that most regimens that include bortezomib have a limited duration in time, being more relevant to focus on patients refractory to IMIDs however we added a clearer explanation of  the strategy to address RRMM according to the prior treatment. (Page 6, Paragraph 2).