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Triplet vs. Quadruplet Myeloma Induction

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Triplet vs. quadruplet myeloma induction? In general, more chemotherapy regimens make induction more effective and more toxic at the same time.

Let me back-up. Imagine this scenario.

You have been diagnosed with an incurable blood cancer called multiple myeloma (MM). Your oncologist explains to you that a quadruplet regimen demonstrates improved PFS, ORR and MRD when compared to the current FDA approved standard-of-care triplet regimen. In other words, adding 0ne more chemotherapy regimen of Daratumumab/darzelex, makes the induction more effective.

Unfortunately, your oncologist cannot tell you that triplet vs. quadruplet myeloma induction differs in terms of OS or overall survival. Yes, on average, you will respond better to a quadruplet therapy but you won’t live any longer.

So what is the NDMM patient to do? What is your goal? Length of life or quality of life?

The decision of how many chemotherapy regimens or how much toxicity you endure should be up to the newly diagnosed myeloma patient, not the FDA or your oncologist. You.

Needless to say, your oncologist should carefully explain the pros and cons, the risks and rewards, of triplet vs. quadruplet induction therapies to you.

Which adverse events are more serious in a quadruplet vs. triplet induction therapy for myeloma?

Generally, adding a fourth drug to the regimen can increase both the efficacy and the toxicity of the treatment. Here’s a comparison of the adverse events typically observed:

Quadruplet Induction Therapy

1. Hematologic Toxicities:

  • Neutropenia: Lower levels of neutrophils, increasing infection risk.
  • Thrombocytopenia: Lower platelet counts, leading to increased bleeding risk.
  • Anemia: Reduced red blood cells, causing fatigue and weakness.

2. Non-Hematologic Toxicities:

  • Gastrointestinal Issues: Nausea, vomiting, diarrhea, and constipation.
  • Peripheral Neuropathy: Tingling, pain, or numbness in the hands and feet.
  • Fatigue: Generalized tiredness and lack of energy.
  • Infections: Increased susceptibility due to immunosuppression.
  • Cardiac Events: Potential for heart-related issues, depending on the drugs used.
  • Renal Toxicity: Impact on kidney function.

Triplet Induction Therapy

1. Hematologic Toxicities:

  • Neutropenia: Typically less severe compared to quadruplet therapy.
  • Thrombocytopenia: Less frequent and severe.
  • Anemia: Present but usually less pronounced.

2. Non-Hematologic Toxicities:

  • Gastrointestinal Issues: Similar to quadruplet but generally less intense.
  • Peripheral Neuropathy: Can occur, but the incidence may be lower.
  • Fatigue: Present but often less severe.
  • Infections: Risk is lower compared to quadruplet therapy.
  • Cardiac Events: Less common, but still a concern depending on the specific drugs.
  • Renal Toxicity: Generally less severe.

Specific Drugs and Their Adverse Events

Quadruplet Therapy:

  • Daratumumab (Monoclonal Antibody): Infusion reactions, respiratory infections.
  • Bortezomib (Proteasome Inhibitor): Peripheral neuropathy, gastrointestinal issues.
  • Lenalidomide (Immunomodulatory Drug): Hematologic toxicities, secondary malignancies.
  • Dexamethasone (Corticosteroid): Hyperglycemia, mood changes, gastrointestinal issues.

Triplet Therapy:

  • Bortezomib, Lenalidomide, and Dexamethasone: Similar adverse events as in quadruplet but generally less severe due to the absence of a fourth drug.


Quadruplet therapy tends to have a higher incidence of severe adverse events due to the increased drug burden. Hematologic toxicities like neutropenia, thrombocytopenia, and anemia are more pronounced. Non-hematologic toxicities, including gastrointestinal issues, peripheral neuropathy, and fatigue, are also more common and severe. However, quadruplet therapy may offer increased efficacy in terms of response rates and progression-free survival, making the risk-benefit ratio a crucial consideration.

Triplet therapy, while potentially less effective, generally results in fewer and less severe adverse events, making it a more tolerable option for some patients.

Ultimately, the choice between quadruplet and triplet therapy should be individualized based on the patient’s overall health, disease characteristics, and treatment goals, with close monitoring for adverse events to manage them effectively.

