What are the second primary malignancies associated with multiple myeloma?

Second Primary Malignancies Associated with Multiple Myeloma

Multiple myeloma patients have an increased risk of developing second primary malignancies, particularly hematologic malignancies and solid tumors, with higher incidence observed in patients receiving lenalidomide maintenance therapy after autologous stem cell transplantation.

Types of Second Primary Malignancies

Hematologic Malignancies

• Acute myeloid leukemia and myelodysplastic syndromes are the most common hematologic second primary malignancies
• Incidence rate of approximately 5.3% at 5 years 1
• Higher risk associated with:
  • Alkylating agents, especially melphalan 2
  • Autologous stem cell transplantation 3
  • Lenalidomide maintenance therapy 1

Solid Tumors

• Incidence rate of approximately 5.8% at 5 years 1
• Various types including:
  • Skin cancers (both melanoma and non-melanoma)
  • Gastrointestinal cancers
  • Lung cancers
  • Other solid organ malignancies

Risk Factors for Second Primary Malignancies

Treatment-Related Risk Factors

1. Lenalidomide maintenance therapy

   • Multiple studies show increased risk, especially when used post-transplant 1
   • In the meta-analysis of lenalidomide maintenance trials, rates of second primary hematologic and solid tumor malignancies were 5.3% and 5.8%, respectively 1

2. Melphalan exposure

   • Significantly increases risk of hematologic malignancies 1, 2
   • Risk is higher when combined with lenalidomide 1

3. Autologous stem cell transplantation

   • Associated with modest increase in second malignancy risk 3
   • High-dose cyclophosphamide used for stem cell mobilization is an independent risk factor 4

4. Thalidomide exposure

   • Shows a trend toward increased risk (odds ratio 3.5) 3
   • Suggests a possible class effect of immunomodulatory drugs

Patient-Related Risk Factors

1. Age

   • Older age (≥55 years) is associated with higher risk (relative risk 2.3) 3
   • Patients >65 years at diagnosis have increased risk 4

2. Race

   • Non-Hispanic white patients have higher risk (relative risk 2.4) 3

3. Disease characteristics

   • IgG myeloma subtype shows increased cumulative incidence of second malignancies 5
   • Indolent myeloma with longer disease latency may allow time for second malignancies to develop 5

Incidence and Timing

• Overall cumulative incidence of second primary malignancies:

  • 7.4% at 5 years and 15.9% at 10 years (including non-melanoma skin cancers) 3
  • 5.3% at 5 years and 11.2% at 10 years (excluding non-melanoma skin cancers) 3
  • Prevalence of 10% at 25 years of follow-up 5

• Timing patterns:

  • Can occur prior to, synchronously with, or subsequent to multiple myeloma diagnosis
  • In one large registry analysis, 63% were prior or synchronous malignancies and 37% were subsequent malignancies 5

Clinical Implications

Risk-Benefit Assessment

• Despite increased risk of second malignancies, the survival benefit of receiving lenalidomide outweighs the increased risk in both transplant-eligible and transplant-ineligible patients 4
• As noted by NCCN guidelines, "The benefits of improved PFS with lenalidomide maintenance must be weighed against the increased rate of severe neutropenia, risk of second cancers, and other toxicities" 1

Monitoring Recommendations

• NCCN guidelines emphasize that "the benefits and risks of maintenance therapy with lenalidomide, including the risk of secondary cancers, should be discussed with patients" 1
• Regular cancer screening according to age-appropriate guidelines is essential for early detection
• Heightened surveillance may be warranted, particularly for hematologic malignancies

Preventive Strategies

• Consider treatment regimens without melphalan when possible, as absence of melphalan is associated with lower incidence of second malignancies 1
• Bortezomib-based regimens may be protective, as they have been associated with decreased risk of second malignancies in some studies 5
• Limit exposure to myelotoxic agents, particularly alkylating agents, when feasible 1

Evolving Understanding

As survival in multiple myeloma continues to improve, second primary malignancies are becoming increasingly important considerations in long-term management. The risk appears to be multifactorial, involving treatment exposure, patient characteristics, and possibly underlying genetic susceptibility. Ongoing research is needed to better define individualized risk profiles and optimal surveillance strategies.