When I was diagnosed with MM at 35 years of age, my priority was length of life. I wanted to beat my MM to a pulp. After living with short, long-term and late stage side effects from my aggressive MM therapies since 1999, I now feel differently. I reached end-stage MM in the fall of 1997. An alternative therapy put me in complete remission by April of 1999. Go figure…

Don’t misunderstand me. Taking an aggressive approach to one’s MM is a perfectly valid approach. I just think that oncology needs to do a better job at explaining the pros and cons to NDMM patients.

Most importantly, many studies cite non-conventional MM therapies as reducing the risk of adverse events. If you would like to learn more about non-conventional therapies shown to reduce the toxicity of chemotherapy email me at David.PeopleBeatingCancer@gmail.com

Hang in there,

David Emerson

  • MM Survivor
  • MM Cancer Coach
  • Director PeopleBeatingCancer

Quadruplet therapy for transplant-eligible newly diagnosed multiple myeloma (TENDMM): A systematic review and meta-analysis.

Background: Immunomodulatory drugs, proteasome inhibitors plus dexamethasone are the standard triplet induction regimen for TENDMM. We analyzed the efficacy of adding either anti-CD38 monoclonal antibodies (mAbs) or anti-SLAMF7 antibody to the triplet therapy.

Methods: Ovid MEDLINE, EMBASE and published abstracts were systematically searched from each database’s inception through 01-31-2024 to identify II/III trials assessing quadruplet therapy versus triplet therapy in TENDMM patients. Hazard ratios (HR) for progression-free survival (PFS) and overall survival (OS), odds ratios (OR) for overall response rates (ORR), measurable residual disease (MRD) negativity rate (with sensitivity of 10 5) and grade 3 or higher treatment-related adverse events (G≥3 TRAE) were summarized using random effects meta-analysis via inverse variance approach. Additional subgroup analyses based on the cytogenetic risk were performed. P-value of interaction (Pint ) < 0.1 was pre-specified as statistically significant for the difference between the two groups.

Results: 3806 studies were screened and seven trials were included with a total of 3546 patients. Four trials (2303 patients) assessed the addition of anti-CD-38 mAbs and three (1243 patients) assessed anti-SLAMF7 mAb, elotuzumab to the triplet regimen.

Quadruplet therapy significantly improved PFS as compared to triplet (HR: 0.63; 95% CI: 0.43-0.92), and the PFS benefit was also observed in standard risk group (HR 0.5; 95% CI 0.2-0.9); however, results were insignificant for high-risk group (HR 0.8; 95% CI 0.62-1.93).

No significant OS benefit was observed (HR: 0.79; 95% CI 0.49–1.26); however, data for three trials (CASSIOPEIA, DSMM XVII, PERSEUS) is immature, with longer-term follow-up ongoing.

Quadruplet therapy showed significant results for:

  • very good partial response or better (OR: 1.7; 95% CI 1.2-2.36),
  • stringent complete response (OR: 1.74; 95% CI 1.27-2.07) and
  • complete response or better (OR: 1.91; 95% CI 1.19-3.06).
  • MRD rate shows benefit with quadruplet therapy (OR: 2.59; 95% CI 2.22-3.01).

Improved MRD rate was also observed for high-risk (OR 2.13; 95% CI 1.4-3.2) and standard-risk group (OR 2.58; 95% CI 1.68-3.94). Secondary analysis for efficacy of anti-CD38 mAbs showed benefit for PFS (HR: 0.44; 95% CI: 0.35-0.56), ORR (OR: 1.77;95% CI: 1.02-3.06), and MRD (OR: 2.98; 95% CI 1.8-4.8). G ≥3 TRAE did not significantly differ between the groups (OR: 1.05; 95% CI 0.97-1.12). However, quadruplet therapy showed significant risk of infection (OR: 1.2; 95% 1.05-1.35) and thrombocytopenia (OR: 1.41; 95% CI 1.24-1.59).

Conclusions: Quadruplet therapy improved PFS, ORR, and MRD rates compared to triplet regimen and has demonstrated promising benefits to be considered the new standard of care for TENDMM patients.

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